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Butterflies in the gut: the interplay between intestinal microbiota and stress

Abstract

Psychological stress is a global issue that affects at least one-third of the population worldwide and increases the risk of numerous psychiatric disorders. Accumulating evidence suggests that the gut and its inhabiting microbes may regulate stress and stress-associated behavioral abnormalities. Hence, the objective of this review is to explore the causal relationships between the gut microbiota, stress, and behavior. Dysbiosis of the microbiome after stress exposure indicated microbial adaption to stressors. Strikingly, the hyperactivated stress signaling found in microbiota-deficient rodents can be normalized by microbiota-based treatments, suggesting that gut microbiota can actively modify the stress response. Microbiota can regulate stress response via intestinal glucocorticoids or autonomic nervous system. Several studies suggest that gut bacteria are involved in the direct modulation of steroid synthesis and metabolism. This review provides recent discoveries on the pathways by which gut microbes affect stress signaling and brain circuits and ultimately impact the host’s complex behavior.

Introduction

The etymology for the phrase to have “butterflies in the stomach” first appeared in the book “The House of Prayer” written by Florence Converse in 1908. This phrase has been widely used as an idiom for over a hundred years, and it describes an unsettling feeling when one is facing a stressful or thrilling event. It is particularly fascinating that people describe this feeling as something that originates in the gut, and not elsewhere. Scientists have been chasing these “butterflies” and their origins for over two decades now, and they realized that this idiom may be associated with a feeling and sensation that is influenced by the commensal microbes in the gastrointestinal (GI) tract. Scientists have made amazing discoveries about understanding the importance of commensal gut microbes in host physiology and pathophysiology.

The flopping butterfly is not only a metaphor for the fluttery feeling in our body, but it is also a term that describes the initial action in a series of chain reactions for a colossal event. Commensal microbes in the gut exert various effects on host behavior through the “gut-brain axis.” The “gut-brain axis” is the distal connection between the GI system and the central nervous system [1]; it is composed of complex signal transduction pathways across the two body systems [2]. Gut bacteria and their metabolites exert their “butterfly effect,” which propagates signals to the brain, ultimately altering the host’s behavior. The hypothalamic–pituitary–adrenal (HPA) axis, the canonical pathway for stress regulation, is one of the most promising routes that connects the commensal gut microbes, GI tract, brain, and behavior to each other [2]; this also reflects the fluttery feeling in the gut. Moreover, stress signaling can be transmitted to the brain via the vagus nerve and afferent/efferent neuron connections.

Stressed, nervous, tense, worried, and anxious are commonly felt in the presence of threats. Recent findings suggest that the stress response and gut microbes reciprocally influence numerous behavioral outcomes in the host. To understand the role of commensal gut microbes in stress regulation and response, the use of gnotobiotic animals, 16S rRNA sequencing, metagenomic sequencing, fecal microbiota transplantation, antibiotic treatment, and probiotics are employed to unravel intertwined host-microbe interactions [2]. This review focuses on rodents as a model organism to explore the causal relationships between the gut microbiota, stress, and behavior. Some clinical observations have also been incorporated to support this review.

Brain response to stress exposure

Stress sensing, integration, and coping are vital functions of the brain when confronted with an aversive stimulus [3, 4]. Stress-related information is integrated into the sensory cortex, which then sends signals to the limbic system, hypothalamus, and brainstem to activate the HPA axis and sympathetic and parasympathetic nerves [3, 5]. The sympathetic and parasympathetic nerves propagate the stress response to evoke rapid adaption in various systems in the body [3]. The brain regions that detect stress signals from the external environment overlap with the brain regions that participate in emotion, which coherently orchestrates the stress responses in animals [3, 6].

Among the brain regions that are involved in regulating the stress response, the paraventricular nucleus of the hypothalamus (PVN) plays a central role in integrating signals from the environmental stimuli and further triggering downstream neural transmission [3, 7]. The PVN receives neural innervation from the limbic system and brainstem to mediate the HPA axis and integrate the response after exposure to stress [3, 7]. Various types of neurons are located in the PVN. Primarily, the corticotrophin-releasing hormone (CRH) neurons in the PVN and other associated brain regions respond to different forms of stress [8, 9]. In Fig. 1, we summarize the findings about the interplay of CRH neurons in the PVN and cells at the bed nucleus of the stria terminalis (BNST) and amygdala in response to stress. These brain regions are crucial for determining the levels of circulating corticosterone and animal behavioral outputs.

Fig. 1
figure 1

The orchestra of the paraventricular nucleus of the hypothalamus (PVN) with other brain regions in response to the stress exposure. CRH: corticotropin-releasing hormone; BNST: the bed nucleus of the stria terminalis; AMG: amygdala; CeA: central nucleus of the amygdala; BLA: basolateral amygdala; MeA: medial amygdala; BS: brainstem; LC: locus coeruleus; NTS: nucleus tractus solitarius; VLM: ventrolateral medulla

As a central hub for the stress response, PVN CRH neurons can be triggered by stressful stimuli and subsequently, evoke several intrinsic behavioral responses [10,11,12]. This section focuses on the cause-and-effect relationships between the PVN CRH neurons and stress coping behaviors. Daviu et al. showed that an increase in CRH neuron activity in the PVN can be detected during a looming-shadow task, a method that mimics predator threat from the sky, where the majority of mice displayed escape behavior with little freezing response to a looming shadow. Silencing the PVN CRH neurons decreased the escape behavior but increased the freezing response. Moreover, PVN CRH neurons anticipate an imminent threat and encode stress controllability [11]. Similarly, another study showed that CRH neurons in the PVN responded to aversive stimuli, such as forced swimming, tail restraint, overhead objects, looming, and even intraperitoneal injection [13]. In one study done by Huang et al., mice susceptible to visceral pain after maternal separation exhibited an increased number of c-Fos-positive CRH neurons in PVN compared to resilient mice [14]. Electrophysiological recordings also revealed higher spontaneous firing frequency of CRH neurons in the PVN and increased evoked firing rates in response to step current injections in mice susceptible to visceral pain after maternal separation [14]. Moreover, susceptible mice displayed elevated gene expression and protein levels of CRH in the PVN, along with higher concentrations of CRH, ACTH, and corticosterone in the serum [14]. Additionally, exposure to water avoidance stress (WAS), an acute stress paradigm, induced an increase in c-Fos-positive cells in the PVN [15, 16]. The stress response to WAS was ameliorated by intracisternal injection of a CRH receptor antagonist [15, 16].

Mice displayed altered home-cage behavior, including self-grooming, rearing, walking, digging, and chewing, immediately after the footshock. Fuzesi et al. demonstrated that optogenetically activating the CRH neurons in the PVN increased self-grooming, shifting other home-cage behaviors similar to mice experiencing foot shock. The increased self-grooming behavior by the optogenetic stimulation of PVN CRH neurons can be attenuated by increasing the presumptive threat level of the context (testing environment) [12]. Furthermore, Sterley et al. found that the transmission of stress signaling from a stressed subject to a naive partner required the activation of PVN CRH neurons in both subjects and partners to drive stress signal transmission [17]. Similarly, Wu et al. showed that the chemogenetic activation of CRH neurons in the PVN during a social interaction test abolished social behavior and increased digging behavior in mice. Moreover, corticosterone levels increased after social interaction when PVN CRH neurons were activated [18]. In contrast, not all stress responses are associated with the PVN CRH neurons. Zhao et al. found that optogenetic activation of excitatory projections from the PVN to the ventrolateral medulla (VLM), but not CRH neurons in the PVN, could recapitulate stress-induced hyperglycemia in mice without stress exposure [19]. Nonetheless, these studies demonstrate that PVN CRH neurons are essential for controlling stress responses and behaviors when exposed to imminent threats (Fig. 1).

The BNST serves as a relay station that connects the various brain regions involved in emotion [20]. Amygdala-BNST and BNST-PVN circuits participate in stress response regulation [21, 22]. Previous studies have shown that the BNST is composed of several subregions and sends various projections to the PVN [20,21,22,23]. Duan et al. demonstrated that optogenetic activation of the basolateral amygdala (BLA) in the BNST circuit prevented anxiety-like behaviors in mice that received social defeat stress [24]. The anterior part of the BNST lesions inhibits the activation of the PVN and HPA axis after stressor exposure [25, 26]. Conversely, Choi et al. showed that lesions in the posterior part of the BNST increased corticosterone levels and the number of c-Fos-positive cells in the PVN after acute restraint stress [27]. Stress exposure also affects neural activity in the BNST. Predator stress, elevated plus maze, and restraint stress enhance the neural activity of CRH neurons in the BNST [28, 29]. However, Wu et al. showed that the inhibition of CRH neurons in the BNST could not rescue stress-induced social deficits [18], which suggests that the BNST might be affected by stress exposure but does not directly regulate the stress response.

The amygdala is a critical structure that is associated with emotional processing and physiological responses to stress [30, 31]. Various subregions of the amygdala participate in distinct mechanisms to modulate different types of stressor exposure [30]. Acute psychological stress increases the number of c-Fos-positive cells in the medial amygdala (MeA) [32] and enhances inhibitory neuron activity in the central nucleus of the amygdala (CeA) [33]. However, limited direct connections between the amygdala and PVN can mediate the stress response [3, 30]. The stress-induced immune dysregulation is associated with distinct neuronal populations in the CeA. Zhang et al. identified a circuit between the CeA/PVN and splenic nerve in the regulation of stress-associated immunity [34]. Artificial activation of CRH neurons in the CeA and PVN increases splenic plasma cell formation. Placing the mouse on the elevated platform not only increased the CRH neuronal activity, but also promoted splenic plasma cell formation, suggesting that the CeA and PVN participated in stress-induced immune response [34]. Furthermore, Xu et al. showed that CeA lesions prevented the release of CRH and adrenocorticotropic hormone (ACTH) after systemic interleukin (IL)-1 injection [35]. Other studies have also shown that peripheral injection of lipopolysaccharide (LPS) increased neural activity in the CeA to decrease food intake [36] and in the BLA to increase anxiety- and depressive-like behavior [37]. CRH neurons in other brain regions have been shown to play a role in stress response. Predator stimuli promote rapid arousal from rapid eye movement sleep in mice. A recent study by Tseng et al. showed that CRH neurons in the medial subthalamic nucleus (mSTN) were activated during rapid eye movement sleep by predator odor exposure in response to external stimuli [38]. The inhibition of CRH neurons in the mSTN increased the latency of freezing and looming behavior when the mice were exposed to predator odor and decreased the duration of the rapid eye movement-sleep response to adapt to the predator threats [38].

Overall, stress exposure triggered the orchestra of PVN CRH neurons with other brain regions in response to various stimuli (Fig. 1). PVN CRH neurons appear to be central hubs that connect other brain areas to initiate stress responses and coping mechanisms. Understanding the central pathway of the stress response is important in discovering the signaling pathway that is modulated by gut microbes.

Stress exposure alters gut microbiome

Stress-coping mechanisms and adaptation are critical for survival. Animals cope with stress in many ways, including changes in their physiology and behavior. Interestingly, scientists have found that stress exposure affects the gut microbiome using rodent models (Table 1).

Table 1 Adaptation of commensal microbiome and behavior under acute and chronic stress conditions

Unpredictable chronic mild stress (UCMS) is an experimental condition that induces physiological and neurological changes that are similar to chronic and unresolved stress exposure. Mice generally display depressive-like behavior, similar to people with depression, with no apparent change in anxiety-like behavior [39,40,41]. Interestingly, the altered Firmicutes [39,40,41] and Tenericutes [40, 41] phyla are consistently observed in the UCMS animals. Of note, Lactobacillaceae seemed to be the main bacteria in Firmicutes that were decreased by UCMS [39, 41]. Coprococcus is a bacterial genus that was found to be reduced in UCMS mice [41] and the human depression cohort [42] (Table 1).

Chronic social defeat stress (CSDS) is a psychosocial stress with exceptional face, construct, and predictive validity. Behavioral outcomes after CSDS are complex, including an increase in depressive-like behavior, anxiety-like behavior, and a decrease in social behavior [43,44,45,46]. Likewise, the microbiome profiling shifted by CSDS was more complex than that shifted by UCMS. Bacteroidetes [44, 46] and Helicobacteracea [43,44,45] were increased after CSDS. In contrast, several bacteria in Firmicutes, such as Ruminococcaceae [44, 45], were altered after CSDS, except for Lactobacillus [43,44,45,46]. Social overcrossing (SOC) is a method that mimics increased housing density. The effect of SOC on behavior was minimal. Mice only showed increased speed in the elevated plus maze and entries to the dark chamber in the light/dark box [47]. However, the change in the microbiome after SOC was more dramatic. SOC increased the relative abundance of Akkermansia muciniphila and Anaerostipes genera and reduced the relative abundance of Erysipelotrichaceae family, Lactobacillus, and Bacteroides acidifaciens species [47]. The complex outcomes produced by social-related stressors could be due to the varied source of the intruders and the subtle difference in the experimental timelines (Table 1).

Restraint stress is a classical method of restricting rodent movement. Rodents develop anxiety- and depression-like behaviors after restraint stress [48,49,50,51,52]. While numerous bacterial taxa in the gut are altered, Firmicutes appears to be the most vulnerable bacteria that can be altered by chronic restraint stress, especially Lactobacillaceae and Lachnospiraceae family [48,49,50,51, 53, 54]. In addition, the Proteobacteria phylum was increased after chronic restraint stress [49, 53, 54]. Interestingly, restraint stress affected the microbiome differently, depending on the intestinal segment [54] (Table 1). WAS was a potent psychological stressor that disrupts gut epithelial tight junction integrity [55, 56]. The sole WAS did not produce much effect on the behavior compared to other stress models [56, 57]. However, the fecal microbiome was affected by WAS, with decreased Bacteroidetes, increased Firmicutes, and increased Proteobacteria. When analyzing the contents of the small intestine and colon, Lactobacillaceae and unclassified Bacteroidetes were lower in WAS mice [58].

Based on the studies we surveyed, the adaptation of the microbiome to stress could be influenced by different types of stress, duration of stress exposure, source of animals, diet, etc. (Table 1). Several bacterial taxa have been reported to have differences across studies after exposure to various types of stress. Stress exposure downregulates the relative abundance of Porphyromonadaceae [58, 59], Lactobacillaceae [39, 47, 49, 54, 58], Ruminococcaceae [44, 53, 58], and Coriobacteriaceae [43, 53] at the family level and Parabacteroides [51, 59] and Lactobacillus [40, 47, 48, 54] at the genus level. In contrast, stress exposure upregulated the relative abundance of Streptococcaceae [54, 58] and Enterobacteriaceae [49, 54] at the family level and Anaerofustis [40, 51] and Helicobacter [43, 49, 59] at the genus level. Among these studies, the Lactobacillus species was the most consistent bacterial taxa that was reduced in rodents following stress exposure.

Levels of stress hormone in microbiome-depleted mice

Studies in mice have suggested that stress exposure alters the composition of the gut microbiome and shifts the bacterial taxa, which leads to another question: Do gut bacteria actively play a role in stress response regulation? To address this question, gnotobiotic and antibiotic-treated rodents are great models for “knocking out” the commensal microbiota constitutively or conditionally. Strikingly, most studies have suggested that the depletion of the microbiota in rodents enhances the stress response and increases the stress hormone corticosterone (Tables 2 and 3). Corticosterone is a glucocorticoid in rodents (cortisol in humans) that serves as a crucial steroid hormone secreted in response to stress [60].

Table 2 Corticosterone levels in germ-free (GF) rodents
Table 3 The effect of antibiotics on corticosterone in rodents

Germ-free (GF) mice, a model organism that was never exposed to bacteria in their lifetime, displayed elevated corticosterone levels after prolonged restraint stress exposure [61,62,63]. In addition, GF rodents exhibit elevated corticosterone levels under various stressful conditions, including maternal separation [64], environmental transition [65, 66], open-field test [67], social interaction [18], bacteria endotoxin LPS injection [68], and inducible-adjuvant arthritis [69].

However, not all studies have shown that GF rodents display excessive stress responses and higher corticosterone levels after exposure to stressful conditions [63, 70]. Consistent findings have not yet been obtained when it comes to measuring baseline corticosterone levels in GF rodents [63,64,65, 67, 70,71,72,73,74]. These studies discovered that the HPA axis is an influential mediator for gut microbes to alter host physiology; this raised the possibility of microorganisms in the gut playing a critical role in stress suppression (Table 2).

GF rodents clearly indicate that the depletion of gut microbiota leads to aberrant stress responses, including increased corticosterone, altered gene expression involved in stress signaling, and abnormal behavioral consequences. While GF models are valuable tools for studying microbial influences on stress-coping mechanisms, it is important to highlight the limitations of the GF model. GF animals, which lack exposure to microbes from birth, can exhibit several developmental differences compared to conventionally raised animals [75]. These distinctions include altered gut morphologies, an immature mucosal immune system, delayed oral tolerance development, deceleration of epithelial turnover, and neuroendocrine function alterations, especially during early life [75, 76]. The caveat regarding these differences recognizes the artificial nature of the GF model in the context of human physiology.

In parallel with GF mice, antibiotic administration was extensively adopted to clarify the role of gut microbiota in stress. Antibiotic administration is a powerful tool for controlling the timing of the elimination of commensal microbes [18, 20, 77, 78]. However, age, treatment time window, type, and dosage for antibiotic administration are critical factors for yielding consistent findings with GF rodents [76]. Furthermore, it is challenging to deplete gut microbes entirely because of the geographical preference of the GI tract for various species of gut bacteria [79]. Only a few studies were able to reproduce an enhanced stress response in GF mice using antibiotics (Table 3). Two studies adopted a similar antibiotic recipe with a broad-spectrum antibiotic cocktail (ABX), showing that chronic treatment of ABX in mice resulted in an increase in baseline corticosterone levels [80] and after social exposure [18]. Two other studies showed that an acute [81] or chronic [59] gavage dosing of a single antibiotic in mice increased corticosterone levels upon acute stress exposure. Intriguingly, developmental treatment of mice with antibiotics reduced corticosterone levels under various conditions [47, 82, 83]. The treatment of rats with antibiotics yielded a reduction in corticosterone, indicating a model-dependent effect [84, 85]. Other studies have shown that antibiotics do not affect corticosterone levels [86,87,88,89,90] (Table 3). While antibiotic administration is a potent approach for investigating the microbiome’s impact on brain and behavior, it demands careful consideration in experimental design.

Dysregulation of stress response in the brain of microbiome-depleted mice

Dysregulation of the stress response in the brain has been widely observed in mice without commensal microbes. Several studies have investigated the gene expression levels of the glucocorticoid receptor (GR), CRH, and downstream signaling pathways in mice with gut microbial depletion. Crumeyrolle-Aria et al. showed that increased corticosterone levels and decreased GR mRNA levels in the CA1 hippocampus and dentate gyrus (DG) were observed in GF rats after exposure to stress [67]. Sudo et al. observed higher CRF expression in the hypothalamus of GF mice. GR gene expression was lower in the cortex, but not in the hypothalamus and hippocampus [62]. Luo et al. showed that hippocampal GR downstream signaling pathways, including Slc22a5, Aqp1, Stat5a, Ampd3, Plekhf1, and Cyb561, were upregulated in GF mice under baseline condition [91]. Gareau et al. showed that a reduction in neural activity in the hippocampal CA1 region was observed in GF mice when compared to SPF mice after WAS [57].

A recent finding illustrates that gut commensal microbes are required to restrain the host stress response and increase social behavior. The stress hormone corticosterone levels were elevated in GF mice after a short social interaction with a stranger mouse. Concurrently, the neural activity in several brain regions that are responsible for coping with stress was upregulated, including the PVN, hippocampal DG, and adrenodorsal BNST (adBNST) [18]. The upregulated stress hormones and neural activity were recapitulated in mice treated with ABX at the adult stage. Furthermore, this study showed that the immediate early genes were upregulated in the hippocampus (ArcFoscJunJunBEgr1, Egr2Gadd45bGadd45gBdnf) and hypothalamus (ArcFosEgr1), but were downregulated in the brainstem (cJunJunBEgr1Gadd45bGadd45gBdnf) of GF mice [18]. However, stress-related gene expression did not change in mice treated with antibiotics under baseline and stressful conditions [18]. Only Crh gene expression was upregulated in ABX mice after social encounters, whereas Ucn gene expression was upregulated in ABX mice after novel cage exposure [18].

To further investigate whether the interference of neurons in brain circuits can alter mouse stress hormones and social behavior, Wu et al. adopted a genetic ablation strategy and chemogenetic approach to disrupt the stress response neurons in ABX-treated mice. Genetic ablation of GR in the DG and adBNST restored social deficits and suppressed corticosterone levels in ABX mice (Fig. 2). In contrast, genetic ablation of GR in the hypothalamus decreases social behavior and increases corticosterone levels after social interaction [18]. Silencing the PVN CRH neurons in ABX mice suppressed the increase in corticosterone levels and prevented the development of social deficits (Fig. 2). These effects were not observed in adBNST CRH neurons from ABX mice [18]. Furthermore, adrenalectomy and pharmacological blockade of the GR and synthesis of corticosterone in microbial-depleted mice sufficiently restored their social interaction behavior [18]. Therefore, Wu et al. suggested that the dysregulation of social behavior and stress response in mice without a microbiome is more likely due to the altered neural activity in PVN CRH neurons, instead of alterations in stress-related gene expression or structural changes in PVN-associated neural circuits [18]. This study provides a defined pathway for stress coping by commensal microbes to drive host behavior (Fig. 2). Advances in neuroscience technologies have allowed scientists to precisely investigate the neural circuits regulated by microbiota and further discover the mechanisms involved in microbiome-mediated stress-associated neural circuits.

Fig. 2
figure 2

Gut commensal microbes are required to restrain the host stress response neurons increasing social behavior. Colonization of Enterococcus faecalis alleviated the social interaction-induced stress response and promoted the social behaviors toward the novel mouse. PVN: the paraventricular nucleus of the hypothalamus; BNST: the bed nucleus of the stria terminalis; DG: dentate gyrus; CRH: corticotropin-releasing hormone; GR: glucocorticoid receptor

Extra-adrenal steroidogenesis in the gut

While neurons in the brain in response to stressful conditions have been extensively explored, gut-derived stress signaling has not yet been fully elucidated. Glucocorticoids, a class of corticosteroids, are secreted mainly by the adrenal gland and partially by the extra-adrenal system [92, 93]. The amount of glucocorticoids released by the adrenal gland is far beyond the amount released by the extra-adrenal system. Although adrenal glucocorticoids play a role in the response to stress, the physiological role of extra-adrenal glucocorticoids in the intestine is still not understood.

The canonical steroidogenesis pathway for corticosterone in the adrenal gland involves a series of steps in the mitochondria. Cholesterol is converted to pregnenolone by two rate-limiting enzymes, steroidogenic acute regulatory protein (StAR) and cytochrome P450 family 11 subfamily A member 1 (CYP11A1). Pregnenolone is then catalyzed to progesterone and 11-deoxycorticosterone by 3β-Hydroxysteroid dehydrogenase (3β-HSD) and CYP21A2, respectively. Then, 11-deoxycorticosterone is catalyzed to corticosterone by CYP11B1 [94]. Corticosterone can also be produced by 11-dehydrocorticosterone with the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and vice versa by 11β-HSD2 [95]. Brunner group demonstrated that the synthesis of extra-adrenal glucocorticoids is independent of the canonical adrenal glucocorticoid synthesis. First, the critical nuclear receptor and transcription factor steroidogenic factor-1 (SF-1) for adrenal steroidogenesis is absent in the intestine and is functionally replaced by liver receptor homolog-1 (LRH- 1) [96, 97]. Second, ACTH, the primary hormone secreted by the anterior pituitary gland; it stimulates steroidogenesis in the adrenal gland, but is not involved in intestinal glucocorticoid synthesis [98]. Based on the fundamental distinction in the biochemical process of synthesizing corticosterone, the physiological role of extra-adrenal glucocorticoids is considered to be independent of stress coping [92, 93, 99, 100].

Intestinal epithelial cells (IEC) are primary producers of extra-adrenal glucocorticoid synthesis [92, 93]. Strikingly, the small and large intestines and appendix express critical enzymes involved in steroidogenesis, including Cyp11a1 and Cyp11b1 [99]. Intestinal glucocorticoids are hypothesized to contribute to the intestinal microenvironment [93]. Brunner group showed that systemic immune challenges upregulate glucocorticoid synthesis and interact with the immune cells in the gut [99]. Anti-CD3 injection or viral infection upregulated steroidogenic enzymes Cyp11a1Hsd3b1Cyp21, Cyp11b1, and Hsd11b1 and immuno-stimulated corticosterone production in the small intestinal mucosa [99]. Moreover, they found that pro-inflammatory cytokine tumor necrosis factor α (TNFα) and LPS-induced immune system activation promote steroidogenesis in the intestine [101, 102]. In contrast, Raddatz et al. showed that IL-1β was shown to inhibit glucocorticoid signaling in IEC in vitro models [103]. Treatment of IEC with dexamethasone, a GR agonist, increased its transepithelial electrical resistance without affecting the tight junction architecture. Increased barrier function due to glucocorticoid agonism could be compromised by co-treatment with cytokines [104]. However, chronic treatment with dexamethasone may interact with the culture time of IEC cell lines since it affects epithelial permeability and ultimately, alters the gene expression for the actomyosin cytoskeleton, tight junction, integrin, and cell cycle pathway [105]. Upon bacterial endotoxin LPS injection in mice prior to ex vivo culture, corticosterone levels produced by extra-adrenal tissues dramatically increased [100]. Therefore, the extra-adrenal glucocorticoids primarily have immunoregulatory functions as suggested by LPS injection studies, distinct from the participation in the canonical stress signaling.

Furthermore, in patients with inflammatory bowel disease (IBD), there is a notable reduction in the expression levels of 11β-HSD1 in the colon, suggesting that impaired intestinal glucocorticoid synthesis may contribute to IBD development [106]. Intestinal glucocorticoids also play a pivotal role in inhibiting tumor development and growth during the inflammatory phase. However, during the tumor phase, glucocorticoid synthesis mediated by Cyp11b1 suppresses anti-tumor immune responses, promoting immune evasion. This presents a promising therapeutic target for tumor treatment [107]. These findings highlight the significant role of intestinal glucocorticoid synthesis in modulating gastrointestinal disorders.

Gnotobiotic rodents have provided clues as to how the loss of microbiota alters the stress response in the gut. Stress-associated gene expression in the intestine is altered in GF mice under baseline, immune challenge, and stress exposure conditions [70, 108, 109]. The expression of steroidogenesis genes in the pituitary gland, adrenal gland, and intestine was compared in SPF and GF mice under social defeat and acute restraint stress conditions. Briefly, the gene expression of Crh and Ucn2 in the colon was upregulated in SPF mice, but unchanged in GF mice after social defeat stress, partially due to the baseline increase in GF mice. Interestingly, the downregulation of Hsd11b1 was observed in both SPF and GF mice after social defeat stress, regardless of increased baseline levels in GF mice [108]. Another study investigated the intestinal segment-specificity of steroidogenesis in the intestine of GF mice. Both acute restraint stress and the presence of microbiota alter Nr5a2 (encoding LRH-1) and Hsd3b2 expression in the ileum and colon. However, it appears that the genes for steroidogenesis are more robustly altered in the colon than in the ileum [70].

These studies suggest that intestinal steroidogenesis may be a crucial pathway by which the gut bacteria regulate stress responses. The precise mechanism by which bacteria in the GI tract affect the HPA axis remains unknown. Extra-adrenal steroidogenesis is a promising pathway for investigation.

Circadian regulation of glucocorticoids and microbial impact

Circadian rhythms are intrinsic timekeeping systems governing a myriad of physiological processes, including the diurnal variations in glucocorticoid levels. These rhythms are not only influenced by endogenous factors but can also be significantly modulated by the gut microbiota. The levels of glucocorticoids fluctuate in accordance with the circadian rhythm in both physiological and pathological conditions. This pattern typically involves a peak in the early morning, followed by declining levels throughout the daytime. Several studies have reported on this circadian variation [110,111,112,113,114,115]. Moreover, clinical studies have suggested that patients with arthritis experience a state of hypercorticosterolism, as evidenced by elevated plasma cortisol levels measured in the morning compared to those measured at midnight [112, 115]. This observation appears to be synchronized with the presence of early morning stiffness in individuals with arthritis [112, 115]. Interestingly, Mukherji et al. characterized ileal IEC in corticosterone overproduction in ABX mice, revealing higher corticosterone levels at a time when ACTH was scarcely released [80]. Remarkably, corticosterone levels remained comparable in adrenalectomized ABX mice [18, 80]. This result indicated signal pathways involved in circadian clock regulation were disrupted in the ileal IEC of ABX mice, leading to hypercorticosterolism [80].

Circadian disruption driven by the microbiota has been observed in various disease conditions, including IBD and prediabetic syndromes [80, 116]. Microbiota can mediate the circadian disruption in mammals. Antibiotic treatment can ablate the microbiota, reprogramming the intestinal circadian transcriptome and rhythmic chromatin dynamic [117]. Another study demonstrated that the depletion of microbiota affected the crucial regulator of circadian rhythm, including a decrease of the transcripts of Bmal1 and Cry1, and an increase the transcripts of Per1 and Per2, while the transcript of Clock remained unaffected [80]. The disrupted signal pathways involved in circadian clock regulation resulted the hypercorticosterolism in ileal IEC [80]. This study indicated the deficiency of microbiota caused a prediabetic syndrome which was induced by ileal corticosterone overproduction and circadian disruption [80]. GF mice were observed of the lower level of circadian clock gene, such as Bmal1, Clock, Per1, and Cry1 in the hypothalamus [118]. Exposure to bacterial metabolites may change circadian gene expression both in vitro and in vivo [118]. Lactobacillus reuteri alleviated the liver gene expression of Nr1d1, the core circadian gene encoding REV-ERBα, in the circadian dysrhythmia-induced polycystic ovary syndrome (PCOS) [119].

A constitutively active myosin light chain kinase (MLCK) in intestinal epithelia transgenic mice results in a colitis-prone phenotype, with an increased number of intraepithelial bacteria in the colonocytes of these mice [116]. Pai et al. reported that their microarray analysis revealed disruptions in the circadian rhythm in wildtype mice when they were co-housed with MLCK transgenic mice, in contrast to wildtype mice housed exclusively with other wildtype mice [116]. These disruptions were associated with changes in circadian gene expression in the colonic mucosa, including reduced Nr1d1, Per1, and Per3, in wildtype mice co-housed with MLCK transgenic mice [116]. Additionally, qPCR analysis demonstrated circadian gene expression with elevated Arntl and Nfil3, as well as reduced Nr1d1, in both colonic mucosa and purified colonocytes of wildtype mice co-housed with MLCK transgenic mice, compared to those exclusively housed with only wildtype mice [116]. The glucocorticoid enzyme Cyp11a1 expression was decreased in the epithelial cell at specific time point in MLCK transgenic mice [116]. Furthermore, when invasive bacteria, found in increased numbers within the intraepithelial bacteria of MLCK transgenic mice, were co-cultured with Caco-2 cells, elevated levels of Nr1d1 and Nfil3 were observed [116]. This suggests that exposure to microbiota caused circadian disruption in the bacteria-epithelial co-culture system [116]. Taken together, this evidence suggests that the increased intraepithelial bacteria led to circadian disruption and glucocorticoid downregulation in the gut.

Transmission of stress response from the gut to the brain via autonomic nervous system

In addition to the gut, the autonomic nervous system (ANS) is an essential pathway composed of sympathetic and parasympathetic nerves innervating the gut and brain, rapidly transmitting signals. ANS complements the body to maintain homeostasis and responds to various stimuli. The parasympathetic system is dominant for the "rest or digest" condition. This system is composed of specific cranial nerves, such as the optic nerve (III), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X), and pelvic splanchnic spinal nerve. Among the cranial and spinal nerves, the vagus nerve is the main component, with approximately 75% of the parasympathetic fibers in this system. Approximately 80% of afferent neurons and 20% of efferent neurons [120] in the vagus nerves innervate the GI tract. Moreover, the vagus nerves innervate the esophagus, lower airways, heart, aorta, liver, GI tract via the vagal branches [121]. The vagus nerve is the most rapid route for signal transduction among the pathways in gut-brain communication [122].

Leveraging advanced neurotechnologies, researchers can closely examine the fundamental roles of the ANS in healthy and disease states [122,123,124]. The parasympathetic vagus nerve is considered as the main interoceptive pathway in the GI tract [4]. The afferent vagus nerve ending is connected with the neuropod cells, which are responsible for enteroendocrine secretion and transduced luminal nutrient signaling in a millisecond fashion [122]. Besides nutrient sensing, GI stretch and gut motility are transmitted through vagal afferent neurons [125]. In addition to the primary function of the digestive system, the vagus nerve participates in other brain functions, including reward [123, 126], cognition [127], and satiety [128].

The causal relationship between the vagus nerve and the stress response has been demonstrated in several studies. Stimulation of the vagus nerve increases the serum corticosterone levels in rats [129, 130]. Genetically selective rat lines with altered glucocorticoid responsiveness display differential vagal tone following stress exposure [131]. In a human study, the injection of metyrapone, a drug that effectively blocks the critical enzyme to synthesize glucocorticoids in healthy subjects, dramatically reduced vagal-mediated heart rate variability [132]. The vagotomy procedure moderately altered nicotine-induced ACTH and corticosterone levels in a rat model [133]. The association between the vagus nerve and the stress response has been extensively investigated in immune challenge models. Subdiaphragmatic vagotomy effectively abolishes IL-1β-induced corticosterone elevation [134,135,136]. However, one report showed that vagotomy did not affect circulating cytokines and corticosterone when injected with LPS, suggesting a vagus-independent pathway [137]. Consistently, our study showed that subdiaphragmatic vagotomy cannot reverse ABX-induced social impairment or corticosterone levels [18]. Interestingly, a probiotic study found that ingestion of Lactobacillus (L.) casei strain Shirota was able to downregulate stress-induced glucocorticoids and relieve stress-associated symptoms in humans and rats. Moreover, treatment of L. casei strain Shirota in rats increased the vagal afferent nerve pulse in a dose-dependent manner and suppressed stress-induced CRF expression at PVN [138]. The differences between these findings can largely be attributed to different animal models, vagus nerve manipulations, and stimuli.

Strikingly, transcriptomic analysis by single-cell RNA sequencing revealed that the nodose and jugular ganglia expressed low levels of GR genes (Nr3c1) under baseline condition by single-cell RNA sequencing [139]. Interestingly, cell clusters with relatively high GR expression were functionally predicted to serve as GI tension sensors or mucosal chemo/mechano sensors [139]. However, GR expressing gastric vagal afferents, including the nodose ganglion and muscular/mucosal gastric vagal neurons, were found not to be affected by corticosterone in response to mechanical stimulation [140]. These data indicate that vagal afferent neurons express GR, but the functional role of glucocorticoid agonism in the GI tract remains unclear.

Sympathetic contributions to gut and gut microorganisms are not yet well-understood. One report showed that the depletion of the gut microbiota activated neural activity in the celiac-superior mesenteric ganglia (CG-SMG), the extrinsic sympathetic neurons responsible for GI tract innervation, thus altering gut motility [124]. Colonizing a specific community of bacteria, altered Schaedler flora, or Clostridium spp., or administering gut fermentation metabolites short-chain fatty acids can suppress the activation of neurons in CG-SMG. Anatomically, vagal innervated brain regions are interconnected with brainstem nuclei critical for CG-SMG activation. Modulating vagal afferent signaling could alter gut sympathetic neural activity, revealing a complex neural innervation from the brain to the gut involving ANS [124].

In brief, the ascending and descending neural inputs of the parasympathetic and sympathetic nerves sense and respond to subtle changes in the lumen of the GI tract, including the commensal microbiota, in the modulation of higher brain functions beyond digestion. Taken together, these studies suggest that the stress-induced response of various compounds in the gut could potentially activate ANS and transmit signals to the brain.

Neural pathways and neurotransmitters in gut-brain signaling via the vagus nerve

The neural pathways from the vagus nerve to the PVN CRH neurons are intricate [141]. The NTS serves as the primary relay for vagal afferent signals connecting to the forebrain [142]. Buller et al. showed that lesions within the NTS significantly decreased c-Fos expressions in PVN CRH neurons when exposed to systemic IL-1β [142]. Adrenergic and noradrenergic neurons were shown to bridge the connection between NTS and PVN. Chen et al. indicated that activation of noradrenergic neurons and adrenergic/neuropeptide Y neurons in NTS has been shown to modulate feeding behavior [143]. Moreover, a recent study showed that activation of NTS noradrenergic neurons resulted in reduced intake of both regular and high-fat diets, while also increasing PVN CRH c-Fos expression and elevating plasma corticosterone levels. This activation of the neural pathway from NTS NE neurons to PVN neurons also led to a decrease in chow food intake [144]. On the other hand, several studies have shown that preproglucagon neurons in NTS bridge the connection between NTS and CRH. Preproglucagon neurons are the primary source of glucagon-like peptide-1 (GLP-1) in the brain, a well-known gut hormone in the periphery [145]. Tracing studies confirm that preproglucagon neurons in NTS project to the PVN [146,147,148,149]. Reciprocally, the PVN contains a high density of GLP-1 receptors (GLP-1R), with colocalization observed in PVN CRH neurons [148]. To prove the functionality of this circuit, activation of NTS PPG neurons through chemogenetics or optogenetics directly stimulates PVN CRH neurons and suppresses food intake [150]. Furthermore, leptin-deficient mice exhibited increased NTS PPG neuron input to the PVN, resulting in higher c-Fos expression in PVN neurons [151]. In addition, intraperitoneal injection of the other gut hormone cholecystokinin (CCK) increased c-Fos expression in both NTS noradrenergic and PVN CRH neurons [152, 153]. The activity of PVN CRH neurons was increased during fasting conditions but was suppressed when the individual was in a fed state [13], suggesting that gut peptides may stimulate vagal terminals and alter forebrain neural activity. These findings collectively highlight the direct projections from NTS to the PVN CRH neurons.

Within the intricate framework of the gut-brain axis, a crucial aspect is the involvement of neural active molecules and their receptors in the gut that transmit signals to the brain. These molecules can be categorized into three main groups: neurotransmitters, gut peptides, and immune molecules. For neurotransmitters, serotonin (5-HT) within the gut primarily released by enterochromaffin cells [154]. It is tightly regulated by commensal microbiota [155] and has the capacity to directly activate the vagus nerve through the 5-HT3R receptor [156, 157]. Moreover, oral administration of selective serotonin reuptake inhibitors (SSRI) has been shown to increase the firing rate of vagal afferent neurons [158]. Notably, gastric distension has been observed to enhance c-Fos expression in the NTS and PVN. This effect can be mitigated through the intravenous injection of a 5-HT3R antagonist [159]. Additionally, intragastric administration of glutamate can activate gastric vagal afferent neurons, with the activation being notably hindered by pharmacological blocking of the 5-HT3R [160].

Gut peptides, including leptin, ghrelin, CCK, GLP-1, and peptide YY (PYY) are other well-known factors capable of activating the vagus nerve. Receptors for these gut peptides, such as the leptin receptor (LepR), GLP-1 receptor (GLP-1R), CCK receptor (CCKR), ghrelin receptor (GHSR), and Y2 receptor (Y2R), are expressed in nodose ganglion cells and the NTS region [125, 141, 161,162,163,164,165,166]. Ghrelin has been shown to decrease vagal afferent activity [161], while leptin, CCK, and GLP-1 were found to increase vagal afferent activity [77, 167,168,169]. Furthermore, vagal afferent neurons have the ability to function as chemosensors and mechanosensors to monitor changes within the gut lumen through gut peptide signaling [125, 141, 170]. Nutrients are also capable of activating vagal afferent neurons. For instance, nutrients like sucrose have been demonstrated to transmit signals through the sodium-dependent glucose cotransporter 1 (SGLT1) on CCK-labeled neuropod cells, subsequently activating the vagus nerve through glutamatergic neurotransmission [171, 172]. The mechanical stretching of the digestive tract, including the stomach and intestine, induces in vivo calcium activity in vagal ganglia neurons [125]. This study further identified that GLP-1R neurons primarily detect mechanical signalling, while GPR65 neurons primarily detect perfused nutrients and serotonin, which are then transferred to the NTS region [125].

For the immune molecules, the activation of vagal terminals in the gut has been notably associated with pro-inflammatory cytokines and bacterial endotoxin. For instance, intravenous injection of IL-1β resulted in a significant increase in c-Fos expression within the nodose ganglion, while concurrently elevating the discharge activity of gastric vagal afferent neurons, all mediated by a prostaglandin-dependent mechanism [173]. Similarly, intraportal administration of IL-1β was found to augment the discharge rate of the hepatic branch of vagal afferent nerves [174]. The specificity of vagal sensory neuron responses to IL-1β was further demonstrated by using IL-1R knockout mice, highlighting the pivotal role of the IL-1R receptor [175, 176]. Moreover, the action potential recording within the cervical vagus nerve was notably absent in TNF receptor knockout mice when exposed to TNF [175]. Toll-like receptor 4 (TLR4), known for mediating the signalling of bacterial endotoxin LPS [177, 178], is expressed in vagal afferent neurons [179, 180]. The administration of LPS promptly induced calcium influx in cultured vagal neurons [181], and notably, it heightened the release of calcitonin gene-related peptide (CGRP) in vagal afferent neurons through the TLR4 pathway [182].

In summary, the intricate neural pathways and neurotransmitters in the gut-brain connection via the vagus nerve have diverse roles. Neurotransmitters, gut peptides, nutrients, mechanosensation, and cytokines influence vagal activity through specialized receptors. This complex interplay shapes various physiological responses, impacting stress, appetite, and sensation. These mechanisms provide insights into the gut-brain axis, with implications for health and diseases.

Probiotic- and bacteria-based effects for stress response

Microbiota-based supplements such as probiotics have been shown to alleviate stress responses by downregulating stress hormones. Interestingly, Lactobacillus bacteria are widely used as probiotics to alleviate stress responses, which are coincidentally observed to be downregulated when animals are exposed to stress (Table 1). Therefore, we summarized the current findings on using probiotics to alleviate stress responses and regulate the stress hormone corticosterone (Table 4).

Table 4 The effect of probiotics on corticosterone in rodents

L. rhamnosus has been used as a probiotic for several decades. L. rhamnosus GG alleviated acute restraint stress-induced corticosterone in maternal separation rats [183] and high-fat diet mice [184]. L. rhamnosus JB-1 reduced acute restraint stress-induced corticosterone levels through the subdiaphragmatic vagus nerve [185] in a strain-dependent manner [186]. The rat pups showed high corticosterone levels immediately after maternal separation. The increase in corticosterone levels can be prevented by oral administration of L. rhamnosus strain R0011 (95%) and L. helveticus strain R0052 (5%) (Lacidofil®) [187].

In addition to the rhamnosus species, paracasei, plantarum, casei, and other species have been shown to modulate stress in various models. Administration of L. paracasei Lpc-37 [188] chronically decreased corticosterone levels induced by chronic daily restraint stress. L. paracasei HT6 effectively prevented early life stressful social experience-induced changes in brain GR expression [189]. L. paracasei PS23 [190] and L. plantarum PS128 [191] reduced corticosterone levels induced by early life stress. L. casei strain Shirota reduced WAS-induced corticosterone levels in rats and academic stress-induced cortisol levels in humans [138]. L. casei DKGF7 suppresses chronic restraint stress-induced corticosterone [192]. L. plantarum CCFM8610 and L. casei M2-01-R02-S01 (M2S01) suppressed corticosterone levels in irritable bowel syndrome (IBS) models induced by WAS and Citrobacter rodentium [193]. L. plantarum LRCC5310L. plantarum LRCC5314, and L. gasseri BNR17 suppressed the elevation of corticosterone induced by chronic cold stress and high-fat diet [194]. L. reuteri exopolysaccharide suppresses ampicillin-induced corticosterone [81]. L. reuteri ATCC-PTA-6475 downregulated corticosterone levels during wound healing [195]. L. reuteri NK33, L. johnsonii isolates, L. johnsonii BS15, and L. mucosae NK41 suppressed corticosterone elevation induced by immobilization stress [49, 196,197,198]. L. fermentum CECT 5716 alleviated the corticosterone levels induced by WAS and maternal separation [199]. Treatment with heat-killed L. fermentum and L. delbrueckii (ADR-159) decreased the baseline levels of corticosterone and increased sociability [200]. L. helveticus NS8 reduces chronic restraint stress-induced corticosterone [201]. Treatment with L. farciminis ML-7 successfully suppressed the activation of the HPA axis induced by partial restraint stress [84]. However, not every Lactobacillus species produces a downregulating effect on the stress response, including L. paracasei N1115 [83], L. plantarum LP12407 [188], L. plantarum LP12418 [188], L. salivarius UCC118 [202], L. casei CRL431 [203], L. salivarius HA113 [204]. Moreover, the renowned probiotic L. rhamnosus JB-1 was not able to change cortisol and release stress compared with the placebo group in humans [205].

In addition to Lactobacillus species, Bifidobacterium (B.) is another genus of bacteria that has been extensively investigated for stress regulation. Monocolonization of B. subtilis in GF mice attenuated the increase in restraint stress-induced ACTH and corticosterone levels [62]. Bifidobacterium adolescentis NK98, B. adolescentis IM38, and B. longum NK46 suppress corticosterone elevation induced by immobilization stress [196, 198, 206]. B. pseudocatenulatum CECT 7765 [207] and B. bifidum G9-1 (BBG9-1) [208] alleviated maternal separation-induced elevation in corticosterone levels. B. breve strains M2CF22M7 [209] and CCFM1025 [210] reduced the UCMS-induced corticosterone production. In a clinical study, the administration of B. longum 1714 decreased stress hormone levels after stress-induced events [211]. Similarly, not all Bifidobacterium species are involved in stress regulation, including B. infantis 35624 [202, 212, 213], B. breve UCC2003 [202], B. longum 1714 [214, 215], B. breve 1205 [214, 215].

Probiotic mixtures that combine Lactobacillus and Bifidobacterium species also exert stress modulation effects. L. helveticus R0052 and B. longum R0175 (Probio'Stick®) reduced the elevation of corticosterone induced by WAS [204]. Treatment with probiotics combining L. helveticus, L. rhamnosusL. caseiB. longum suppressed ACTH and corticosterone levels in UCMS rats [216]. However, the mechanisms by which different bacteria interact with one another can be complicated. In contrast, maternal B. animalis subsp. actis BB-12® with Propionibacterium jensenii 702 increased neonatal corticosterone [217].

Other bacteria, not commonly used as probiotics, have also been shown to modulate stress-induced hormones to a lesser extent. Monocolonization by E. coli, but not Bacteroides fragilis in GF mice reduced the basal levels of corticosterone [71]. Administration of Klebsiella oxytoca [81] and E. coli [49] increased baseline corticosterone levels. Wu et al. treated mice with a combination of antibiotics (ampicillin, vancomycin, and metronidazole; AVM) and found that the social behavior was preserved, and the stress response was restrained compared to mice treated with the full spectrum of ABX. The preserved social behavior and reduced stress response were transferred when transplanting the AVM gut microbiota to GF recipient mice, indicating that the gut bacteria in the AVM microbiome played an active role. Enterococcus (E.) faecalis was identified as the key bacterium that promotes social behavior and suppresses increased corticosterone levels during social encounters. Colonization of E. faecalis in ABX and GF mice can promote their social behavior, but only suppresses corticosterone levels in ABX, and not GF mice [18].

E. faecalis is a lactic acid bacterium that is resistant to antibiotics and many other stressors. The functional roles of E. faecalis in the host are multifaceted and strain-specific. E. faecalis is a well-known pathogen commonly found in urinary tract infections [218]. In contrast, E. faecalis has been widely used as a probiotic or food additive [219]. Interestingly, several studies have shown that E. faecalis can modulate the nervous system and host behavior. E. faecalis EC-12 strain reduces the anxiety response and alters the receptors for norepinephrine and vasopressin in the prefrontal cortex [220]. E. faecalis SF3B strain [221] and EF-2001 [222] strains have been shown to alleviate colitis-induced enteric neurotransmission and pathologies. In addition, E. faecalis can synthesize tyramine and-phenylethylamine, two neuroactive molecules known as trace amines and are considered to be able to modulate the host nervous system [223,224,225,226]. Substance P stimulates the production of tyramine and lactic acid in E. faecalis V583 strain and enhances cytotoxicity and bacterial translocation in an intestinal in vitro model [227]. E. faecalis AG5 can increase both long- and short-chain fatty acids in the host, which might indirectly affect the nervous system through an indirect fashion [228]. One report found that infection of mice with pathogenic E. faecalis strains, K9 and CP-1, increased corticosterone in an acute manner, suggesting that E. faecalis can alter glucocorticoid signaling in the host [229]. Clinically, E. faecalis was present in 89.3% of healthy controls, whereas only in 58.3% of neurodevelopmental disorders, 58.3% of mixed specific developmental disorders, and 55.6% of expressive and receptive language disorder [230]. In addition, the administration of E. faecalis did not produce any effect on repetitive behavior and anxiety-like behavior in the offspring of maternal immune activation [231].

Altogether, the molecular and cellular mechanisms by which gut bacteria exert their effects on host emotion and stress responses will be investigated in the future. Despite the remarkable effects of microbiota on the HPA axis in animal studies, more clinical studies are required to support the concept of using probiotics to alleviate stress levels in humans.

Prebiotic- and synbiotic-based effects for stress response

Prebiotics are non-digestible ingredients derived from food that have been used to promote the growth of microbes, mostly in the GI tract. Synbiotic treatment combines prebiotic and probiotic treatments to synergistically affect the host. Previous studies have shown that both prebiotic and synbiotic treatments can alter the corticosterone levels in rodent models. Few studies have investigated the interactions between prebiotics and stress exposure and their implications in the control of corticosterone levels.

Burokas et al. demonstrated that treatment with fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) produces anxiolytic and antidepressant effects in adult mice. Moreover, acute stress-induced corticosterone by forced swim test was effectively downregulated by GOS and the combination of FOS + GOS [232]. Interestingly, the relative abundances of Akkermansia, Bacteroides, and Parabacteroides were increased in the FOS and GOS treatments, while the relative abundances of Desulfovibrio, Ruminococcus, Allobaculum, Turicibacter, Lactobacillus, and Bifidobacterium were decreased by FOS + GOS [232]. However, two other studies using different compounds of prebiotics did not yield an inhibitory effect on corticosterone induced by inescapable stress (GOS, polydextrose, and the glycoprotein lactoferrin) [233] or by social disruption stress (human milk oligosaccharides 3’ sialyllactose or 6’ sialyllactose) [234]. We speculate that various compounds, treatment duration, and onset of treatment can influence the effects of prebiotics.

In addition to stress exposure, Liu et al. showed that chronic treatment with mannan oligosaccharide (MOS) decreased the baseline levels of corticosterone and CRH in the serum of a 5xFAD transgenic Alzheimer’s disease mouse model but not in wild-type mice. Furthermore, they found that butyrate levels in the serum and feces were increased by MOS and negatively correlated with serum corticosterone [235]. However, another study by Rodrigues et al. showed that MOS treatment decreased plasma corticosterone levels in wild-type Whistar rats during adulthood [236]. Interestingly, a drug-induced constipation rat model showed higher ACTH and lower corticosterone levels, which can be normalized by inulin and isomalto-oligosaccharide [237].

Synbiotic treatments with both prebiotics and probiotics are complex and have various combinations. To date, no study has used the same recipe with bacterial strains and prebiotic compounds for stress regulation. In a chronic stress model, Seong et al. found that combining maltodextrin L. paracasei DKGF1 with Opuntia humifusa extract suppressed corticosterone levels induced by restraint stress in a time-dependent manner in rats exposed to chronic daily restraint stress [238]. Joung et al. found that the probiotic L. gasseri 505 suppressed UCMS-induced corticosterone. Adding leaf extract Cudrania tricuspidata did not produce an additional effect on corticosterone [239]. In acute stress, Barrera-Bugueno et al. showed that co-treatment with L. casei 54-2-33 and inulin in rats decreased the elevated plus maze-induced corticosterone [240]. Few studies have adopted synbiotic strategies to alleviate the stress response and corticosterone, possibly due to the lack of a foundation regarding the mechanistic points of view on both probiotics and prebiotics.

Direct modulation of biosynthesis and metabolism of steroids by microbiota

Steroidogenesis is a biosynthetic process that converts cholesterol to steroids in the host. In glucocorticoids, cholesterol is converted to corticosterone via several steps by several critical enzymes, including pregnenolone, progesterone, and deoxy-corticosterone. Corticosterone is then metabolized to aldosterone. Interestingly, several studies support the hypothesis that indigenous microbes directly modulate steroid synthesis in the host [241, 242]. This section discusses the potential bacterial candidates by which de novo bacteria convert cholesterol into steroids, which could interfere with the synthesis of glucocorticoid steroids.

The biosynthesis of steroids in bacteria is one way to directly influence steroid hormone levels. Pernigoni et al. found treatment with pregnenolone in the culture of Ruminococcus (R.) gnavus, Bacteroides (B.) acidifaciens, and Clostridium (C.) scindens under anaerobic conditions for 48 h can synthesize androgenic steroids; they measured the levels of steroid pathway intermediates using liquid chromatography-tandem mass spectrometry [242]. They detected hydroxypregnenolone, progesterone, dehydroepiandrosterone, and testosterone in bacterial conditioned media. Similarly, the same bacterial strain can metabolize hydroxypregnenolone to progesterone, dehydroepiandrosterone, and testosterone in vitro. However, R. gnavus and B. acidifaciens did not show any metabolic capability for cholesterol, cortisol, or aldosterone. Moreover, treatment with pregnenolone and hydroxypregnenolone in other commensal bacterial strains, including E. faecalis, Enterobacter cloacae, Klebsiella pneumoniae 27, Proteus mirabilis, Serratia marcescens, Staphylococcus haemoliticus, E. coli, yielded negative results, indicating the specificity of bacteria in the metabolism of steroid intermediates [242].

On the other hand, metabolizing steroid hormone can be the other pathway for bacteria to impact the levels of hormones in the host. Schaaf and Dettner isolated two Bacillus strains (HA-V6-3 and HA-V6-11) from the gut of a water beetle and showed that they were capable of metabolizing pregnenolone [243]. The other evidence demonstrated by Mosa et al. showing that indole and skatole, the two gut bacteria-derived metabolites of tryptophan fermentation, can inhibit CYP11A1, the rate-limiting enzyme for the steroidogenesis, to decrease pregnenolone [244]. Moreover, testosterone deficiency has been associated with depressive symptoms. Li et al. recently found that Mycobacterium neoaurum isolated from patients with depression can degrade testosterone into androstenedione [241]. A gene encoding 3β-hydroxysteroid dehydrogenase was identified in Mycobacterium neoaurum that degrades testosterone. 3β-hydroxysteroid dehydrogenase was introduced into E. coli to generate 3β-hydroxysteroid dehydrogenase-producing bacteria. Colonization of 3β-hydroxysteroid dehydrogenase-producing E. coli in ABX mice induced depressive-like behaviors [241]. A recent study done by Hsiao et al. investigated the effects of administering Thauera sp. strain GDN1, a betaproteobacterium with the ability to catabolize testosterone, to C57BL/6 mice. The results showed that the administration of strain GDN1 led to a significant reduction in serum androgen levels, as well as the detection of androgenic ring-cleaved metabolites in fecal extracts, suggesting that gut bacteria capable of androgen catabolism may regulate host circulating androgen levels and could potentially be utilized as probiotics in the alternative therapy of hyperandrogenism [245].

Although no study has shown that the specific bacteria's capability could directly influence corticosterone levels, the Hylemon laboratory at Virginia Commonwealth University discovered that C. scindens, a bacterium isolated from human feces, can convert glucocorticoids cortisol into androgens by a mechanism called side-chain cleavage [246]. A cortisol-inducible operon desABCD was identified in C. scindens ATCC 35704 using RNA-seq. C. scindens transports cortisol into bacteria via a sodium-dependent cortisol transporter encoded by desD. Cortisol can then be metabolized to 11β-hydro-xyandrost-4-ene-3,17-dione (11beta-OHA) by steroid-17,20-demolase, a putative transketolase encoded by desAB. 11beta-OHA can then be pumped out of the cell by ABC transporter [247]. It is not known whether there are bacteria that share a similar mechanism for converting corticosterone into other steroids. Another study from the Hylemon laboratory identified an enzyme corticosteroid 21-hydroxylase in the cell extracts of Eggerthella lenta (previously known as Eubacterium lentum). Interestingly, enzyme 21-hydroxylase uses deoxycorticosterone, deoxycortisol, dehydrocorticosterone, and corticosterone as substrates. This could be another mechanism by which microbes convert steroids to corticosterone in mammals. However, both C. scindens and Eggerthella lenta were neither reported in rodents after stress exposure (Table 1), nor were they found to colonize the guts of microbiome-deficient rodents.

From the perspective of biosynthesis and metabolism of corticosterone, some bacteria can promote corticosterone precursors, whereas others can have the opposite effect. Therefore, it remains challenging to identify a single pathway to clarify the hypercorticosterone found in GF and ABX-treated mice. The field faces a highly complicated situation in the gut that modulates stress hormones and stress-induced behavioral abnormalities.

Clinical implication

Stress-related disorders, exemplified by irritable bowel syndrome (IBS), often involve microbial dysbiosis. IBS, a GI complication characterized by symptoms like abdominal discomfort, altered stool patterns, and accompanying anxiety, affects 5–10% of the population [248]. Despite extensive investigation, the precise etiology of IBS remains elusive, with recognized risk factors encompassing genetics, diet, psychological stress, and gut microbiome composition [249].

Studies reveal reduced α-diversity and notable differences in 21 bacterial species relative abundance in IBS patients compared to healthy controls [250]. IBS subtypes exhibited distinct alterations in gut microbiota-derived metabolites; constipation-predominant IBS (IBS-C) features reduced fecal bile acid concentration [251], whereas diarrhea-predominant IBS (IBS-D) showed elevated primary bile acids [252], which could be attributed to changes in the composition of the gut microbiota. Zhai et al. has shown that specific bacteria in IBS-D, like Ruminococcus gnavus, can stimulate serotonin biosynthesis by producing phenethylamine and tryptamine, accelerating gut motility [253]. Bercik group showed that Klebsiella aerogenes, found in some IBS patients, enhances histamine production, leading to visceral hyperalgesia through histamine 4 receptor signaling [254]. Notably, successful animal models for IBS can be established via fecal microbiota transplantation (FMT) from human IBS patient donors to GF recipients. This approach effectively replicates GI and anxiety symptoms observed in human IBS patients [254, 255].

Stress exposure is a known risk factor for the occurrence of IBS, commonly affecting gut motility and HPA axis [256]. IBS patients differ from healthy individuals in stress response hormone levels. Posserud et al. demonstrated acute mental stress leads to significant increases in plasma CRH and ACTH in IBS patients [257]. Further, Dinan group showed that ACTH and cortisol release augment in IBS patients following CRH infusion [258]. Colorectal distention (CRD), a method to detect visceral sensitivity [254], in animal model for IBS results in elevated c-Fos expression in PVN CRH neurons and increased plasma CRH, ACTH, and corticosterone levels [259]. Collectively, these findings indicate that individuals with IBS exhibit heightened stress hormone secretion and microbial dysbiosis compared to healthy subjects.

Conclusion

Stress coping is an essential strategy for animals to face life-threatening events that may be harmful to their bodies. Stress dysregulation is strongly associated with affective diseases [3]. The COVID-19 pandemic has drastically escalated the global prevalence of stress-associated disorders and this impacts society profoundly [260]. Recent studies have suggested that the gut microbiota do not only arise in the background of stress exposure, but they also act as an “active modifier,” regulating the nervous and endocrine systems. We suggest that the fluttery feeling perceived as having “butterflies in the stomach” originates from the gut microbes. Gut microbes directly and locally modulate steroidogenesis, potentially altering stress hormone levels. Stress hormone signaling can then be propagated to the brain through defined pathways, extra-adrenal steroidogenesis, the autonomic system, and various bacterial components. Ultimately, the brain receives a message from the microbes and responds adequately to the PVN and other brain regions. Furthermore, the coping and adapting mechanisms determined by the brain can alter outputs based on behavior and endocrine function. Microbes can then be further adapted to the host physiology under stress. This controlling loop pathway, starting from the gut microbiota, is based on the current understanding of the interplay between intestinal microbes and stress. The molecular and cellular mechanisms, pathways, and circuits by which gut microbes regulate behavior remain largely unexplored. Identifying the key bacteria and bacteria-associated factors that contribute to and affect the stress response will benefit the innovation of alternative medicine using microbiome-based therapeutics.

Availability of data and materials

Not applicable.

Abbreviations

ABX:

Antibiotic cocktail

ACTH:

Adrenocorticotropic hormone

adBNST:

Adrenodorsal bed nucleus of the stria terminalis

ANS:

Autonomic nervous system

AVM:

Ampicillin, vancomycin, and metronidazole

BLA:

Basolateral amygdala

CeA:

Central nucleus of the amygdala

CG-SMG:

Celiac-superior mesenteric ganglia

CRH:

Corticotrophin-releasing hormone

CSDS:

Chronic social defeat stress

FOS:

Fructo-oligosaccharides

GF:

Germ-free

GI:

Gastrointestinal

GOS:

Galacto-oligosaccharides

GR:

Glucocorticoid receptor

HPA:

Hypothalamic–pituitary–adrenal

IBS:

Irritable bowel syndrome

IEC:

Intestinal epithelial cells

IL:

Interleukin

LPS:

Lipopolysaccharide

MeA:

Medial amygdala

MOS:

Mannan oligosaccharide

mSTN:

Medial subthalamic nucleus

PVN:

Paraventricular nucleus of the hypothalamus

SOC:

Social overcrossing

UCMS:

Unpredictable chronic mild stress

WAS:

Water avoidance stress

References

  1. Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22(10):1079–89.

    Article  CAS  PubMed  Google Scholar 

  2. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701–12.

    Article  CAS  PubMed  Google Scholar 

  3. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10(6):397–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen WG, Schloesser D, Arensdorf AM, Simmons JM, Cui C, Valentino R, Gnadt JW, Nielsen L, Hillaire-Clarke CS, Spruance V, Horowitz TS, Vallejo YF, Langevin HM. The emerging science of interoception: sensing, integrating, interpreting, and regulating signals within the self. Trends Neurosci. 2021;44(1):3–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol. 2003;24(3):151–80.

    Article  CAS  PubMed  Google Scholar 

  6. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169–91.

    Article  PubMed  Google Scholar 

  7. Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6(2):603–21.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Swanson LW, Kuypers HG. The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods. J Comp Neurol. 1980;194(3):555–70.

    Article  CAS  PubMed  Google Scholar 

  9. Jiang Z, Rajamanickam S, Justice NJ. CRF signaling between neurons in the paraventricular nucleus of the hypothalamus (PVN) coordinates stress responses. Neurobiol Stress. 2019;11: 100192.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lin X, Itoga CA, Taha S, Li MH, Chen R, Sami K, Berton F, Francesconi W, Xu X. c-Fos mapping of brain regions activated by multi-modal and electric foot shock stress. Neurobiol Stress. 2018;8:92–102.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Daviu N, Fuzesi T, Rosenegger DG, Rasiah NP, Sterley TL, Peringod G, Bains JS. Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection. Nat Neurosci. 2020;23(3):398–410.

    Article  CAS  PubMed  Google Scholar 

  12. Fuzesi T, Daviu N, Wamsteeker Cusulin JI, Bonin RP, Bains JS. Hypothalamic CRH neurons orchestrate complex behaviours after stress. Nat Commun. 2016;7:11937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim J, Lee S, Fang YY, Shin A, Park S, Hashikawa K, Bhat S, Kim D, Sohn JW, Lin D, Suh GSB. Rapid, biphasic CRF neuronal responses encode positive and negative valence. Nat Neurosci. 2019;22(4):576–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang ST, Wu K, Guo MM, Shao S, Hua R, Zhang YM. Glutamatergic and GABAergic anteroventral BNST projections to PVN CRH neurons regulate maternal separation-induced visceral pain. Neuropsychopharmacology. 2023;48(12):1778–88.

    Article  CAS  PubMed  Google Scholar 

  15. Bonaz B, Tache Y. Water-avoidance stress-induced c-fos expression in the rat brain and stimulation of fecal output: role of corticotropin-releasing factor. Brain Res. 1994;641(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  16. Million M, Wang L, Martinez V, Tache Y. Differential Fos expression in the paraventricular nucleus of the hypothalamus, sacral parasympathetic nucleus and colonic motor response to water avoidance stress in Fischer and Lewis rats. Brain Res. 2000;877(2):345–53.

    Article  CAS  PubMed  Google Scholar 

  17. Sterley TL, Baimoukhametova D, Fuzesi T, Zurek AA, Daviu N, Rasiah NP, Rosenegger D, Bains JS. Social transmission and buffering of synaptic changes after stress. Nat Neurosci. 2018;21(3):393–403.

    Article  CAS  PubMed  Google Scholar 

  18. Wu WL, Adame MD, Liou CW, Barlow JT, Lai TT, Sharon G, Schretter CE, Needham BD, Wang MI, Tang W, Ousey J, Lin YY, Yao TH, Abdel-Haq R, Beadle K, Gradinaru V, Ismagilov RF, Mazmanian SK. Microbiota regulate social behaviour via stress response neurons in the brain. Nature. 2021;595(7867):409–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao Z, Wang L, Gao W, Hu F, Zhang J, Ren Y, Lin R, Feng Q, Cheng M, Ju D, Chi Q, Wang D, Song S, Luo M, Zhan C. A central catecholaminergic circuit controls blood glucose levels during stress. Neuron. 2017;95(1):138–52.

    Article  CAS  PubMed  Google Scholar 

  20. Liou CW, Cheng SJ, Yao TH, Lai TT, Tsai YH, Chien CW, Kuo YL, Chou SH, Hsu CC, Wu WL. Microbial metabolites regulate social novelty via CaMKII neurons in the BNST. Brain Behav Immun. 2023;113:104–23.

    Article  CAS  PubMed  Google Scholar 

  21. Gungor NZ, Pare D. Functional heterogeneity in the bed nucleus of the stria terminalis. J Neurosci. 2016;36(31):8038–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lebow MA, Chen A. Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol Psychiatry. 2016;21(4):450–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ch’ng S, Fu J, Brown RM, McDougall SJ, Lawrence AJ. The intersection of stress and reward: BNST modulation of aversive and appetitive states. Prog Neuropsychopharmacol Biol Psychiatry. 2018;87(Pt A):108–25.

    Article  PubMed  Google Scholar 

  24. Duan K, Gu Q, Petralia RS, Wang YX, Panja D, Liu X, Lehmann ML, Zhu H, Zhu J, Li Z. Mitophagy in the basolateral amygdala mediates increased anxiety induced by aversive social experience. Neuron. 2021;109(23):3793–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Spencer SJ, Buller KM, Day TA. Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. J Comp Neurol. 2005;481(4):363–76.

    Article  PubMed  Google Scholar 

  26. Choi DC, Furay AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP. Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs. J Neurosci. 2007;27(8):2025–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Choi DC, Furay AR, Evanson NK, Ulrich-Lai YM, Nguyen MM, Ostrander MM, Herman JP. The role of the posterior medial bed nucleus of the stria terminalis in modulating hypothalamic-pituitary-adrenocortical axis responsiveness to acute and chronic stress. Psychoneuroendocrinology. 2008;33(5):659–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Butler RK, Oliver EM, Sharko AC, Parilla-Carrero J, Kaigler KF, Fadel JR, Wilson MA. Activation of corticotropin releasing factor-containing neurons in the rat central amygdala and bed nucleus of the stria terminalis following exposure to two different anxiogenic stressors. Behav Brain Res. 2016;304:92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fetterly TL, Basu A, Nabit BP, Awad E, Williford KM, Centanni SW, Matthews RT, Silberman Y, Winder DG. alpha2A-adrenergic receptor activation decreases parabrachial nucleus excitatory drive onto BNST CRF neurons and reduces their activity in vivo. J Neurosci. 2019;39(3):472–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang WH, Zhang JY, Holmes A, Pan BX. Amygdala circuit substrates for stress adaptation and adversity. Biol Psychiatry. 2021;89(9):847–56.

    Article  PubMed  Google Scholar 

  31. Zhang X, Ge TT, Yin G, Cui R, Zhao G, Yang W. Stress-induced functional alterations in amygdala: implications for neuropsychiatric diseases. Front Neurosci. 2018;12:367.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Dayas CV, Buller KM, Crane JW, Xu Y, Day TA. Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci. 2001;14(7):1143–52.

    Article  CAS  PubMed  Google Scholar 

  33. Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, Oleata CS, Heilig M, Roberto M. Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci. 2014;34(2):363–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang X, Lei B, Yuan Y, Zhang L, Hu L, Jin S, Kang B, Liao X, Sun W, Xu F, Zhong Y, Hu J, Qi H. Brain control of humoral immune responses amenable to behavioural modulation. Nature. 2020;581(7807):204–8.

    Article  CAS  PubMed  Google Scholar 

  35. Xu Y, Day TA, Buller KM. The central amygdala modulates hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1beta administration. Neuroscience. 1999;94(1):175–83.

    Article  CAS  PubMed  Google Scholar 

  36. Cai H, Haubensak W, Anthony TE, Anderson DJ. Central amygdala PKC-delta(+) neurons mediate the influence of multiple anorexigenic signals. Nat Neurosci. 2014;17(9):1240–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng ZH, Tu JL, Li XH, Hua Q, Liu WZ, Liu Y, Pan BX, Hu P, Zhang WH. Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain Behav Immun. 2021;91:505–18.

    Article  CAS  PubMed  Google Scholar 

  38. Tseng YT, Zhao B, Chen S, Ye J, Liu J, Liang L, Ding H, Schaefke B, Yang Q, Wang L, Wang F, Wang L. The subthalamic corticotropin-releasing hormone neurons mediate adaptive REM-sleep responses to threat. Neuron. 2022;110:1223.

    Article  CAS  PubMed  Google Scholar 

  39. Chevalier G, Siopi E, Guenin-Mace L, Pascal M, Laval T, Rifflet A, Boneca IG, Demangel C, Colsch B, Pruvost A, Chu-Van E, Messager A, Leulier F, Lepousez G, Eberl G, Lledo PM. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. Nat Commun. 2020;11(1):6363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Marin IA, Goertz JE, Ren T, Rich SS, Onengut-Gumuscu S, Farber E, Wu M, Overall CC, Kipnis J, Gaultier A. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci Rep. 2017;7:43859.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Siopi E, Chevalier G, Katsimpardi L, Saha S, Bigot M, Moigneu C, Eberl G, Lledo PM. Changes in gut microbiota by chronic stress impair the efficacy of fluoxetine. Cell Rep. 2020;30(11):3682–90.

    Article  CAS  PubMed  Google Scholar 

  42. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, Schiweck C, Kurilshikov A, Joossens M, Wijmenga C, Claes S, Van Oudenhove L, Zhernakova A, Vieira-Silva S, Raes J. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4(4):623–32.

    Article  CAS  PubMed  Google Scholar 

  43. McGaughey KD, Yilmaz-Swenson T, Elsayed NM, Cruz DA, Rodriguiz RM, Kritzer MD, Peterchev AV, Roach J, Wetsel WC, Williamson DE. Relative abundance of Akkermansia spp. and other bacterial phylotypes correlates with anxiety- and depressive-like behavior following social defeat in mice. Sci Rep. 2019;9(1):3281.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Huang YJ, Choong LC, Panyod S, Lin YE, Huang HS, Lu KH, Wu WK, Sheen LY. Gastrodia elata Blume water extract modulates neurotransmitters and alters the gut microbiota in a mild social defeat stress-induced depression mouse model. Phytother Res. 2021;35(9):5133–42.

    Article  CAS  PubMed  Google Scholar 

  45. van de Wouw M, Boehme M, Lyte JM, Wiley N, Strain C, O’Sullivan O, Clarke G, Stanton C, Dinan TG, Cryan JF. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol. 2018;596(20):4923–44.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Suzuki K, Nakamura K, Shimizu Y, Yokoi Y, Ohira S, Hagiwara M, Wang Y, Song Y, Aizawa T, Ayabe T. Decrease of alpha-defensin impairs intestinal metabolite homeostasis via dysbiosis in mouse chronic social defeat stress model. Sci Rep. 2021;11(1):9915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Delaroque C, Chervy M, Gewirtz AT, Chassaing B. Social overcrowding impacts gut microbiota, promoting stress, inflammation, and dysglycemia. Gut Microbes. 2021;13(1):2000275.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Dodiya HB, Forsyth CB, Voigt RM, Engen PA, Patel J, Shaikh M, Green SJ, Naqib A, Roy A, Kordower JH, Pahan K, Shannon KM, Keshavarzian A. Chronic stress-induced gut dysfunction exacerbates Parkinson’s disease phenotype and pathology in a rotenone-induced mouse model of Parkinson’s disease. Neurobiol Dis. 2020;135: 104352.

    Article  CAS  PubMed  Google Scholar 

  49. Jang HM, Lee KE, Lee HJ, Kim DH. Immobilization stress-induced Escherichia coli causes anxiety by inducing NF-kappaB activation through gut microbiota disturbance. Sci Rep. 2018;8(1):13897.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J, Kentish S, Xie P, Morrison M, Wesselingh SL, Rogers GB, Licinio J. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry. 2016;21(6):797–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Deng Y, Zhou M, Wang J, Yao J, Yu J, Liu W, Wu L, Wang J, Gao R. Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain. Gut Microbes. 2021;13(1):1–16.

    Article  PubMed  Google Scholar 

  52. Wu CY, Chen HH, Tao PL, Yuan ZF. Comparisons of stress-related neuronal activation induced by restraint in adult male rat offspring with prenatal exposure to buprenorphine, methadone, or morphine. Chin J Physiol. 2023;66(2):65–72.

    Article  PubMed  Google Scholar 

  53. Rengarajan S, Knoop KA, Rengarajan A, Chai JN, Grajales-Reyes JG, Samineni VK, Russler-Germain EV, Ranganathan P, Fasano A, Sayuk GS, Gereau RWT, Kau AL, Knights D, Kashyap PC, Ciorba MA, Newberry RD, Hsieh CS. A potential role for stress-induced microbial alterations in IgA-associated irritable bowel syndrome with diarrhea. Cell Rep Med. 2020;1(7):100124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shaler CR, Parco AA, Elhenawy W, Dourka J, Jury J, Verdu EF, Coombes BK. Psychological stress impairs IL22-driven protective gut mucosal immunity against colonising pathobionts. Nat Commun. 2021;12(1):6664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gareau MG, Silva MA, Perdue MH. Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med. 2008;8(4):274–81.

    Article  CAS  PubMed  Google Scholar 

  56. Pusceddu MM, Barboza M, Keogh CE, Schneider M, Stokes P, Sladek JA, Kim HJD, Torres-Fuentes C, Goldfild LR, Gillis SE, Brust-Mascher I, Rabasa G, Wong KA, Lebrilla C, Byndloss MX, Maisonneuve C, Baumler AJ, Philpott DJ, Ferrero RL, Barrett KE, Reardon C, Gareau MG. Nod-like receptors are critical for gut-brain axis signalling in mice. J Physiol. 2019;597(24):5777–97.

    Article  CAS  PubMed  Google Scholar 

  57. Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, Macqueen G, Sherman PM. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011;60(3):307–17.

    Article  PubMed  Google Scholar 

  58. Sun Y, Zhang M, Chen CC, Gillilland M 3rd, Sun X, El-Zaatari M, Huffnagle GB, Young VB, Zhang J, Hong SC, Chang YM, Gumucio DL, Owyang C, Kao JY. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology. 2013;144(7):1478–87.

    Article  CAS  PubMed  Google Scholar 

  59. Zhao Z, Wang B, Mu L, Wang H, Luo J, Yang Y, Yang H, Li M, Zhou L, Tao C. Long-term exposure to ceftriaxone sodium induces alteration of gut microbiota accompanied by abnormal behaviors in mice. Front Cell Infect Microbiol. 2020;10:258.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Selye H. Stress and the general adaptation syndrome. Br Med J. 1950;1(4667):1383–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nukina H, Sudo N, Aiba Y, Oyama N, Koga Y, Kubo C. Restraint stress elevates the plasma interleukin-6 levels in germ-free mice. J Neuroimmunol. 2001;115(1–2):46–52.

    Article  CAS  PubMed  Google Scholar 

  62. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004;558(Pt 1):263–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lyte JM, Gheorghe CE, Goodson MS, Kelley-Loughnane N, Dinan TG, Cryan JF, Clarke G. Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent. Neurogastroenterol Motil. 2020;32(11): e13881.

    Article  CAS  PubMed  Google Scholar 

  64. De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, Denou E, Silva MA, Santacruz A, Sanz Y, Surette MG, Verdu EF, Collins SM, Bercik P. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun. 2015;6:7735.

    Article  PubMed  Google Scholar 

  65. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18(6):666–73.

    Article  CAS  PubMed  Google Scholar 

  66. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23(3):255–64.

    Article  CAS  PubMed  Google Scholar 

  67. Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Dauge V, Naudon L, Rabot S. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology. 2014;42:207–17.

    Article  CAS  PubMed  Google Scholar 

  68. Ikeda M, Hamada K, Sumitomo N, Okamoto H, Sakakibara B. Serum amyloid A, cytokines, and corticosterone responses in germfree and conventional mice after lipopolysaccharide injection. Biosci Biotechnol Biochem. 1999;63(6):1006–10.

    Article  CAS  PubMed  Google Scholar 

  69. van de Langerijt AG, van Lent PL, Hermus AR, Sweep CG, Cools AR, van den Berg WB. Susceptibility to adjuvant arthritis: relative importance of adrenal activity and bacterial flora. Clin Exp Immunol. 1994;97(1):33–8.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Vagnerova K, Vodicka M, Hermanova P, Ergang P, Srutkova D, Klusonova P, Balounova K, Hudcovic T, Pacha J. Interactions between gut microbiota and acute restraint stress in peripheral structures of the hypothalamic-pituitary-adrenal axis and the intestine of male mice. Front Immunol. 2019;10:2655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Menezes-Garcia Z, Do Nascimento Arifa RD, Acurcio L, Brito CB, Gouvea JO, Lima RL, Bastos RW, Fialho Dias AC, Antunes Dourado LP, Bastos LFS, Queiroz-Junior CM, Igidio CED, Bezerra RO, Vieira LQ, Nicoli JR, Teixeira MM, Fagundes CT, Souza DG. Colonization by Enterobacteriaceae is crucial for acute inflammatory responses in murine small intestine via regulation of corticosterone production. Gut Microbes. 2020;11(6):1531–46.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Giri P, Hu F, La Gamma EF, Nankova BB. Absence of gut microbial colonization attenuates the sympathoadrenal response to hypoglycemic stress in mice: implications for human neonates. Pediatr Res. 2019;85(4):574–81.

    Article  CAS  PubMed  Google Scholar 

  73. Kamimura I, Watarai A, Takamura T, Takeo A, Miura K, Morita H, Mogi K, Kikusui T. Gonadal steroid hormone secretion during the juvenile period depends on host-specific microbiota and contributes to the development of odor preference. Dev Psychobiol. 2019;61(5):670–8.

    Article  CAS  PubMed  Google Scholar 

  74. Kawai Y, Suegara N, Yazawa K. Intestinal microflora and aging: age-related change of lipid metabolism in germ-free and conventional rats. Mech Ageing Dev. 1981;16(2):149–58.

    Article  CAS  PubMed  Google Scholar 

  75. Kennedy EA, King KY, Baldridge MT. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front Physiol. 2018;9:1534.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Needham BD, Tang W, Wu WL. Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder. Dev Neurobiol. 2018;78(5):474–99.

    Article  PubMed  Google Scholar 

  77. Lai TT, Tsai YH, Liou CW, Fan CH, Hou YT, Yao TH, Chuang HL, Wu WL. The gut microbiota modulate locomotion via vagus-dependent glucagon-like peptide-1 signaling. NPJ Biofilms Microbiomes. 2023;Accept with minor revision.

  78. Wu JT, Sun CL, Lai TT, Liou CW, Lin YY, Xue JY, Wang HW, Chai LMX, Lee YJ, Chen SL, Chang AYW, Hung JH, Hsu CC, Wu WL. Oral short-chain fatty acids administration regulates innate anxiety in adult microbiome-depleted mice. Neuropharmacology. 2022;214: 109140.

    Article  CAS  PubMed  Google Scholar 

  79. Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol. 2016;14(1):20–32.

    Article  CAS  PubMed  Google Scholar 

  80. Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell. 2013;153(4):812–27.

    Article  CAS  PubMed  Google Scholar 

  81. Jang HM, Lee HJ, Jang SE, Han MJ, Kim DH. Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice. Mucosal Immunol. 2018;11(5):1386–97.

    Article  CAS  PubMed  Google Scholar 

  82. Han G, Nishigawa T, Ikeda H, Hamada M, Yang H, Maesono S, Aso K, Jing A, Furuse M, Zhang R. Dysregulated metabolism and behaviors by disrupting gut microbiota in prenatal and neonatal mice. Anim Sci J. 2021;92(1): e13566.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang Y, Pu F, Cheng R, Guo J, Shen X, Wang S, Zhu H, Zhang X, Cheng G, Li M, He F. Effect of heat-inactivated Lactobacillus paracasei N1115 on microbiota and gut-brain axis related molecules. Biosci Microbiota Food Health. 2020;39(3):89–99.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L, Houdeau E, Fioramonti J, Bueno L, Theodorou V. Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology. 2012;37(11):1885–95.

    Article  CAS  PubMed  Google Scholar 

  85. Wu Q, Xu Z, Song S, Zhang H, Zhang W, Liu L, Chen Y, Sun J. Gut microbiota modulates stress-induced hypertension through the HPA axis. Brain Res Bull. 2020;162:49–58.

    Article  CAS  PubMed  Google Scholar 

  86. Kiraly DD, Walker DM, Calipari ES, Labonte B, Issler O, Pena CJ, Ribeiro EA, Russo SJ, Nestler EJ. Alterations of the host microbiome affect behavioral responses to cocaine. Sci Rep. 2016;6:35455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Mosaferi B, Jand Y, Salari AA. Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease. Sci Rep. 2021;11(1):22941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. LaGamma EF, Hu F, Pena CF, Bouchev P, Nankova BB. Bacteria—derived short chain fatty acids restore sympathoadrenal responsiveness to hypoglycemia after antibiotic-induced gut microbiota depletion. Neurobiol Stress. 2021;15:100376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ceylani T, Jakubowska-Dogru E, Gurbanov R, Teker HT, Gozen AG. The effects of repeated antibiotic administration to juvenile BALB/c mice on the microbiota status and animal behavior at the adult age. Heliyon. 2018;4(6): e00644.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Ikeda S, Takahashi S, Suzuki N, Hanzawa F, Horio F, Oda H. Gut microbiota is not involved in the induction of acute phase protein expression caused by vitamin C deficiency. J Nutr Sci Vitaminol (Tokyo). 2020;66(1):19–23.

    Article  CAS  PubMed  Google Scholar 

  91. Luo Y, Zeng B, Zeng L, Du X, Li B, Huo R, Liu L, Wang H, Dong M, Pan J, Zheng P, Zhou C, Wei H, Xie P. Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Transl Psychiatry. 2018;8(1):187.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Phan TS, Merk VM, Brunner T. Extra-adrenal glucocorticoid synthesis at epithelial barriers. Genes Immun. 2019;20(8):627–40.

    Article  PubMed  Google Scholar 

  93. Ahmed A, Schmidt C, Brunner T. Extra-adrenal glucocorticoid synthesis in the intestinal mucosa: between immune homeostasis and immune escape. Front Immunol. 2019;10:1438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Simpson ER, Waterman MR. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol. 1988;50:427–40.

    Article  CAS  PubMed  Google Scholar 

  95. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25(5):831–66.

    Article  CAS  PubMed  Google Scholar 

  96. Mueller M, Cima I, Noti M, Fuhrer A, Jakob S, Dubuquoy L, Schoonjans K, Brunner T. The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine. J Exp Med. 2006;203(9):2057–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mueller M, Atanasov A, Cima I, Corazza N, Schoonjans K, Brunner T. Differential regulation of glucocorticoid synthesis in murine intestinal epithelial versus adrenocortical cell lines. Endocrinology. 2007;148(3):1445–53.

    Article  CAS  PubMed  Google Scholar 

  98. Atanasov AG, Leiser D, Roesselet C, Noti M, Corazza N, Schoonjans K, Brunner T. Cell cycle-dependent regulation of extra-adrenal glucocorticoid synthesis in murine intestinal epithelial cells. FASEB J. 2008;22(12):4117–25.

    Article  CAS  PubMed  Google Scholar 

  99. Cima I, Corazza N, Dick B, Fuhrer A, Herren S, Jakob S, Ayuni E, Mueller C, Brunner T. Intestinal epithelial cells synthesize glucocorticoids and regulate T cell activation. J Exp Med. 2004;200(12):1635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kostadinova F, Schwaderer J, Sebeo V, Brunner T. Why does the gut synthesize glucocorticoids? Ann Med. 2014;46(7):490–7.

    Article  CAS  PubMed  Google Scholar 

  101. Noti M, Corazza N, Mueller C, Berger B, Brunner T. TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis. J Exp Med. 2010;207(5):1057–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Noti M, Corazza N, Tuffin G, Schoonjans K, Brunner T. Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner. FASEB J. 2010;24(5):1340–6.

    Article  CAS  PubMed  Google Scholar 

  103. Raddatz D, Toth S, Schworer H, Ramadori G. Glucocorticoid receptor signaling in the intestinal epithelial cell lines IEC-6 and Caco-2: evidence of inhibition by interleukin-1beta. Int J Colorectal Dis. 2001;16(6):377–83.

    Article  CAS  PubMed  Google Scholar 

  104. Fischer A, Gluth M, Weege F, Pape UF, Wiedenmann B, Baumgart DC, Theuring F. Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1. Am J Physiol Gastrointest Liver Physiol. 2014;306(3):G218-228.

    Article  CAS  PubMed  Google Scholar 

  105. Robinson JM, Turkington S, Abey SA, Kenea N, Henderson WA. Differential gene expression and gene-set enrichment analysis in Caco-2 monolayers during a 30-day timeline with Dexamethasone exposure. Tissue Barriers. 2019;7(3): e1651597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ahmed A, Schwaderer J, Hantusch A, Kolho KL, Brunner T. Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients. Genes Immun. 2019;20(7):566–76.

    Article  CAS  PubMed  Google Scholar 

  107. Ahmed A, Reinhold C, Breunig E, Phan TS, Dietrich L, Kostadinova F, Urwyler C, Merk VM, Noti M, Toja da Silva I, Bode K, Nahle F, Plazzo AP, Koerner J, Stuber R, Menche C, Karamitopoulou E, Farin HF, Gollob KJ, Brunner T. Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids. Mol Oncol. 2023;17(8):1545–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Vodicka M, Ergang P, Hrncir T, Mikulecka A, Kvapilova P, Vagnerova K, Sestakova B, Fajstova A, Hermanova P, Hudcovic T, Kozakova H, Pacha J. Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress. Brain Behav Immun. 2018;73:615–24.

    Article  CAS  PubMed  Google Scholar 

  109. Ergang P, Vagnerova K, Hermanova P, Vodicka M, Jagr M, Srutkova D, Dvoracek V, Hudcovic T, Pacha J. The gut microbiota affects corticosterone production in the murine small intestine. Int J Mol Sci. 2021;22(8):4229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dallman MF, Akana SF, Bhatnagar S, Bell ME, Strack AM. Bottomed out: metabolic significance of the circadian trough in glucocorticoid concentrations. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S40-46.

    Article  CAS  PubMed  Google Scholar 

  111. Gamble KL, Berry R, Frank SJ, Young ME. Circadian clock control of endocrine factors. Nat Rev Endocrinol. 2014;10(8):466–75.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Harkness JA, Richter MB, Panayi GS, Van de Pette K, Unger A, Pownall R, Geddawi M. Circadian variation in disease activity in rheumatoid arthritis. Br Med J (Clin Res Ed). 1982;284(6315):551–4.

    Article  CAS  PubMed  Google Scholar 

  113. Kalsbeek A, van Heerikhuize JJ, Wortel J, Buijs RM. A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist. J Neurosci. 1996;16(17):5555–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Oster H, Challet E, Ott V, Arvat E, de Kloet ER, Dijk DJ, Lightman S, Vgontzas A, Van Cauter E. The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr Rev. 2017;38(1):3–45.

    Article  PubMed  Google Scholar 

  115. Perry MG, Kirwan JR, Jessop DS, Hunt LP. Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(1):63–8.

    Article  CAS  PubMed  Google Scholar 

  116. Pai YC, Li YH, Turner JR, Yu LC. Transepithelial barrier dysfunction drives microbiota dysbiosis to initiate epithelial clock-driven inflammation. J Crohns Colitis. 2023;17(9):1471–88.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Thaiss CA, Levy M, Korem T, Dohnalova L, Shapiro H, Jaitin DA, David E, Winter DR, Gury-BenAri M, Tatirovsky E, Tuganbaev T, Federici S, Zmora N, Zeevi D, Dori-Bachash M, Pevsner-Fischer M, Kartvelishvily E, Brandis A, Harmelin A, Shibolet O, Halpern Z, Honda K, Amit I, Segal E, Elinav E. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell. 2016;167(6):1495–510.

    Article  CAS  PubMed  Google Scholar 

  118. Leone V, Gibbons SM, Martinez K, Hutchison AL, Huang EY, Cham CM, Pierre JF, Heneghan AF, Nadimpalli A, Hubert N, Zale E, Wang Y, Huang Y, Theriault B, Dinner AR, Musch MW, Kudsk KA, Prendergast BJ, Gilbert JA, Chang EB. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe. 2015;17(5):681–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Li S, Zhai J, Chu W, Geng X, Wang D, Jiao L, Lu G, Chan WY, Sun K, Sun Y, Chen ZJ, Du Y. Alleviation of Limosilactobacillus reuteri in polycystic ovary syndrome protects against circadian dysrhythmia-induced dyslipidemia via capric acid and GALR1 signaling. NPJ Biofilms Microbiomes. 2023;9(1):47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Prechtl JC, Powley TL. The fiber composition of the abdominal vagus of the rat. Anat Embryol (Berl). 1990;181(2):101–15.

    Article  CAS  PubMed  Google Scholar 

  121. Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 2000;85(1–3):1–17.

    Article  CAS  PubMed  Google Scholar 

  122. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohorquez DV. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018;361(6408).

  123. Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, Ferreira TL, Quinn D, Liu ZW, Gao XB, Kaelberer MM, Bohorquez DV, Shammah-Lagnado SJ, de Lartigue G, de Araujo IE. A neural circuit for gut-induced reward. Cell. 2018;175(3):665–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Muller PA, Schneeberger M, Matheis F, Wang P, Kerner Z, Ilanges A, Pellegrino K, Del Marmol J, Castro TBR, Furuichi M, Perkins M, Han W, Rao A, Pickard AJ, Cross JR, Honda K, de Araujo I, Mucida D. Microbiota modulate sympathetic neurons via a gut-brain circuit. Nature. 2020;583(7816):441–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD. Sensory neurons that detect stretch and nutrients in the digestive system. Cell. 2016;166(1):209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Alhadeff AL, Goldstein N, Park O, Klima ML, Vargas A, Betley JN. Natural and drug rewards engage distinct pathways that converge on coordinated hypothalamic and reward circuits. Neuron. 2019;103(5):891–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Suarez AN, Hsu TM, Liu CM, Noble EE, Cortella AM, Nakamoto EM, Hahn JD, de Lartigue G, Kanoski SE. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun. 2018;9(1):2181.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Su Z, Alhadeff AL, Betley JN. Nutritive, Post-ingestive signals are the primary regulators of AgRP neuron activity. Cell Rep. 2017;21(10):2724–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hosoi T, Okuma Y, Nomura Y. Electrical stimulation of afferent vagus nerve induces IL-1beta expression in the brain and activates HPA axis. Am J Physiol Regul Integr Comp Physiol. 2000;279(1):R141-147.

    Article  CAS  PubMed  Google Scholar 

  130. De Herdt V, Puimege L, De Waele J, Raedt R, Wyckhuys T, El Tahry R, Libert C, Wadman W, Boon P, Vonck K. Increased rat serum corticosterone suggests immunomodulation by stimulation of the vagal nerve. J Neuroimmunol. 2009;212(1–2):102–5.

    Article  PubMed  Google Scholar 

  131. Huzard D, Ghosal S, Grosse J, Carnevali L, Sgoifo A, Sandi C. Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses. Psychoneuroendocrinology. 2019;101:101–10.

    Article  CAS  PubMed  Google Scholar 

  132. Agorastos A, Heinig A, Stiedl O, Hager T, Sommer A, Muller JC, Schruers KR, Wiedemann K, Demiralay C. Vagal effects of endocrine HPA axis challenges on resting autonomic activity assessed by heart rate variability measures in healthy humans. Psychoneuroendocrinology. 2019;102:196–203.

    Article  CAS  PubMed  Google Scholar 

  133. Bugajski AJ, Zurowski D, Thor P, Gadek-Michalska A. Effect of subdiaphragmatic vagotomy and cholinergic agents in the hypothalamic-pituitary-adrenal axis activity. J Physiol Pharmacol. 2007;58(2):335–47.

    CAS  PubMed  Google Scholar 

  134. Fleshner M, Goehler LE, Hermann J, Relton JK, Maier SF, Watkins LR. Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated. Brain Res Bull. 1995;37(6):605–10.

    Article  CAS  PubMed  Google Scholar 

  135. Fleshner M, Goehler LE, Schwartz BA, McGorry M, Martin D, Maier SF, Watkins LR. Thermogenic and corticosterone responses to intravenous cytokines (IL-1beta and TNF-alpha) are attenuated by subdiaphragmatic vagotomy. J Neuroimmunol. 1998;86(2):134–41.

    Article  CAS  PubMed  Google Scholar 

  136. Wieczorek M, Dunn AJ. Effect of subdiaphragmatic vagotomy on the noradrenergic and HPA axis activation induced by intraperitoneal interleukin-1 administration in rats. Brain Res. 2006;1101(1):73–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hansen MK, Nguyen KT, Fleshner M, Goehler LE, Gaykema RP, Maier SF, Watkins LR. Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide. Am J Physiol Regul Integr Comp Physiol. 2000;278(2):R331-336.

    Article  CAS  PubMed  Google Scholar 

  138. Takada M, Nishida K, Kataoka-Kato A, Gondo Y, Ishikawa H, Suda K, Kawai M, Hoshi R, Watanabe O, Igarashi T, Kuwano Y, Miyazaki K, Rokutan K. Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterol Motil. 2016;28(7):1027–36.

    Article  CAS  PubMed  Google Scholar 

  139. Kupari J, Haring M, Agirre E, Castelo-Branco G, Ernfors P. An atlas of vagal sensory neurons and their molecular specialization. Cell Rep. 2019;27(8):2508–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Li H, Page AJ. Activation of CRF2 receptor increases gastric vagal afferent mechanosensitivity. J Neurophysiol. 2019;122(6):2636–42.

    Article  CAS  PubMed  Google Scholar 

  141. Waise TMZ, Dranse HJ, Lam TKT. The metabolic role of vagal afferent innervation. Nat Rev Gastroenterol Hepatol. 2018;15(10):625–36.

    Article  PubMed  Google Scholar 

  142. Buller K, Xu Y, Dayas C, Day T. Dorsal and ventral medullary catecholamine cell groups contribute differentially to systemic interleukin-1beta-induced hypothalamic pituitary adrenal axis responses. Neuroendocrinology. 2001;73(2):129–38.

    Article  CAS  PubMed  Google Scholar 

  143. Chen J, Cheng M, Wang L, Zhang L, Xu D, Cao P, Wang F, Herzog H, Song S, Zhan C. A vagal-NTS neural pathway that stimulates feeding. Curr Biol. 2020;30(20):3986–98.

    Article  CAS  PubMed  Google Scholar 

  144. Murphy S, Collis GM, Dixon TN, Grill HJ, McNally GP, Ong ZY. Nucleus of the solitary tract A2 neurons control feeding behaviors via projections to the paraventricular hypothalamus. Neuropsychopharmacology. 2023;48(2):351–61.

    Article  CAS  PubMed  Google Scholar 

  145. Holt MK, Richards JE, Cook DR, Brierley DI, Williams DL, Reimann F, Gribble FM, Trapp S. Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food. Diabetes. 2019;68(1):21–33.

    Article  CAS  PubMed  Google Scholar 

  146. Huang Z, Liu L, Zhang J, Conde K, Phansalkar J, Li Z, Yao L, Xu Z, Wang W, Zhou J, Bi G, Wu F, Seeley RJ, Scott MM, Zhan C, Pang ZP, Liu J. Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism. Sci Adv. 2022;8(23):eabn5345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience. 1997;77(1):257–70.

    Article  CAS  PubMed  Google Scholar 

  148. Sarkar S, Fekete C, Legradi G, Lechan RM. Glucagon like peptide-1 (7–36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Brain Res. 2003;985(2):163–8.

    Article  CAS  PubMed  Google Scholar 

  149. Singh I, Wang L, Xia B, Liu J, Tahiri A, El Ouaamari A, Wheeler MB, Pang ZP. Activation of arcuate nucleus glucagon-like peptide-1 receptor-expressing neurons suppresses food intake. Cell Biosci. 2022;12(1):178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Liu J, Conde K, Zhang P, Lilascharoen V, Xu Z, Lim BK, Seeley RJ, Zhu JJ, Scott MM, Pang ZP. Enhanced AMPA receptor trafficking mediates the anorexigenic effect of endogenous glucagon-like peptide-1 in the paraventricular hypothalamus. Neuron. 2017;96(4):897–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Biddinger JE, Lazarenko RM, Scott MM, Simerly R. Leptin suppresses development of GLP-1 inputs to the paraventricular nucleus of the hypothalamus. Elife. 2020;9.

  152. Maniscalco JW, Rinaman L. Overnight food deprivation markedly attenuates hindbrain noradrenergic, glucagon-like peptide-1, and hypothalamic neural responses to exogenous cholecystokinin in male rats. Physiol Behav. 2013;121:35–42.

    Article  CAS  PubMed  Google Scholar 

  153. Verbalis JG, Stricker EM, Robinson AG, Hoffman GE. Cholecystokinin activates C-fos expression in hypothalamic oxytocin and corticotropin-releasing hormone neurons. J Neuroendocrinol. 1991;3(2):205–13.

    Article  CAS  PubMed  Google Scholar 

  154. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132(1):397–414.

    Article  CAS  PubMed  Google Scholar 

  155. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Blackshaw LA, Brookes SJ, Grundy D, Schemann M. Sensory transmission in the gastrointestinal tract. Neurogastroenterol Motil. 2007;19(1 Suppl):1–19.

    Article  CAS  PubMed  Google Scholar 

  157. Hillsley K, Grundy D. Serotonin and cholecystokinin activate different populations of rat mesenteric vagal afferents. Neurosci Lett. 1998;255(2):63–6.

    Article  CAS  PubMed  Google Scholar 

  158. Zhang Y, Zhang Y, Song G, He Y, Zhang X, Liu Y, Ju H. A DNA-azobenzene nanopump fueled by upconversion luminescence for controllable intracellular drug release. Angew Chem Int Ed Engl. 2019;58(50):18207–11.

    Article  CAS  PubMed  Google Scholar 

  159. Mazda T, Yamamoto H, Fujimura M, Fujimiya M. Gastric distension-induced release of 5-HT stimulates c-fos expression in specific brain nuclei via 5-HT3 receptors in conscious rats. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G228-235.

    Article  CAS  PubMed  Google Scholar 

  160. Uneyama H, Niijima A, San GA, Torii K. Luminal amino acid sensing in the rat gastric mucosa. Am J Physiol Gastrointest Liver Physiol. 2006;291(6):G1163-1170.

    Article  CAS  PubMed  Google Scholar 

  161. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology. 2002;123(4):1120–8.

    Article  CAS  PubMed  Google Scholar 

  162. Burdyga G, Spiller D, Morris R, Lal S, Thompson DG, Saeed S, Dimaline R, Varro A, Dockray GJ. Expression of the leptin receptor in rat and human nodose ganglion neurones. Neuroscience. 2002;109(2):339–47.

    Article  CAS  PubMed  Google Scholar 

  163. de Lartigue G, Ronveaux CC, Raybould HE. Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity. Mol Metab. 2014;3(6):595–607.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Peiser C, Springer J, Groneberg DA, McGregor GP, Fischer A, Lang RE. Leptin receptor expression in nodose ganglion cells projecting to the rat gastric fundus. Neurosci Lett. 2002;320(1–2):41–4.

    Article  CAS  PubMed  Google Scholar 

  165. Burdyga G, de Lartigue G, Raybould HE, Morris R, Dimaline R, Varro A, Thompson DG, Dockray GJ. Cholecystokinin regulates expression of Y2 receptors in vagal afferent neurons serving the stomach. J Neurosci. 2008;28(45):11583–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Cheng W, Ndoka E, Hutch C, Roelofs K, MacKinnon A, Khoury B, Magrisso J, Kim KS, Rhodes CJ, Olson DP, Seeley RJ, Sandoval D, Myers MG Jr. Leptin receptor-expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice. JCI Insight. 2020;5(7).

  167. Bucinskaite V, Tolessa T, Pedersen J, Rydqvist B, Zerihun L, Holst JJ, Hellstrom PM. Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat. Neurogastroenterol Motil. 2009;21(9):978-e978.

    Article  CAS  PubMed  Google Scholar 

  168. Gaisano GG, Park SJ, Daly DM, Beyak MJ. Glucagon-like peptide-1 inhibits voltage-gated potassium currents in mouse nodose ganglion neurons. Neurogastroenterol Motil. 2010;22(4):470–9.

    Article  CAS  PubMed  Google Scholar 

  169. Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M. The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology. 2005;146(5):2369–75.

    Article  CAS  PubMed  Google Scholar 

  170. Brookes SJ, Spencer NJ, Costa M, Zagorodnyuk VP. Extrinsic primary afferent signalling in the gut. Nat Rev Gastroenterol Hepatol. 2013;10(5):286–96.

    Article  CAS  PubMed  Google Scholar 

  171. Buchanan KL, Rupprecht LE, Kaelberer MM, Sahasrabudhe A, Klein ME, Villalobos JA, Liu WW, Yang A, Gelman J, Park S, Anikeeva P, Bohorquez DV. The preference for sugar over sweetener depends on a gut sensor cell. Nat Neurosci. 2022;25(2):191–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Liu WW, Bohorquez DV. The neural basis of sugar preference. Nat Rev Neurosci. 2022;23(10):584–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ek M, Kurosawa M, Lundeberg T, Ericsson A. Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci. 1998;18(22):9471–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Niijima A. The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat. J Auton Nerv Syst. 1996;61(3):287–91.

    Article  CAS  PubMed  Google Scholar 

  175. Steinberg BE, Silverman HA, Robbiati S, Gunasekaran MK, Tsaava T, Battinelli E, Stiegler A, Bouton CE, Chavan SS, Tracey KJ, Huerta PT. Cytokine-specific neurograms in the sensory vagus nerve. Bioelectron Med. 2016;3:7–17.

    Article  PubMed  Google Scholar 

  176. Zanos TP, Silverman HA, Levy T, Tsaava T, Battinelli E, Lorraine PW, Ashe JM, Chavan SS, Tracey KJ, Bouton CE. Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity. Proc Natl Acad Sci U S A. 2018;115(21):E4843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Beutler B. Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol. 2000;12(1):20–6.

    Article  CAS  PubMed  Google Scholar 

  178. Bryant CE, Spring DR, Gangloff M, Gay NJ. The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol. 2010;8(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  179. de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab. 2011;301(1):E187-195.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Hosoi T, Okuma Y, Matsuda T, Nomura Y. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton Neurosci. 2005;120(1–2):104–7.

    Article  CAS  PubMed  Google Scholar 

  181. Riley TP, Neal-McKinney JM, Buelow DR, Konkel ME, Simasko SM. Capsaicin-sensitive vagal afferent neurons contribute to the detection of pathogenic bacterial colonization in the gut. J Neuroimmunol. 2013;257(1–2):36–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Jia L, Lee S, Tierney JA, Elmquist JK, Burton MD, Gautron L. TLR4 signaling selectively and directly promotes CGRP release from vagal afferents in the mouse. eNeuro. 2021;8(1).

  183. McVey Neufeld KA, Strain CR, Pusceddu MM, Waworuntu RV, Manurung S, Gross G, Moloney GM, Hoban AE, Murphy K, Stanton C, Dinan TG, Cryan JF, O’Mahony SM. Lactobacillus rhamnosus GG soluble mediators ameliorate early life stress-induced visceral hypersensitivity and changes in spinal cord gene expression. Neuronal Signal. 2020;4(4):NS20200007.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Foroozan P, Koushkie Jahromi M, Nemati J, Sepehri H, Safari MA, Brand S. Probiotic supplementation and high-intensity interval training modify anxiety-like behaviors and corticosterone in high-fat diet-induced obesity mice. Nutrients. 2021;13(6):1762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Liu Y, Sanderson D, Mian MF, McVey Neufeld KA, Forsythe P. Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response. Neuropharmacology. 2021;195: 108682.

    Article  CAS  PubMed  Google Scholar 

  186. McVey Neufeld KA, Kay S, Bienenstock J. Mouse strain affects behavioral and neuroendocrine stress responses following administration of probiotic Lactobacillus rhamnosus JB-1 or traditional antidepressant fluoxetine. Front Neurosci. 2018;12:294.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut. 2007;56(11):1522–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Stenman LK, Patterson E, Meunier J, Roman FJ, Lehtinen MJ. Strain specific stress-modulating effects of candidate probiotics: a systematic screening in a mouse model of chronic restraint stress. Behav Brain Res. 2020;379: 112376.

    Article  CAS  PubMed  Google Scholar 

  189. Karen C, Shyu DJH, Rajan KE. Lactobacillus paracasei supplementation prevents early life stress-induced anxiety and depressive-like behavior in maternal separation model-possible involvement of microbiota-gut-brain axis in differential regulation of MicroRNA124a/132 and glutamate receptors. Front Neurosci. 2021;15: 719933.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Liao JF, Hsu CC, Chou GT, Hsu JS, Liong MT, Tsai YC. Lactobacillus paracasei PS23 reduced early-life stress abnormalities in maternal separation mouse model. Benef Microbes. 2019;10(4):425–36.

    Article  CAS  PubMed  Google Scholar 

  191. Liu YW, Liu WH, Wu CC, Juan YC, Wu YC, Tsai HP, Wang S, Tsai YC. Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naive adult mice. Brain Res. 2016;1631:1–12.

    Article  CAS  PubMed  Google Scholar 

  192. Seong G, Lee S, Min YW, Jang YS, Kim HS, Kim EJ, Park SY, Kim CH, Chang DK. Effect of heat-killed Lactobacillus casei DKGF7 on a rat model of irritable bowel syndrome. Nutrients. 2021;13(2):568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Liu Y, Xiao W, Yu L, Tian F, Wang G, Lu W, Narbad A, Chen W, Zhai Q. Evidence from comparative genomic analyses indicating that Lactobacillus-mediated irritable bowel syndrome alleviation is mediated by conjugated linoleic acid synthesis. Food Funct. 2021;12(3):1121–34.

    Article  CAS  PubMed  Google Scholar 

  194. Youn HS, Kim JH, Lee JS, Yoon YY, Choi SJ, Lee JY, Kim W, Hwang KW. Lactobacillus plantarum reduces low-grade inflammation and glucose levels in a mouse model of chronic stress and diabetes. Infect Immun. 2021;89(8): e0061520.

    Article  PubMed  Google Scholar 

  195. Varian BJ, Poutahidis T, DiBenedictis BT, Levkovich T, Ibrahim Y, Didyk E, Shikhman L, Cheung HK, Hardas A, Ricciardi CE, Kolandaivelu K, Veenema AH, Alm EJ, Erdman SE. Microbial lysate upregulates host oxytocin. Brain Behav Immun. 2017;61:36–49.

    Article  CAS  PubMed  Google Scholar 

  196. Han SK, Kim DH. Lactobacillus mucosae and Bifidobacterium longum synergistically alleviate immobilization stress-induced anxiety/depression in mice by suppressing gut dysbiosis. J Microbiol Biotechnol. 2019;29(9):1369–74.

    Article  CAS  PubMed  Google Scholar 

  197. Wang H, He S, Xin J, Zhang T, Sun N, Li L, Ni X, Zeng D, Ma H, Bai Y. Psychoactive effects of Lactobacillus johnsonii against restraint stress-induced memory dysfunction in mice through modulating intestinal inflammation and permeability-a study based on the gut-brain axis hypothesis. Front Pharmacol. 2021;12: 662148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Jang HM, Lee KE, Kim DH. The preventive and curative effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on immobilization stress-induced anxiety/depression and colitis in mice. Nutrients. 2019;11(4):819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Vanhaecke T, Aubert P, Grohard PA, Durand T, Hulin P, Paul-Gilloteaux P, Fournier A, Docagne F, Ligneul A, Fressange-Mazda C, Naveilhan P, Boudin H, Le Ruyet P, Neunlist ML. fermentum CECT 5716 prevents stress-induced intestinal barrier dysfunction in newborn rats. Neurogastroenterol Motil. 2017;29(8).

  200. Warda AK, Rea K, Fitzgerald P, Hueston C, Gonzalez-Tortuero E, Dinan TG, Hill C. Heat-killed lactobacilli alter both microbiota composition and behaviour. Behav Brain Res. 2019;362:213–23.

    Article  PubMed  Google Scholar 

  201. Liang S, Wang T, Hu X, Luo J, Li W, Wu X, Duan Y, Jin F. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience. 2015;310:561–77.

    Article  CAS  PubMed  Google Scholar 

  202. McKernan DP, Fitzgerald P, Dinan TG, Cryan JF. The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. Neurogastroenterol Motil. 2010;22(9):1029–35.

    Article  CAS  PubMed  Google Scholar 

  203. Palomar MM, Maldonado GC, Perdigon G. Influence of a probiotic lactobacillus strain on the intestinal ecosystem in a stress model mouse. Brain Behav Immun. 2014;35:77–85.

    Article  CAS  PubMed  Google Scholar 

  204. Ait-Belgnaoui A, Colom A, Braniste V, Ramalho L, Marrot A, Cartier C, Houdeau E, Theodorou V, Tompkins T. Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterol Motil. 2014;26(4):510–20.

    Article  CAS  PubMed  Google Scholar 

  205. Kelly JR, Allen AP, Temko A, Hutch W, Kennedy PJ, Farid N, Murphy E, Boylan G, Bienenstock J, Cryan JF, Clarke G, Dinan TG. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav Immun. 2017;61:50–9.

    Article  CAS  PubMed  Google Scholar 

  206. Jang HM, Jang SE, Han MJ, Kim DH. Anxiolytic-like effect of Bifidobacterium adolescentis IM38 in mice with or without immobilisation stress. Benef Microbes. 2018;9(1):123–32.

    Article  CAS  PubMed  Google Scholar 

  207. Moya-Perez A, Perez-Villalba A, Benitez-Paez A, Campillo I, Sanz Y. Bifidobacterium CECT 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice. Brain Behav Immun. 2017;65:43–56.

    Article  CAS  PubMed  Google Scholar 

  208. Fukui H, Oshima T, Tanaka Y, Oikawa Y, Makizaki Y, Ohno H, Tomita T, Watari J, Miwa H. Effect of probiotic Bifidobacterium bifidum G9–1 on the relationship between gut microbiota profile and stress sensitivity in maternally separated rats. Sci Rep. 2018;8(1):12384.

    Article  PubMed  PubMed Central  Google Scholar 

  209. Tian P, Wang G, Zhao J, Zhang H, Chen W. Bifidobacterium with the role of 5-hydroxytryptophan synthesis regulation alleviates the symptom of depression and related microbiota dysbiosis. J Nutr Biochem. 2019;66:43–51.

    Article  CAS  PubMed  Google Scholar 

  210. Tian P, O’Riordan KJ, Lee YK, Wang G, Zhao J, Zhang H, Cryan JF, Chen W. Towards a psychobiotic therapy for depression: Bifidobacterium breve CCFM1025 reverses chronic stress-induced depressive symptoms and gut microbial abnormalities in mice. Neurobiol Stress. 2020;12: 100216.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, Murphy E, Cryan JF, Dinan TG, Clarke G. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry. 2016;6(11): e939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res. 2008;43(2):164–74.

    Article  PubMed  Google Scholar 

  213. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 2010;170(4):1179–88.

    Article  CAS  PubMed  Google Scholar 

  214. Savignac HM, Kiely B, Dinan TG, Cryan JF. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil. 2014;26(11):1615–27.

    Article  CAS  PubMed  Google Scholar 

  215. Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res. 2015;287:59–72.

    Article  CAS  PubMed  Google Scholar 

  216. Li Q, Li L, Niu X, Tang C, Wang H, Gao J, Hu J. Probiotics alleviate depressive behavior in chronic unpredictable mild stress rat models by remodeling intestinal flora. NeuroReport. 2021;32(8):686–93.

    Article  CAS  PubMed  Google Scholar 

  217. Barouei J, Moussavi M, Hodgson DM. Effect of maternal probiotic intervention on HPA axis, immunity and gut microbiota in a rat model of irritable bowel syndrome. PLoS ONE. 2012;7(10): e46051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Garcia-Solache M, Rice LB. The enterococcus: a model of adaptability to its environment. Clin Microbiol Rev. 2019;32(2).

  219. Hanchi H, Mottawea W, Sebei K, Hammami R. The genus enterococcus: between probiotic potential and safety concerns-an update. Front Microbiol. 2018;9:1791.

    Article  PubMed  PubMed Central  Google Scholar 

  220. Kambe J, Watcharin S, Makioka-Itaya Y, Inoue R, Watanabe G, Yamaguchi H, Nagaoka K. Heat-killed Enterococcus fecalis (EC-12) supplement alters the expression of neurotransmitter receptor genes in the prefrontal cortex and alleviates anxiety-like behavior in mice. Neurosci Lett. 2020;720: 134753.

    Article  CAS  PubMed  Google Scholar 

  221. Shiina T, Shima T, Naitou K, Nakamori H, Sano Y, Horii K, Shimakawa M, Ohno H, Shimizu Y. Actions of probiotics on trinitrobenzenesulfonic acid-induced colitis in rats. Biomed Res Int. 2015;2015: 528523.

    Article  PubMed  PubMed Central  Google Scholar 

  222. Takahashi K, Nakagawasai O, Nemoto W, Odaira T, Sakuma W, Onogi H, Nishijima H, Furihata R, Nemoto Y, Iwasa H, Tan-No K, Tadano T. Effect of Enterococcus faecalis 2001 on colitis and depressive-like behavior in dextran sulfate sodium-treated mice: involvement of the brain-gut axis. J Neuroinflammation. 2019;16(1):201.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Mazzoli R, Pessione E. The neuro-endocrinological role of microbial glutamate and GABA signaling. Front Microbiol. 2016;7:1934.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Shimazu S, Miklya I. Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(3):421–7.

    Article  CAS  PubMed  Google Scholar 

  225. Pessione E, Pessione A, Lamberti C, Coisson DJ, Riedel K, Mazzoli R, Bonetta S, Eberl L, Giunta C. First evidence of a membrane-bound, tyramine and beta-phenylethylamine producing, tyrosine decarboxylase in Enterococcus faecalis: a two-dimensional electrophoresis proteomic study. Proteomics. 2009;9(10):2695–710.

    Article  CAS  PubMed  Google Scholar 

  226. Han S, Van Treuren W, Fischer CR, Merrill BD, DeFelice BC, Sanchez JM, Higginbottom SK, Guthrie L, Fall LA, Dodd D, Fischbach MA, Sonnenburg JL. A metabolomics pipeline for the mechanistic interrogation of the gut microbiome. Nature. 2021;595(7867):415–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Biaggini K, Borrel V, Szunerits S, Boukherroub R, N’Diaye A, Zebre A, Bonnin-Jusserand M, Duflos G, Feuilloley M, Drider D, Dechelotte P, Connil N. Substance P enhances lactic acid and tyramine production in Enterococcus faecalis V583 and promotes its cytotoxic effect on intestinal Caco-2/TC7 cells. Gut Pathog. 2017;9:20.

    Article  PubMed  PubMed Central  Google Scholar 

  228. Mishra AK, Kumar SS, Ghosh AR. Probiotic Enterococcus faecalis AG5 effectively assimilates cholesterol and produces fatty acids including propionate. FEMS Microbiol Lett. 2019;366(4).

  229. Papasian CJ, Qureshi N, Morrison DC. Endogenous and exogenous glucocorticoids in experimental enterococcal infection. Clin Vaccine Immunol. 2006;13(3):349–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Bojovic K, Ignjatovic Eth I, Sokovic Bajic S, Vojnovic Milutinovic D, Tomic M, Golic N, Tolinacki M. Gut microbiota dysbiosis associated with altered production of short chain fatty acids in children with neurodevelopmental disorders. Front Cell Infect Microbiol. 2020;10:223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G, Stanton C, Dinan TG, Cryan JF. Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol Psychiatry. 2017;82(7):472–87.

    Article  CAS  PubMed  Google Scholar 

  233. Mika A, Day HE, Martinez A, Rumian NL, Greenwood BN, Chichlowski M, Berg BM, Fleshner M. Early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on learned helplessness behaviours and alter gene expression within neural circuits important for stress resistance. Eur J Neurosci. 2017;45(3):342–57.

    Article  PubMed  Google Scholar 

  234. Tarr AJ, Galley JD, Fisher SE, Chichlowski M, Berg BM, Bailey MT. The prebiotics 3’Sialyllactose and 6’Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut-brain axis. Brain Behav Immun. 2015;50:166–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Liu Q, Xi Y, Wang Q, Liu J, Li P, Meng X, Liu K, Chen W, Liu X, Liu Z. Mannan oligosaccharide attenuates cognitive and behavioral disorders in the 5xFAD Alzheimer’s disease mouse model via regulating the gut microbiota-brain axis. Brain Behav Immun. 2021;95:330–43.

    Article  CAS  PubMed  Google Scholar 

  236. Rodrigues LE, Kishibe MM, Keller R, Caetano H, Rufino MN, Sanches OC, Giometti IC, Giuffrida R, Bremer-Neto H. Prebiotics mannan-oligosaccharides accelerate sexual maturity in rats: a randomized preclinical study. Vet World. 2021;14(5):1210–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lan J, Wang K, Chen G, Cao G, Yang C. Effects of inulin and isomalto-oligosaccharide on diphenoxylate-induced constipation, gastrointestinal motility-related hormones, short-chain fatty acids, and the intestinal flora in rats. Food Funct. 2020;11(10):9216–25.

    Article  CAS  PubMed  Google Scholar 

  238. Seong G, Lee S, Min YW, Jang YS, Park SY, Kim CH, Lee C, Hong SN, Chang DK. Effect of a synbiotic containing Lactobacillus paracasei and Opuntia humifusa on a murine model of irritable bowel syndrome. Nutrients. 2020;12(10):3205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Joung JY, Lim W, Seo YJ, Ham J, Oh NS, Kim SH. A synbiotic combination of Lactobacillus gasseri 505 and Cudrania tricuspidata leaf extract prevents stress-induced testicular dysfunction in mice. Front Endocrinol (Lausanne). 2022;13: 835033.

    Article  PubMed  Google Scholar 

  240. Barrera-Bugueno C, Realini O, Escobar-Luna J, Sotomayor-Zarate R, Gotteland M, Julio-Pieper M, Bravo JA. Anxiogenic effects of a Lactobacillus, inulin and the synbiotic on healthy juvenile rats. Neuroscience. 2017;359:18–29.

    Article  CAS  PubMed  Google Scholar 

  241. Li D, Liu R, Wang M, Peng R, Fu S, Fu A, Le J, Yao Q, Yuan T, Chi H, Mu X, Sun T, Liu H, Yan P, Wang S, Cheng S, Deng Z, Liu Z, Wang G, Li Y, Liu T. 3beta-Hydroxysteroid dehydrogenase expressed by gut microbes degrades testosterone and is linked to depression in males. Cell Host Microbe. 2022;30(3):329–39.

    Article  PubMed  Google Scholar 

  242. Pernigoni N, Zagato E, Calcinotto A, Troiani M, Mestre RP, Cali B, Attanasio G, Troisi J, Minini M, Mosole S, Revandkar A, Pasquini E, Elia AR, Bossi D, Rinaldi A, Rescigno P, Flohr P, Hunt J, Neeb A, Buroni L, Guo C, Welti J, Ferrari M, Grioni M, Gauthier J, Gharaibeh RZ, Palmisano A, Lucchini GM, D’Antonio E, Merler S, Bolis M, Grassi F, Esposito A, Bellone M, Briganti A, Rescigno M, Theurillat JP, Jobin C, Gillessen S, de Bono J, Alimonti A. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science. 2021;374(6564):216–24.

    Article  CAS  PubMed  Google Scholar 

  243. Schaaf O, Dettner K. Transformation of steroids by Bacillus strains isolated from the foregut of water beetles (Coleoptera: Dytiscidae): II. Metabolism of 3 beta-hydroxypregn-5-en-20-one (pregnenolone). J Steroid Biochem Mol Biol. 2000;75(2–3):187–99.

    Article  CAS  PubMed  Google Scholar 

  244. Mosa A, Gerber A, Neunzig J, Bernhardt R. Products of gut-microbial tryptophan metabolism inhibit the steroid hormone-synthesizing cytochrome P450 11A1. Endocrine. 2016;53(2):610–4.

    Article  CAS  PubMed  Google Scholar 

  245. Hsiao TH, Chou CH, Chen YL, Wang PH, Brandon-Mong GJ, Lee TH, Wu TY, Li PT, Li CW, Lai YL, Tseng YL, Shih CJ, Chen PH, Chen MJ, Chiang YR. Circulating androgen regulation by androgen-catabolizing gut bacteria in male mouse gut. Gut Microbes. 2023;15(1):2183685.

    Article  PubMed  PubMed Central  Google Scholar 

  246. Winter J, Morris GN, O’Rourke-Locascio S, Bokkenheuser VD, Mosbach EH, Cohen BI, Hylemon PB. Mode of action of steroid desmolase and reductases synthesized by Clostridium “scindens” (formerly Clostridium strain 19). J Lipid Res. 1984;25(10):1124–31.

    Article  CAS  PubMed  Google Scholar 

  247. Ridlon JM, Ikegawa S, Alves JM, Zhou B, Kobayashi A, Iida T, Mitamura K, Tanabe G, Serrano M, De Guzman A, Cooper P, Buck GA, Hylemon PB. Clostridium scindens: a human gut microbe with a high potential to convert glucocorticoids into androgens. J Lipid Res. 2013;54(9):2437–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet. 2020;396(10263):1675–88.

    Article  CAS  PubMed  Google Scholar 

  249. Black CJ, Ford AC. Global burden of irritable bowel syndrome: trends, predictions and risk factors. Nat Rev Gastroenterol Hepatol. 2020;17(8):473–86.

    Article  PubMed  Google Scholar 

  250. Kim GH, Lee K, Shim JO. Gut bacterial dysbiosis in irritable bowel syndrome: a case-control study and a cross-cohort analysis using publicly available data sets. Microbiol Spectr. 2023;11(1): e0212522.

    Article  PubMed  Google Scholar 

  251. Shin A, Camilleri M, Vijayvargiya P, Busciglio I, Burton D, Ryks M, Rhoten D, Lueke A, Saenger A, Girtman A, Zinsmeister AR. Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013;11(10):1270–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Duboc H, Rainteau D, Rajca S, Humbert L, Farabos D, Maubert M, Grondin V, Jouet P, Bouhassira D, Seksik P, Sokol H, Coffin B, Sabate JM. Increase in fecal primary bile acids and dysbiosis in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil. 2012;24(6):513–20.

    Article  CAS  PubMed  Google Scholar 

  253. Zhai L, Huang C, Ning Z, Zhang Y, Zhuang M, Yang W, Wang X, Wang J, Zhang L, Xiao H, Zhao L, Asthana P, Lam YY, Chow CFW, Huang JD, Yuan S, Chan KM, Yuan CS, Lau JY, Wong HLX, Bian ZX. Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis. Cell Host Microbe. 2023;31(1):33–44.

    Article  CAS  PubMed  Google Scholar 

  254. De Palma G, Shimbori C, Reed DE, Yu Y, Rabbia V, Lu J, Jimenez-Vargas N, Sessenwein J, Lopez-Lopez C, Pigrau M, Jaramillo-Polanco J, Zhang Y, Baerg L, Manzar A, Pujo J, Bai X, Pinto-Sanchez MI, Caminero A, Madsen K, Surette MG, Beyak M, Lomax AE, Verdu EF, Collins SM, Vanner SJ, Bercik P. Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Sci Transl Med. 2022;14(655):eabj1895.

    Article  PubMed  Google Scholar 

  255. De Palma G, Lynch MD, Lu J, Dang VT, Deng Y, Jury J, Umeh G, Miranda PM, Pigrau Pastor M, Sidani S, Pinto-Sanchez MI, Philip V, McLean PG, Hagelsieb MG, Surette MG, Bergonzelli GE, Verdu EF, Britz-McKibbin P, Neufeld JD, Collins SM, Bercik P. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci Transl Med. 2017;9(379).

  256. Chang L. The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome. Gastroenterology. 2011;140(3):761–5.

    Article  PubMed  Google Scholar 

  257. Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abrahamsson H, Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut. 2004;53(8):1102–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’Mahony L, O’Mahony S, Shanahan F, Keeling PW. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006;130(2):304–11.

    Article  CAS  PubMed  Google Scholar 

  259. Zhang G, Yu L, Chen ZY, Zhu JS, Hua R, Qin X, Cao JL, Zhang YM. Activation of corticotropin-releasing factor neurons and microglia in paraventricular nucleus precipitates visceral hypersensitivity induced by colorectal distension in rats. Brain Behav Immun. 2016;55:93–104.

    Article  CAS  PubMed  Google Scholar 

  260. Collaborators C-MD. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398(10312):1700–12.

    Article  Google Scholar 

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Acknowledgements

The authors apologize to colleagues whose work could not be included in this review due to space considerations. Figures were created using the Mind the Graph platform (www.mindthegraph.com).

Funding

This review was supported by the scholarship from Prof. Kun-Yen Huang Education Fund of Cheng-Hsing Medical Foundation to C.-W.L. and T.-T.L.; the scholarship Pilot Program of Ministry of Science and Technology (MOST) to Subsidize Universities and Colleges to Cultivate Outstanding Doctoral Students at NCKU (MOST 110-2926-I-006-001-MY4) to T.-T.L.; the funds from the MOST in Taiwan: (107-2320-B-006-072-MY3; 109-2314-B-006-046; 110-2314-B-006-114) to W.-L.W.; the funds from the National Science and Technology Council (NSTC) in Taiwan: (110-2320-B-006-018-MY3; 111–2314-B-006-008; and 112-2628-B-006-013-) to W.-L.W.; the funds from National Cheng Kung University Hospital (NCKUH-11210009) to W.-L.W. and the Higher Education Sprout Project, Ministry of Education to the Headquarters of University Advancement at NCKU to W.-LW.

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