Fig. 1

Schematic of gut microenvironmental changes in PD and their contribution to disease pathophysiology. Enteric α-synuclein deposition, gastrointestinal inflammation, and intestinal epithelial barrier dysfunction are observed in PD. Pathological α-synuclein is found in enteroendocrine cells (EECs) and enteric neurons, which propagates through the vagus nerve to the brainstem, resulting in Lewy pathology in the central nervous system. Enteric α-synuclein also induces inflammatory responses involving activation of the caspase-1-dependent inflammasome and production of pro-inflammatory cytokines, leading to intestinal barrier malfunction [87]. Meanwhile, alteration of the gut microbiota composition in PD may accelerate α-synuclein aggregation, partly through secretion of bacterial amyloid [101, 117, 197]. Gut dysbiosis may also trigger enteric inflammation and increased intestinal permeability with systemic infiltration of microbial toxins and metabolites that activate and modulate immune responses and promote PD pathogenesis [85, 103]. Intestinal and systemic inflammation involving increased expression of TLR-4, T cells, and associated pro-inflammatory cytokines (e.g., TNF, IL-1ß, IL-6) results in greater permeability of the blood–brain barrier, neuroinflammation, and dopaminergic neuronal degeneration [64, 74, 166, 198]. BA, bile acid; HA, hippuric acid; IL-1ß, interleukin-1ß; TNF, tumor necrosis factor; TLR, toll-like receptor; TMA, trimethylamine; TMAO, trimethylamine N-oxide; Trp, tryptophan; LPS, lipopolysaccharide; SCFAs, short chain fatty acids