Fig. 2

Representative schematic of TLR-driven gut dysfunction which may contribute to PD. Microbial dysbiosis and pro-inflammatory gut responses can result in a complex positive feedback loop of gut leakiness and inflammation. For example, microbial dysbiosis (1) contributes to the signalling of epithelial toll-like receptors (TLRs) (2), which can result in a leaky gut (3) and further TLR signalling (4) with subsequent cytokine secretion (5) and immune cell activation (6), leading to TLR-associated dysbiosis [3, 4]. Such gut inflammation can alter the enteric nervous system signalling and result in altered motility (7) [135]. It is hypothesised that α-synuclein is secreted by enteric neurons in response to infection to function as an immune-signalling molecule [159], and α-synuclein can directly activate and also change the expression of TLR2 and TLR4, causing further inflammatory responses [57, 58]. Over time, chronic TLR signalling, gut inflammation and sustained α-synuclein secretion may contribute to the formation of insoluble α-synuclein aggregates in the gut, especially if combined with other molecular deficits (e.g., lysosomal dysfunction). This may cause gut dysfunction (e.g. constipation), which is increasingly recognised as a ‘prodromal PD’ phase [20, 36]. Studies demonstrate that insoluble α-synuclein aggregates can spread from the gut to the brain via peripheral nerves (e.g., vagus nerve), where they cause Lewy body pathology in the CNS, neuroinflammation and neurodegeneration, resulting in the characteristic motor impairments of PD [27,28,29,30]. Figure created with Biorender.com