## 5 Gut Microbiota: Role of Toll-Like Receptors  
Commensal microbiota and microbial metabolites are sensed by Toll-like receptors (TLRs), the most extensively characterized class of pattern-recognition receptors (PRRs), via which the innate immune system in the gut recognizes pathogen-associated molecular patterns (PAMPs) and endogenous molecules generated by damaged cell and tissues, named damage-associated molecular patterns (DAMPs) [88]. About 10 TLRs (TLR1-10) were identified in neurons and glial cells of human CNS and gut. Their expression undergoes modifications following microbial infections and during sterile inflammation. Multifaceted TLR signaling influences brain function and immune-mediated processes both in the gut and in the brain. Gut epithelial cells express minimal TLRs under physiological conditions, and the gut has a high tolerance to TLR ligands [89]. However, an altered gut microbiota releases a variety of TLRs ligands which can activate downstream signaling pathways in glial cells, initiating an inflammatory response which involves myeloid differentiation primary gene 88 response adaptor protein and downstream nuclear factor kappa B (NF-kB), interferon regulatory factor, and mitogen-activated protein kinase pathways, which culminate in the release of chemokine, cytokine, and type I interferon production [90]. This activation cascade triggers a vicious circle leading to an increase in proinflammatory cytokines, oxidative and nitrosative stress, and finally neuronal death. Enteric neurons express TLRs to detect Gram-negative bacterial LPS, an outer-membrane component of all Gram-negative bacteria. TLRs, mainly TLR2 and TLR4, were shown to play a key role in several aspects of neurodegenerative diseases including PD. Reports showed that misfolded \(\alpha\)-syn released by damaged neurons can act as a DAMP for TLR4, promoting microglial and astroglia activation, which culminates in proinflammatory cytokine overproduction and oxidative stress [91]. Animal studies revealed that TLR4 affects the cerebral biochemical changes in a mouse model of PD [92], and the ablation of this receptor modulates the dopaminergic cell number and \(\alpha\)-syn accumulation [93]. Intestinal TLR4 dysregulation may play a role in the pathology of PD. Furthermore, extracellular \(\alpha\)-syn was found to be an effective agonist of TLR2 and downstream neurotoxic signals [94]. Increasing evidence suggests that TLRs can modulate the priming of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the gut. Moreover, [PERSON] and coworkers showed that NLRP3 is associated with depression, and the gut microbiota composition of NLRPP3-deficient mice was significantly altered compared to control animals. In particular, an increased Firmicutes/Bacteroidetes ratio was found in the NLRP3 knockout (KO) group, suggesting that microbiota may be a factor contributing to behavioral characteristics [95]. Nevertheless, it is important to point out that the precise role of TLR2 and TLR4 in neurodegeneration is controversial since they can trigger neurotoxicity but might be essential for the clearance of misfolded \(\alpha\)-synuclein, thus exhibiting neuroprotective effects [96]. TLR2 and TLR4 also seem to play a dual role in the pathogenesis and progression of AD. In AD patients, the population of pro-inflammatory bacteria increases [97]. However, on one hand, microglial TLR4 mediates A\(\beta\)-induced neurotoxicity [98]. On the other hand, TLR4-mutant AD mice had less microglial activation [99]. Intriguingly, \(\alpha\)-syn in PD can cause intestinal permeability as well as translocation of bacteria and their toxic products [100; 101]; in turn, extracellular fibers and SCFAs produced by microbes in the GI tract may affect \(\alpha\)-syn aggregation and motor dysfunction [102]. Clostridia or botulinum toxins spread to multiple organs, including the CNS, affecting synaptic neurotransmission.