## 6 Molecular Mechanism of NMOSD
### Involvement of Gut Microbiome and NMOSD  
Numerous microbial populations inhabit the gastrointestinal tract. They are involved in various functions in the host, such as digestion, absorption, protection, energy balance, immune response, intestinal permeability, enteric nervous system activity, and brain functions such as emotions, pain, behaviour, stress responses, etc. The gut is linked with the neural networks through vagus nerves and organizes the exchange of metabolites [155]. The gut microbiota (GM) is vital in developing neuroimmunological disorders. Recent studies signify the association between GM dysbiosis and NMOSD through intestinal mucosal barrier destruction and intestinal and peripheral immunity. Any abnormality in GM functions may cause the release of endotoxins, microbial products, and proinflammatory cells and cytokines, which affects the intestinal mucosal barrier function, allowing the substances to enter the bloodstream, thereby damaging the BBB and producing demyelination, axonal loss, and CNS damage and initiating NMOSD pathology [33]. Th17 cells involved in organ-specific immunity originate from the gut and are abundant in the intestinal lamina propria. The differentiation or migration of Th17 cells to the lymphoid-rich sites depends on the gut commensals [156]. The magnitude and frequency of T cell proliferation are higher in NMOSD patients than in healthy controls in response to AQP4 determinants. The adenosine triphosphate-binding cassette transporter permease (ABC-TP) of _Clostridium perfringens_ has 90% similarity to AQP4 p61-80 peptide. AQP4 p61-80 peptide binds to T cells, but T cells mimic the homologous sequence of _C. perfringens_, bind with the ABC-TP transporter peptide, and cause cross-reaction and Th17 polarization. Other AQP4 sequences, such as p63-76, also exhibit 60-70% homology with the ABC-TP of other commensal and pathogenic species of _Clostridium_, such as _C. scindens_, _C. hylemonae_ and _C. sporogenes_. Thus, _Clostridium_ species stimulate proinflammatory immune responses by influencing the balance between Th17 and Treg cells [157]. _C. perfrigens_ has dual functions; i.e., promoting the polarization of proinflammatory Th17 cells and exposing ABC-TP homologous determinants that cross-react with AQP4-producing reactive T cells and regulate the balance between T cells and Th17 cells, eventually resulting in immunologic dysfunctions and NMOSD [158]. [PERSON] and his team examined faecal microbiota in NMOSD patients for the first time. The study revealed that microbial diversity was reduced, and _C. perfringens_ abundance was increased significantly in NMOSD patients, suggesting that _C. perfringens_ could be involved in NMOSD pathogenesis [159]. _C. perfringens_ is also implicated in MS and NMO. Other members, such as _Fibrobacteres_, were over-presented in NMO patients' gut microbiota. Th-17 cells proliferate in response to the ABC peptide of _C. perfringens_, which shows the link between NMO and gut microbiota [159]. The abundance of butyrate-producing bacteria such as _Faecalibacterium_, _Roseburia_, _Ruminococcus_, and _Coprococcus_ was reduced in AQP4\({}^{+}\) and AQP4\({}^{-}\) groups. _Bacteroides_ and _Parabacteroides_ were predominant in AQP4\({}^{-}\) groups [160]. Investigation of possible foreign proteins that possess structural homology with AQP4 revealed that transmembrane proteins from _Klebsiella pneumoniae_ were involved in cross-reactivity in place of AQP4 in the case of NMO [161]. A Chinese cohort study revealed the presence of a high abundance of _Streptococcus_ in NMOSD patients. The high abundance of _Streptococcus_ was associated with reduced short-chain fatty acids and increased CD4\({}^{+}\) T cells promoting inflammatory reactions in NMOSD patients [162]. Another study in NMOSD patients showed that distributions of _Streptococcus_, _Shigella_, and _Faecalibacterium_ were positively associated with NMOSD severity. Some species of _Streptococcus_, including _S. oralis_, _S. salivarius_, _S. parasanguinis_, _S. pneumoniae_, and _S.