## 6 Molecular Mechanism of NMOSD
### Involvement of Gut Microbiome and NMOSD
mitis_, varied significantly between healthy subjects and NMOSD patients [163]. Studies showed that Bacteroides, Firmicutes, and Proteobacteria were more abundant, and other phyla such as Tenericutes and Actinobacteria were less abundant in NMOSD patients and healthy subjects [34]. Phyla Proteobacteria and Verrucomicrobia were significantly higher in AQP4\({}^{+}\) and AQP4\({}^{-}\) NMOSD patients. Members of genera _Clostridium_, _Streptococcus_, _Megamonas_, _Enterobacteriaceae_, and _Bilophila_ were predominant in AQP4\({}^{+}\) cases, whereas members of _Bacteroides_, _Megamonas_, _Phascalorctobacterium_, and _Akkermansia_ were prominent in AQP4\({}^{-}\) cases. At the species level, AQP4\({}^{+}\) NMOSD patients had _Clostridium boltae_ and _Flavorificator_. In the case of AQP4\({}^{-}\) NMOSD patients, _Megamonas funiformis_ and _Clostridium ramosum_ were significantly abundant. _Megamonas funiformis_, _Phascalorctobacterium facecium_, _Flavorificator plautii_, and _Clostridium ramosum_ were described in both AQP4 seropositive and seronegative patients [34]. Like the _C. perfringens_ ABC peptide, peptide 59-71 from _C. boltae_ also showed homology with the AQP4 p91-110 peptide, was highly reactive to AQP4-specific T cells [34], and initiated disease pathogenesis. _C. boltae_ caused immunopathogenesis in NMOSD patients through Th17, which induces inflammatory responses and influences the balance between Th17 and Treg cells [34]. NMOSD patients with high annual reoccurrence rates have a high abundance of _Actinomyces_ and _Sphingomonas_ and lower abundances of _Veillomonas_, _Atopobium_, and _Haemophilus_[31]. The studies on gut microbiota and NMOSD explain the correlation between gut dysbiosis and NMOSD by signifying the abundance of pathogenic bacteria and reduction in commensal organisms, which cause abnormal metabolism and metabolic signals in the pathogenesis of autoimmune diseases such as NMOSD. The exposure of intestinal epithelium to microbial pathogens provokes an inflammatory response. The transported pathogens and certain toxins are endocytosed in the lamina propria [164]. Still, failed defense mechanisms in the mucosal immune system damage gut integrity, which can elicit inflammatory responses [165] and disturb BBB integrity in NMOSD patients [166]. _Streptococcus_ induces inflammatory factors, causes damage to the intestinal mucosal barrier, and affects immune function [33]. Once the tight junction in the intestinal barrier is affected, it increases gut leakage. The T helper1 cells and Th17 and Treg cells are stimulated by cytokines such as IL12 and IL18; later, this cascade induces interferon-\(\gamma\) production and results in inflammation and damage in the intestine [167]. A high abundance of _Streptococcus_ might indicate the inducing of neuroinflammation and BBB degradation through Th17 activation [33]. Certain microbial antigens stimulate immunomodulation in autoimmune diseases of the CNS. A few bacterial species, such as _Fusobacterium nucleatum_ and members of _Clostriidium_, contain potent encephalitogenic peptides that closely mimic the myelin basic protein and myelin oligodendrocyte protein that trigger autoimmunity [168]. The immunomododulation of the CNS in autoimmune diseases needs to be further studied to reveal the involvement of the gut microbiome and its products.