## 4 The Role of the Gut Microbiome in MS and the Influence of Sex on the Gut Microbiome Composition  
A condition of gut dysbiosis has been described in both animal models and people with autoimmune diseases [28]. Consistent changes observed across multiple studies included a reduced abundance of the _Bacteroidaceae_ family, _Facelibacteriumum_, _Clostridium_ species, and _Prerotella_ strains and an increase in the genus _Akkermansia_[28; 29; 30; 31; 32]. The Clostridium species and Polysaccharide A from the capsule of the human commensal _Bacteroides fragilis_ were shown to exert an immunomodulatory effect, promoting Treg accumulation in the colon and IL-10 secretion in T and B cells [33; 34]. Whether these gut microbiota alterations in MS could contribute to the disease pathogenesis or are just a consequence remains unknown. Supporting a real pathogenic role is the finding that gut microbiota or gut-derived molecules obtained from people with MS could modulate EAE when transferred into mice [29; 35]. Accumulating evidence shows that the gut microbiota modulate neuroinflammation [36]. Indeed the gut microbiota, acting on the intestinal production of serotonin, can play a role in the activation of the immune system, and it can influence its, interacting directly with T and B cells [36]. Interestingly, mucosal-associated invariant T (MAIT) cells that seem strictly interconnected with intestinal microbiota, which are absent in germ-free mice, localize in the CNS at MS onset and for many years [37]. Furthermore, they express CD103 as resident cells do and release pro-inflammatory cytokines, such as IFN\(\gamma\) and IL-17, with a detrimental effect for the CNS. Indeed, an open question that is relevant for MS is establishing if gut microbiota can interact with the blood-brain barrier (BBB). Some bacterial wall components, such as acid lipoteichoic (LTA), have exchanges with the brain endothelium passing through the BBB. Other species cross the BBB indirectly by taking advantage of peripheral immune cells or simply during BBB damage [38]. Furthermore, LTA and LPS can modulate the BBB permeability, attracting pro-inflammatory cytokines and changing BBB biology [39]. These findings support the hypothesis that gut microbiota could trigger and/or exacerbate neuroinflammation processes, worsening MS disease. An increasing number of microbiome studies reveals a bidirectional cross-talk between microbiota and the endocrine system with bacteria able to produce, respond to, and regulate the effect of hormones [40]. In detail, sex hormones have been demonstrated to influence gut microbiota composition (Figure 1) [40]. In healthy people, sex influences the gut microbiome composition. Healthy male subjects have a higher abundance of _Bacteroides_ compared to females [41]. Postmenopausal woman gut microbiota did not differ from adult males [41]. In a study comparing male and female gut microbiota, when correcting for other possible confounding factors, such as diet and BMI, women had a lower abundance of _Bacteroides_, and in women only, obesity determined a more pro-inflammatory gut microbiota composition compared to lean subjects [10]. For many autoimmune disease animal models, gender bias occurs more often in specific pathogen free (SPF) female mice, and the risk can be reversed by transplanting the gut microbiome obtained from SPF male mice [42]. The transplantation of the male gut microbiome at weaning has been associated with increased levels of testosterone and changes in serum metabolic profile [42]. Members of the gut microbiome are reported to interact with steroids, possibly impacting the steroid balance at the intestinal level [42]. Specific taxa have the capacity to metabolize sex steroid hormones. For instance, the intestinal commensal _Clostridium_ expresses enzymes involved in glucocorticoid conversion into androgens [42]. The _Slackia_ species, a common member of the gut microbiome, can exert the interconversion of B-estradiol and estrogen.