## 5 Oral Microbiome in MS  
As outlined above, the interplay between the gut microbiome and host immune system is recently investigated to clarify the pathophysiology of multiple sclerosis (MS). A multi-omics approach to the study of MS revealed that gut microbiome dysbiosis without a unique signature for MS patients can indicate an extra-intestinal pathophysiology associated with an increased circulating proinflammatory marker [45]. In this context, the involvement of the oral microbiome should be considered principally for two reasons: (1) the human oral microbiome harbors the second most abundant, most heterogeneous, and most complex microbial community after the gut one; (2) emerging evidence demonstrates a strictly interconnection between oral and gut microbiome to the extent that oral bacteria can colonize and compete with the gut microbiota (Figure 1) [46; 47]. Furthermore, in a dysbiosis scenario, oral microbes could contribute to stimulate the Th1 of the gut-associated lymphoid tissue, driving an aberrant inflammation and activation of the immune response of the GI tract (Figure 1) [48]. This mutual interaction between the oral and gut microbiome in MS is scarcely investigated since evidence of oral dysbiosis linked to neurological diseases are likewise poorly studied. Despite that, mouth dysbiosis may contribute to neuroinflammation-function indirectly through the spreading of inflammatory mediators or directly by microbes entering the CNS, most likely using the bloodstream [49]. Interestingly, in AD, a Treponema species have been detected in the trigeminal ganglia, suggesting another possible propagating route of oral bacteria to the brain strictly related to MS, as trigeminal neuralgia is common at the early stage of MS [50; 51]. Unfortunately, there is a lack of research regarding the role of the oral microbiome in MS. A few articles described a correlation among oral dysbiosis and MS. In particular, periodontitis has been recently linked to a higher risk of developing different neurodegenerative diseases, including MS [52]. In addition, a case control study using a population-based dataset in Taiwan provides evidence on an association between chronic periodontitis and MS in female, but not male, subjects [53]. In contrast of these findings, in a large Norwegian cohort of MS patients, the association between periodontitis and disease was not demonstrated when taking into account the covariate smoking habits of patients versus controls [54]. Smoking is a notorious risk factor of periodontitis, and it should be considered to have more affordable results. Despite that, the link between periodontitis and MS also seems to be found in _in vivo_ MS mice models. Indeed, the ligature-induced periodontitis (LIP) aggravated MS-like symptoms in EAE mice through the expansion of T helper 17 (Th17) cells [55]. Furthermore, fecal microbiota transplantation from EAE mice with LIP also promoted EAE symptoms. These results highlight the role of oral pathogens in EAE [55]. One of the bacteria implicated in periodontal disease is _Porphyomonas gingivalis_ (_P. gingivalis_) [56]. _P. gingivalis_ levels have been correlated with MS and other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia, dementia with Lewy Bodies, and Huntington's disease [56]. Further, _P. gingivalis_ can be found far from the oral cavity as it has been isolated from women with bacterial vagnosis [56; 57; 58]. This evidence could be in favor of the higher risk of MS in women even though no studies are present in the literature regarding the correlation between _P. gingivalis_ and MS in women. Considering the whole oral microbiome community, the work of [PERSON] and coworkers demonstrated that the oral microbiota composition is altered in patients with MS, and these microbial changes have been linked to MS disease activity and progression [59].