## 5 Oral Microbiome in MS
This study showed a specific microbial fingerprint observed in oral swabs in MS patients: the microbial stool changes associated with disease severity at baseline and the long-term reversibility of these compositional differences following B-cell depletion. In conclusion, the study suggests that not only stool, but also oral microbiota composition is altered in MS patients, defining a precise disease signature. Furthermore, treatment with B-cell depleting antibodies in MS patients does not only reduce the overall disease activity, but also associates with specific changes in stool and oral microbiota composition. In the light of these findings, dysbiotic oral bacteria can lead to systemic inflammation and contribute to neuroinflammation by acting on: (a) the release of proinflammatory cytokines into the bloodstream, which eventually reach the brain; (b) gut microbiota alterations through the oral-gut-brain axis; and (c) crossing the BBB via the trigeminal nerve. In the brain, microglia can react by regulating the immune response while astrocytes amplify the release of proinflammatory cytokines and neuroinflammation. Importantly, although the intra-subject variability of the oral microbiome is extremely marked, cultures of a person's saliva share some similarity with the stool coming from the same subject, suggesting a continuum in the individual oral-gut microbiota along the GI tract [60]. Unfortunately, there are not studies on the sex bias in the composition of the oral microbiome in the context of autoimmune diseases. However, this line of research might be particularly interesting to pursue since saliva collection could be the easiest way to detect gut microbiome changes correlated with an increased risk to develop MS. Furthermore, an oral microbiome signature could be a more specific marker in MS disease progression, and saliva could represent, in perspective, a source of potential analytes monitoring the progression of MS and, more broadly, of neurodegenerative diseases [61]. Saliva is an easy biofluid to study due to its non-invasive and inexpensive collection procedure. In this way, saliva could be helpful in the screening of a broad group of healthy individuals and in the early diagnosis of MS. At the time being, the differential diagnosis of neurodegenerative diseases is complex and relies on the biomarker levels present in the cerebrospinal fluid. Compared with other standard tests and imaging procedures performed to diagnose neurological diseases, saliva could help detect an early specific marker at the earliest time [62]. Brain-derived extracellular vesicles (EVs) are also detectable in saliva. EVs secreted from different types of neural cells, such as neurons, astrocytes, microglia, and oligodendrocytes, present on their molecular surface markers almost completely specific to the donor cell [63]. They can cross the blood-brain barrier, and it is possible to speculate that, through the brain-axis consisting of the trigeminal nerve, they may reach the salivary glands where EVs are supposedly secreted with the saliva. Through their cargo, EVs can become a reservoir of potential peripheral biomarkers, mirroring brain pathology. In this regard, MS was, more than 30 years ago, the first neurological disorder identified where the release of EVs is closely related to the disease progression and neuroinflammation [64]. Thus, detecting specific CNS-derived EVs in saliva and other peripheral biofluids could represent a non-invasive and easy way to analyze the CNS status remotely [64]. In this line, EVs should deserve greater attention from the scientific community considering that they provide information not only in the pathogenesis, but also as therapeutic tools due to the intrinsic possibility of EVs carrying disease-modifying drugs back to the CNS donor cell.