As described above, the microbiota is influenced by genetics, nutrition, and other lifestyle factors. ways to resolve the vast inter-individual diversity of cerebrovascular disease and mechanisms for personalized prevention and Fenticonazole nitrate treatment. and strains of spp, and a reduction of is gaining attention as a possible next-generation probiotic.45 improves several metabolic parameters in both model mice46 and even in a proof-of-concept exploratory human study.47 Various studies demonstrated the effect of microbiota-derived metabolites of carbohydrates and proteins on host metabolism. Reduced production of SCFAs, including acetate and propionate, has inconsistent effects on energy CD4 homeostasis and glucose and lipid metabolism.48 Acetate, the most abundant SCFA, induces glucagon-like peptide (GLP)-1 production in enteroendocrine L cells through G-protein-coupled receptor (GPR)-43, improving insulin sensitivity.49 Additionally, rodent studies demonstrated that acetate reaches the hypothalamus through the BBB, which induces the production of gamma-aminobutyric acid, resulting in suppression of central appetite.50 On the other hand, propionate causes peptide YY production through GPR41, which inhibits intestinal motility and increases the absorption rate of nutrients through the intestinal epithelium.51 The advance of metabolomic analyses enabled discovery of the molecular mechanisms between bacteria-derived metabolites of amino-acids and host glucose metabolism. Important examples are the beneficial role of indole and its derivatives and the harmful effect of imidazole propionate, a microbial metabolites of histidine. Indole and its derivatives increase the production of the incretin hormone GLP-1 from intestinal enteroendocrine cells and modulate innate and adaptive immune response via the aryl hydrocarbon receptor.52 Koh et?al.53 identified that imidazole propionate impairs insulin receptor activation via the p38-p62-mammalian target of rapamycin complex1 (mTORC1) pathway in peripheral tissues. Furthermore, microbial-derived metabolites control bile acid homeostasis via farnesoid X receptors, which can also influence glucose metabolism. 54 Hypertension Hypertension is the leading cause of stroke and heart diseases. Genetic and environmental factors influence the individual variation of increased blood pressure (BP). Extensive populational genome-wide association studies (GWAS) identified several genetic factors associated with blood pressure control, including the renin-angiotensin-aldosterone system, sympathetic nervous system, atrial natriuretic peptide signaling, and dopaminergic system; however, these genetic factors contribute to only 3% of hypertension in humans.55 Now, growing evidence supports different roles of the GI tract in BP regulation, not only as an organ for salt absorption, but also controlling autonomic and endocrine functions. The gut microbiome in patients with hypertension is comprised by a higher percentage of bacteria from the genus and expressing the collagen-binding protein Cnm (Cnm-positive have gene among Japanease population.85 We have reported that Cnm-positive in the oral cavity is associated with both Fenticonazole nitrate hypertensive ICH and deep CMBs in a hospital cohort study,86 and cognitive decline accompanied by increased burden of CMBs in a populational cohort study.87 We hypothesized that Cnm-positive translocates from the oral cavity into the Fenticonazole nitrate bloodstream, adheres to and invades cerebral small vessels, and evokes local inflammation.79,86 However, to elucidate this brain-oral-microbial axis, a more detailed molecular assessment in vitro and in animal models, and more extensive cohort studies in multiethnic populations Fenticonazole nitrate are necessary. Cerebral amyloid angiopathy Even though there is little human data investigating the role of the microbiome in patients with cerebral amyloid angiopathy (CAA), there is accumulating evidence about Alzheimers disease (AD), which has shared pathophysiology with CAA. The amyloid cascade hypothesis suggests that vascular amyloid- (A) accumulation plays a central role in elucidating the pathogenesis of AD.88 However, repeated failures of anti-amyloidogenic trials prompted us to explore the brainCmicrobiota axis as an alternative to the amyloid cascade hypothesis, from initiation to aggravation Fenticonazole nitrate of AD and CAA. We have proposed that functional bacterial amyloid proteins in the gut may cause cross-seeding of A via a prion-like mechanism. In studies of aged rats, we showed that exposure to bacterial amyloid initiates cross-seeding of cerebral alpha synuclein aggregation and neuroinflammation.89 For instance, curli, a functional amyloid protein expressed by and other bacteria, can accelerate cross-seeding of amyloid formation in vivo and in vitro.90.