Effect of Gut Microbiome Dysbiosis in the Pathobiology of Multiple Sclerosis

Despite the association between gut microbiota and multiple sclerosis (MS) being increasingly appreciated, the mechanism through which gut bacteria and their metabolites modulate disease in MS is poorly understood. We and others have shown a link between perturbations in the gut microbiota in MS patients. Gut

dysbiosis, a qualitative alteration in healthy gut microbiota is characterized by an increased abundance of inflammation-promoting bacteria (pathobiont) and depletion of beneficial bacteria (symbionts). As MS is an inflammatory disease, an increase in pathobionts and/or decrease in symbionts might promote pro-

inflammatory environment influencing disease development and progression. Pathobionts are known to promote pro-inflammatory environment by causing increased intestinal permeability which leads to leaky gut syndrome by allowing leakage of bacterial products (LPS and other inflammatory mediators) into the systemic

circulation. Increased systemic levels of gut permeability linked inflammatory mediators (GPLIMS) can induce inflammation through canonical and non-canonical pathways including suppression of specialized pro-resolving mediators (SPMs), a set of naturally occurring molecules produced within our body to dampen inflammation. It

is important to highlight that gut microbiota help in production of SPMs from diet. Alteration in the ratio of GPLIMs and SPMs could modulate the disease course and clinical outcomes. Additionally, depletion of symbionts responsible for maintaining immune homeostasis can also promote a pro-inflammatory environment

by tilting balance between pro- and anti-inflammatory immune responses towards pro-inflammatory response. We have earlier reported that multiple gut bacteria associated with metabolism of dietary phytoestrogens into Equol is depleted in MS patients, thus highlighting a critical role of phytoestrogen metabolism in mediating

beneficial effect of gut microbiome. Although, an inverse correlation between leaky gut and Equol had been reported in some inflammatory diseases, its role in the pathobiology of MS is unknown. There is a knowledge gap in our understanding about the mechanism(s) of gut dysbiosis in MS patients. To this end, our proposal is significant and critical to fill this void by determining the relative

contributions of pathobionts (leaky gut syndrome) and symbionts (phytoestrogen metabolism) in MS. Our long- term goal is to determine mechanism(s) through which gut bacteria and their metabolites influence protection from or predisposition/progression to MS. We hypothesize that gut dysbiosis promotes MS through

enrichment of pathobionts which leads to leaky gut syndrome in addition to depletion of beneficial Equol producing gut bacteria. We, therefore, propose to determine the significance of leaky gut and Equol producing gut bacteria in the pathogenesis of MS in the following three aims. In the first aim, we will test the hypothesis

that gut dysbiosis in MS patients results in leaky gut and increased pro-inflammatory (GPLIMs) and decreased anti-inflammatory mediators specifically SPMs. Second aim will enable us to test the hypothesis that treatment naïve MS patients will have reduced levels of equol and equol producing bacteria compared to HCs. In the last

aim, we will test the hypothesis that MS patients on disease modifying therapies (DMTs) will restore the levels of SPMs and equol/equol synthesizing bacteria. By the end of this study, we expect to identify the potential mechanism by which gut dysbiosis influences clinical outcomes in MS patients, especially the significance of

GPLIMs, SPMs, and Equol producing bacteria. We expect to identify potential therapeutic biomolecules such as SPMs and gut commensal bacteria which can suppress disease in the murine model of MS. This project has the potential to discover an indigenous set of biomolecules that can be utilized in clinical medicine as

potential biomarkers. Thus, data from our study will enable us to take a bench side discovery to the bedside in MS patients.