A probiotic approach identifies a Treg-centred immunoregulation via modulation of gut microbiota metabolites in people with multiple sclerosis and healthy individuals.

BACKGROUND: Modulation of the gut microbiota composition has been suggested as a potential disease modifying therapy in immune-mediated diseases such as multiple sclerosis (MS). However, a conclusive mechanism linking gut microbiota modulation to peripheral immune responses has remained elusive so far. METHODS: In this exploratory cohort study, people with MS (pwMS) and healthy controls (HC) supplemented a lactobacilli-rich probiotic for two or six weeks and were additionally investigated six weeks after the last intake. Immune cell phenotyping was performed in blood samples, complemented by mRNA expression analysis, serum cytokine measurements, and Treg suppression assays. Besides gut microbiota composition analysis, metabolite production was investigated in stool and serum. Links between metabolites and peripheral immune system were investigated in in vitro T cell differentiation assays. FINDINGS: In peripheral blood, Treg cells increased in both groups, while Th1 cells were significantly reduced in pwMS. This promotion of a regulatory immunophenotype was complemented by increased concentrations of IL-10 in serum and higher expression of IL10 and CTLA4. Functional assays revealed an enhanced suppressive capacity of Treg cells due to the probiotic intervention. The tryptophan metabolite indole-3-acetate (IAA) increased in stool and serum samples of pwMS during the probiotic intake. In vitro, IAA specifically enhanced the formation of IL-10 secreting T cells together with CYP1a1 expression. This effect was blocked by addition of an aryl hydrocarbon receptor (AHR) inhibitor. INTERPRETATION: A lactobacilli-enriched probiotic promotes a regulatory immunophenotype in pwMS, probably by enhancing AHR agonists in the gut. It may be of interest as add-on therapy in immune-mediated diseases such as MS. FUNDING: This study has in part been funded by Novartis Pharma GmbH and BMBF grant no. 01EJ2202B.