Mining for microbial metabolites associated with disease progression in an age-dependent model of experimental autoimmune encephalomyelitis

People with Multiple Sclerosis (pwMS) exhibit alterations in the gut microbiome and its associated metabolites. Identifying causal links between specific fecal microbiome-derived metabolites and disease susceptibility has been shown using fecal microbial transfer (FMT) into animal models of MS (experimental autoimmune encephalomyelitis, EAE). However, a pipeline that identifies microbiome-associated metabolites that can alter age-dependent disease progression is lacking. We recently established a mouse model of MS disease progression that is induced by adoptive transfer of T H 17 cells from young SJL/J mice immunized with myelin peptide into aged recipients. Adapting this model to FMT, we tested the role of young versus aged murine and human fecal microbial communities on disease progression. We demonstrate that microbiota derived from aged SJL/J mice is not sufficient to drive the progressive disease phenotype in young mice. However, human fecal microbiota from young versus aged donors induced a range of EAE phenotypes. Taking advantage of this variability, we were able to identify fecal communities that promote an “aged EAE” phenotype in chronologically young mice that were associated with distinct microbiota-derived metabolites. Our findings provide a framework for metabolite discovery associated with EAE disease chronicity and severity.