Abstract
In multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation/ infiltration; and promotes remyelination and in vitro oligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR). Supplementation of ILA, a reductive indole metabolite, restores the gut microbiome’s oxidative/reductive metabolic balance by lowering circulating indole acetate (IAA), an oxidative indole metabolite, that blocks remyelination and oligodendrocyte maturation. The ILA-induced reduction in circulating IAA is linked to changes in IAA-producing gut microbiota taxa and pathways that are also dysregulated in MS. Notably, a lower ILA:IAA ratio correlates with worse MS outcomes. Overall, these findings identify ILA as a new potential anti-inflammatory remyelinating agent and provide novel insights into the role of gut dysbiosis-related metabolic alterations in MS progression.
Competing Interest Statement
The authors declare no conflicts of interest in relation to this work, except for a pending patent (PCT Application No. PCT/US24/27239) concerning the application of ILA as a therapeutic agent for multiple sclerosis. The patent applicant is Johns Hopkins University, and the authors of the patent are PB, KCF, PAC and MK. This patent is currently under review.
