Role of a gut microbiota metabolite indole lactate in myelin repair - Project Summary Multiple sclerosis (MS) is the most common neurodegenerative disease in young adults. Changes in the serum metabolome have been reported in MS and our preliminary data demonstrate that they are also associated with MS disease severity. We specifically show that aromatic amino acid-derived lactate metabolites, produced by the gut microbiota, are reduced in MS and higher levels are associated with lower disease severity. One of the metabolites indole lactate (ILA) besides being associated with lower disease severity also ameliorates neuroinflammation and promotes remyelination in animal models of MS. Our long-term goals are to demonstrate that ILA may be a novel therapeutic agent to promote myelin repair in people with MS. The objectives of this R01 application are to demonstrate that ILA promotes remyelination in vivo in the presence of barriers to remyelination that are present in MS and to understand the mechanism by which it promotes remyelination. The rationale for this project, supported by preliminary data, is that lower ILA levels in circulation are related to more severe MS and in vitro ILA promotes oligodendrocyte precursor cell (OPC) differentiation while also promoting remyelination in the cuprizone model of demyelination in vivo. The proposed research study will pursue two specific aims: 1) to demonstrate the ability of ILA to overcome barriers to remyelination in MS; 2) to identify the mechanism by which ILA promotes remyelination. For the first aim, we will first test the effects of ILA on remyelination in two models – the adoptive transfer cuprizone model of demyelination, the lysolecithin-induced focal spinal cord demyelination model and an adoptive transfer lysolecithin model to compare the effects of oral ILA to vehicle treatment using various histopathological measures. We will then test the ability of ILA to promote remyelination in the setting of aging by testing ILA in the cuprizone and lysolecithin models in aged (18-month-old) mice. For the second aim, we will utilize OPC-specific and myeloid-specific knockouts of arylhydrocarbon receptor (AhR) to understand the mechanism by which ILA mediates its reparative effects. We will also plan to utilize single cell RNA and ATAC sequencing of tissues obtained from cuprizone and lysolecithin mice treated with ILA or vehicle to determine whether additional mechanisms besides AhR may be involved and whether other cell types may be mediating the effects 0f ILA. This project is innovative in that it proposes to test a novel hypothesis that a gut microbiota-derived metabolite ILA promotes differentiation of OPCs and mediates myelin repair in animal models of MS and also utilizes several novel tools to accomplish the proposed aims. The proposed research is significant because it could identify a novel therapeutic agent that could promote myelin repair and be used to treat this common disabling neurological disorder.
