Multi-omics identification of a microbial metabolite driving OXPHOS-mediated epithelial damage in experimental autoimmune encephalomyelitis.

Bowel syndrome is a prevalent and debilitating symptom in patients with multiple sclerosis (MS), substantially impairing their quality of life. However, the underlying mechanisms of MS development remain poorly understood. In this study, we demonstrated that intestinal epithelial cells (IECs) and the mucosal barrier were disrupted during experimental autoimmune encephalomyelitis (EAE) induction, driven by the inhibition of mitochondrial oxidative phosphorylation (OXPHOS). Proteomic analysis confirmed alterations in OXPHOS complexes, with a pronounced decrease in the expression of cytochrome c oxidase and ATP synthase subunits in small intestinal epithelial cells (sIECs). We identified a gut microbiota-derived metabolite that induces IEC dysfunction by downregulating OXPHOS protein complexes. Specifically, metabolomic analysis revealed an enrichment of phenyllactic acid (PLA), a phenolic acid typically produced by Lactobacillus murinus, in the cecal contents of EAE mice. Our findings indicate that PLA actively downregulates OXPHOS complexes and restrains maximal mitochondrial respiration. Using a multi-omics approach, this study elucidated a potential mechanism by which gut microbiota dysbiosis observed in EAE mice compromises IEC integrity and disrupts the mucosal barrier. [BMB Reports 2026; 59(2): 151-160].