Fecal microbiota transplantation alleviates chronic cerebral hypoperfusion-induced axonal hypomyelination by regulating gut microbiota-derived metabolism and oligodendrogenesis.

Fecal microbiota transplantation (FMT), aimed at rebuilding gut microbiota, has been proposed as a potential therapeutic approach to central nervous system (CNS) diseases. However, the therapeutic effects of FMT against demyelination-related white matter injury (WMI) have not yet been clarified under chronic cerebral hypoperfusion (CCH) condition. We therefore explored the potential roles and mechanisms of FMT on CCH-induced WMI, focusing on myelin integrity, axonal survival, and oligodendrogenesis. FMT restored mitochondrial electron transport chain (ETC) complex I-V activities and promoted the changes of pyruvate metabolism from lactate-generated to acetyl-CoA-generated mode, strengthening mitochondrial ATP production. Furthermore, FMT mitigated CCH-induced demyelination and axonal degeneration, effects mediated in part by oligodendrogenesis-dependent remyelination. Moreover, FMT altered CCH-induced gut microbiota composition by increasing the proportions of some bacterial groups including Verrucomicrobiae, Akkermansiaceae, Verrucomicrobiales, Verrucomicrobiota, Akkermansia, and Akkermansia_muciniphila. These gut microbiota were strongly associated with elevated fecal levels of L-tryptophan, 5-hydroxyindoleacetic acid, and N-a-acetylcitrulline, as well as with increased hippocampal concentrations of L-arginine, L-glutamine, N2-succinyl-L-ornithine, N-acetylornithine, indolepyruvate, indoleacetaldehyde, kynurenic acid, 11, 12-EET, 11, 12-DiHETrE and prostaglandin A2, which were almost involved in tryptophan and arginine related metabolism pathways. This study highlights the beneficial effects of FMT strategy in response to demyelination-mediated WMI under chronic cerebral ischemia condition.