Dietary leucine restriction remodels the gut microbiota and serum glycerophospholipids to combat obesity

Abstract
Background The gut microbiota mediates dietary impacts on host metabolism, but the roles of specific amino acids remain elusive. We investigated the mechanism by which dietary leucine restriction combats obesity.
Methods Combining Mendelian randomization in humans with intervention studies in high-fat diet mice, we assessed leucine restriction's effects. Mechanisms were probed via fecal microbiota transplantation, 16S rRNA sequencing, and serum non-targeted metabolomics.
Results Human genetics suggested a causal role for leucine in obesity. In mice, leucine restriction ameliorated metabolic disorders, and this effect was transferable by microbiota transplantation. We identified Faecalibaculum rodentium (F. rodentium) as a key enriched bacterium. Monocolonization with this strain replicated the anti-obesity benefits, which were linked to upregulated levels of the metabolite glycerophospho-N-oleoyl ethanolamine (GNOE), which correlated negatively with obesity phenotypes and was implicated in lipid and bile acid metabolism.
Conclusion Dietary leucine restriction confers metabolic benefits by enriching the gut microbe F. rodentium, which modulates host glycerophospholipid metabolite GONE to reduce obesity.
Key words: Obesity; Leucine restriction; Gut microbiota; Faecalibaculum rodentium; Glycerophospho-N-oleoyl ethanolamine