Intestinal microbiota contributes to the heterogeneity of fat deposition by promoting mitochondrial fatty acid β-oxidation

The gut microbiota plays a crucial role in lipid metabolism in both humans and animals. However, the specific contributions of gut microbiota and their associated metabolites to fat deposition, as well as the underlying mechanisms, remain largely unexplored. In this study, we demonstrated that the intestinal microbiota mediated the heterogeneity of mesenteric fat index (MFI), as evidenced by fecal microbiota transplantation (FMT) experiments. Notably, analysis of the 16S rRNA gene amplicon sequencing of 44 samples revealed a significantly higher abundance of <i>Cetobacterium somerae</i> in the Low MFI group, with a positive correlation to reduced MFI. Serum metabolomics analysis confirmed that L-Carnitine emerged as the most differentially abundant metabolite in the Low MFI group and exhibited a strong positive correlation with <i>C. somerae</i> abundance. Metagenomic analysis showed that microbial genes related to L-Carnitine biosynthesis were significantly enriched in the Low MFI group. Further, <i>C. somerae</i> was isolated and cultured, and its subsequent monocolonization in germ-free zebrafish and tilapia demonstrated its lipid-lowering effects by enhancing mitochondrial fatty acid <i>β</i>-oxidation. Whole genome sequencing demonstrated <i>C. somerae</i> could encode the [EC:1.2.1.3] gene, which promotes the production of 4-trimethylammoniobutanoate, a precursor of L-Carnitine, thereby enhancing L-Carnitine biosynthesis by the host and gut microbiota, leading to the reduced fat deposition in Nile tilapia. In conclusion, <i>C. somerae</i>, a core gut microbe with high abundance in aquatic teleost intestines, plays an important role in host lipid metabolism. This study advances our understanding of how core gut microbes shape host phenotypes and provides novel insights into manipulating core gut colonizers to reduce fat deposition.