Obesity-enriched gut microbe degrades myo-inositol and promotes lipid absorption

Highlights•A Megamonas-dominated, enterotype-like cluster is associated with human obesity•Megamonas and polygenic risk exhibit an additive impact on obesity•Megamonas rupellensis promotes intestinal lipid absorption, leading to obesity in mice•Gut microbial myo-inositol degradation enhances lipid uptake and obesitySummaryNumerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of Megamonas and polygenic risk exhibited an additive impact on obesity. Megamonas rupellensis possessed genes for myo-inositol degradation, as demonstrated in vitro and in vivo, and the addition of myo-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with M. rupellensis or E. coli heterologously expressing the myo-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for M. rupellensis as a myo-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.Graphical abstract