A commensal-derived sugar protects against obesity by regulating immunometabolism

Obesity is a worsening global epidemic that is partially regulated by the microbiota through unknown factors. We discovered a human commensal bacterium, Clostridium immunis, which prevents and treats obesity in mice by secreting a phosphocholine-modified exopolysaccharide. Loss- and gain-of-function bacterial mutants involving the phosphocholine biosynthesis locus (licABC) revealed that the phosphocholine moiety is required to protect against metabolic disease. This C. immunis exopolysaccharide decreases small-intestinal and visceral fat levels of IL-22, which increases metabolic activity specifically in visceral adipose tissue; C. immunis lacks activity against obesity when IL-22 or group 3 innate lymphoid cells, predominant secretors of IL-22, are absent. Importantly, phosphocholine biosynthesis genes are less abundant in humans with obesity or hypertriglyceridemia, suggesting conserved functions of bacterial phosphocholine. These results define a bacterial molecule-and its key structural motif-that provides immunometabolic control of obesity. More broadly, they highlight a clinically translatable strategy to reduce visceral fat.