Gut commensal Bacteroides-derived pantothenic acid alleviates metabolic syndrome

Pantothenic acid (PA), or vitamin B5, can be synthesized by gut commensals, but the contribution of microbial PA to metabolic health remains unclear. Here, we find that microbial PA supply is reduced in individuals with metabolic syndrome (MetS) and is associated with impaired gut barrier function and disease severity. Tracing microbial PA identifies Bacteroides fragilis as a key contributor, with panC required for PA biosynthesis, as confirmed by isotope tracing, bacterial culture, and germ-free colonization. In MetS models, colonization with wild-type, but not ΔpanC B. fragilis, restores PA, preserves gut barrier integrity, reduces endotoxemia, and improves metabolic dysfunction. Mechanistically, microbial PA requires host pantothenate kinase activity, as silencing pantothenate kinase 2/3 (PANK2/3) in colonic organoids and in vivo reduces coenzyme A (CoA)/acetyl-CoA metabolism, suppresses Krüppel-like factor 4 (KLF4)-associated differentiation programs, and blunts the protective effects of microbial PA. Finally, a plant-derived polysaccharide enriches PA-producing Bacteroides and restores colonic PA, highlighting a strategy for colonic homeostasis and metabolic health.