Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression
Menée à l'aide de lignées cellulaires, de modèles murins et d'organoïdes dérivés de tumeurs colorectales d'origine humaine, cette étude met en évidence un mécanisme par lequel une alimentation riche en graisses et l'obésité favorisent la progression tumorale en modifiant le métabolisme des cellules épithéliales via l'appauvrissement du microbiote en Bacteroides ovatus, bactéries commensales sécrétrices d'acide gamma-aminobutyrique
Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal Bacteroides ovatus, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K–HIF1
α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient B. ovatus mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type B. ovatus markedly reduces tumor burden. These findings identify a microbiota
–neurotransmitter–metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.
Nature Communications , article en libre accès, 2026