Food Funct. 2026 Sep 1. doi: 10.1039/d6fo03036j. Online ahead of print.
ABSTRACT
Prebiotic inulin improves obesity-related metabolic disturbances, yet its clinical efficacy shows marked interindividual heterogeneity. The key microbial players, interspecies interactions, and downstream effector pathways governing differential responsiveness remain poorly defined. This study is aimed at identifying functional bacteria driving response heterogeneity, delineating the underlying mechanisms, and establishing a predictive biomarker system. Humanized obese mice were generated by high-fat diet preconditioning, and donor-specific response differences were recapitulated by one-to-one fecal microbiota transplantation. Causal links were validated via multi-omics integration, in vitro co-culture, in vivo bacterial recolonization/clearance, and independent cohort verification. Response heterogeneity was driven by antagonism between Desulfovibrio desulfuricans and Roseburia intestinalis. HS derived from D. desulfuricans directly suppressed R. intestinalis growth and butyrate production, and this microbial interaction axis was functionally relevant to the heterogeneous metabolic responses to inulin. An inulin response index (IRI) based on the Roseburia-to-Desulfovibrio abundance ratio prospectively predicted responder phenotypes. D. desulfuricans gavage markedly attenuated inulin benefits in high-responder microbiota-colonized mice, while sodium molybdate-mediated HS inhibition, R. intestinalis or sodium butyrate supplementation restored metabolic benefits in low-responder microbiota-colonized mice. Butyrate conferred protection by strengthening gut barrier function, activating GLP-1/PYY secretion, and suppressing adipose inflammation. We uncover a novel D. desulfuricans-HS-R. intestinalis-butyrate antagonistic axis that mechanistically explains inulin response heterogeneity, providing a mechanistic rationale for personalized nutrition and supporting a clinically translatable predictive index and targeted intervention strategy.
PMID:42678246 | DOI:10.1039/d6fo03036j