Abstract

Background: Gut microbiota modulates obesity through metabolic, inflammatory, and neuroregulatory pathways. While fecal microbiota transplantation (FMT) from obese donors typically induces obesity in mice under high-fat diets (HFD) or isocaloric feeding regimens, emerging evidence suggests regional dietary variations may confound microbial composition and functional outcomes.

Results: Germ-free mice receiving gut microbiota from Asian lean or obese donors exhibited no significant body weight changes throughout the study under a standard chow diet. However, transplantation of obesity-associated microbiota reduced food intake while inducing lipid dysregulation in the absence of glucose metabolism alterations. Longitudinal 16S rRNA sequencing in both human donors and FMT mice demonstrated conserved reductions in microbial diversity and richness across species barriers. Metabolomic profiling revealed that recipient mice of obese-derived microbiota developed distinct metabolic perturbations, including lipid metabolism dysfunction, imbalances in branched-chain amino acid (BCAA) metabolism. Integrated multi-omics analysis identified g. Sellimonas as a key microbial regulator, mechanistically linking gut microbiota composition to both lipid metabolism dysregulation and appetite suppression through coordinated modulation of WAT gene expression profiles and circulating or fecal metabolites.

Conclusions: Our findings establish that obesity-associated microbiota can independently regulate metabolic homeostasis and appetite circuits without driving weight gain under normocaloric conditions. This work provides mechanistic clarity for microbiota-mediated obesity models and highlights g. Sellimonas targeted interventions as a novel therapeutic strategy for metabolic disorders.

 Keywords: Gut microbiota, Fecal microbiota transplantation (FMT), Obesity, Lipid metabolism dysregulation, Sellimonas.