Perinatal antibiotics in a db/db mouse model impact obesity and hyperglycemia in a microbiome-dependent manner

Obesity affects over one billion people globally; however, the role of the gut microbiome and host genetics in its manifestation is poorly understood. We demonstrate that genetic obesity in leptin-receptor-deficient db/db mice requires a permissive gut microbiome, which is established during early life. Using perinatally-administered antibiotic cocktail treatment until pups were 8-weeks-old, we demonstrate that microbiome perturbation substantially reduces weight gain and significantly reduces hyperglycemia in homozygous, leptin-receptor-deficient db/db (Hom) mice without altering caloric intake or extraction efficiency. 16S rRNA sequencing revealed that antibiotic treatment depletes Muribaculaceae while enriching Akkermansiaceae and Bacteroidaceae. Differential abundance analysis identified Duncaniella muris, a recently characterized Muribaculaceae species, as the most depleted taxon in antibiotic-treated mice. Oral gavage of cultured D. muris into antibiotic-treated db/db mice restored hyperglycemia to pre-treatment levels without affecting body weight, establishing a direct causal link between this specific microbe and glucose increase. These findings reveal that hyperglycemia is not solely genetic, but depends critically on specific microbiota members in a permissive microbial context.