Frontiers in Microbiology · Oct 30, 2026
Association between gut microbiome, genetic risk, and obesity in a retrospective observational employer cohort
By Shreyas V. Kumbhare, Inti Pedroso, Karthik M. Muthukumar et al.
Obesity is a complex metabolic disorder shaped by both genetic and gut microbiome factors, with substantial health and economic consequences. In this observational, cross-sectional study of a self-insured employer cohort, we integrated gut microbiome and host genetic data to identify microbial and genetic signatures associated with obesity. We analyzed gut microbiome profiles (n = 3,283) and polygenic scores (PGS; n = 2,851) for their association with BMI. Using regression models, we identified 48 bacterial taxa and 35 PICRUSt2-inferred microbial metabolic pathways whose abundance was significantly associated with baseline BMI (local false-discovery rate [lfdr] < 0.05). Taxa negatively associated with BMI included Oscillospiraceae (β = −0.00995, 95% CI −0.0133 to −0.00656, lfdr = 2.9 × 10⁻⁷) and UCG-005 (β = −0.0147, 95% CI −0.0194 to −0.00989, lfdr = 1.5 × 10⁻⁷), whereas Lachnoclostridium (β = 0.0120, 95% CI 0.00867 to 0.0154, lfdr = 1.4 × 10⁻¹⁰) and Dorea (β = 0.00958, 95% CI 0.00605 to 0.0131, lfdr = 2.6 × 10⁻⁶) were positively associated. Among inferred pathways, arginine degradation III showed the strongest inverse association with BMI (β = −0.0196, 95% CI −0.0245 to −0.0147, lfdr = 2.1 × 10⁻¹²). In longitudinal data (n = 176), changes in microbial features were not significantly associated with BMI change. Of 105 polygenic scores examined, the BMI PGS was the only score associated with baseline BMI (β = 0.021, 95% CI 0.016 to 0.026, p = 5.1 × 10⁻¹⁵, lfdr = 2.1 × 10⁻¹¹). In an exploratory interaction analysis restricted to the BMI PGS, Eisenbergiella abundance showed a negative interaction with the BMI PGS (β = −0.99, 95% CI −1.52 to −0.46, p = 2.5 × 10⁻⁴, lfdr = 0.023): the positive association between the BMI PGS and BMI was weaker among participants with higher Eisenbergiella abundance. These findings confirm that genetic factors and gut microbiome composition are each associated with BMI and raise the hypothesis that the association of genetic risk with BMI differs by microbiome composition. The cross-sectional microbiome–BMI associations were robust to adjustment for multiple potential confounders; all associations, including the exploratory interaction, are observational and require independent validation.