Abstract 54: Body Weight, Human Gut Microbiome, Blood Metabolome, and incident Type 2 Diabetes- A Multi-Omics Integration Study

Background: Few prospective human studies have characterized interrelationships between body weight, gut microbiome, plasma metabolome, and incident type 2 diabetes (T2D). Aims: To identify microbial profiles associated with adiposity, derive its responsive metabolomic signatures, and evaluate their associations with future weight change and incident T2D. Methods: Shotgun stool metagenomes were profiled in the Men’s Lifestyle Validation Study (MLVS; n=924). Body mass index (BMI)-associated microbial species were identified after adjusting for age, total energy, physical activity, alcohol and smoking, and were synthesized into a composite microbiome score. We evaluated its association with waist-to-hip ratio (WHR) and DEXA-measured fat mass in MLVS and validated its association with BMI in female Mind–Body Study (MBS; n=807). Next, the score was examined for its association with prevalent T2D in the multiethnic Micro-Cardio consortium (n=8,117). Prospectively, we tested its predictability of 2-year BMI increase and incident T2D risk in the Micro-N (n=3,318). To further characterize the downstream metabolism of this microbial profile, we linked it to >300 LC–MS metabolites in the MLVS and derived a microbiome-informed multi-metabolite score, which was validated in the MBS. We examined the metabolomic score for incident T2D risk in a prospective cohort, the Nurses’ Health Study (NHS; n=1,057). Results: We identified 23 microbial species associated with BMI in MLVS. The 23-species composite score was correlated with higher BMI (High vs.Low: MLVS β=3.45; MBS β=4.37 both P<0.001), and also correlated with WHR (r=0.45) and fat mass (r=0.73). Additionally, higher microbiome score consistently predicted 2-year BMI increase (β=0.22, P =0.003) and predicts incident T2D in Micro-N (HR [high vs. low] = 2.19, P=0.01), as well as prevalent T2D in the Micro-Cardio (HR [per SD] =1.19, P<0.001). A 32-plasma metabolite signature was responsive to this microbial profile in MLVS (r=0.66) and validated in MBS (r=0.38), and also predicted incident T2D in NHS (RR=2.18, P<0.0001) independent of baseline BMI. Conclusions: We identified and validated a gut microbiome score predictive of adiposity across multiple cohorts, showing consistent associations with plasma metabolomic signatures and increased risk of T2D. This highlights a potential role of the gut microbiome in weight regulation and T2D development, providing new insights into microbiome-informed strategies for T2D prevention.