Causal associations between gut microbiota and type 2 diabetes mellitus subtypes: a mendelian randomization analysis.

Abstract

Purpose: To investigate the causal relationships between gut microbiota and novel adult-onset type 2 diabetes mellitus(T2DM) subtypes.

Methods: We conducted Mendelian randomization (MR) analyses using genome-wide association data from European populations. Initial MR analyses examined associations between gut microbiota and four T2DM subtypes, followed by validation analyses using type 1 diabetes mellitus(T1DM) and T2DM GWAS data. We also performed bidirectional MR analyses and tested for heterogeneity and pleiotropy across all analyses.

Results: Our MR analyses revealed distinctive associations between gut microbiota and T2DM subtypes: six bacterial taxa with severe insulin-deficient diabetes (SIDD), four with severe insulin-resistant diabetes (SIRD), eight with mild obesity-related diabetes (MOD), and eight with mild age-related diabetes (MARD). These associations were distinct from T1DM findings. Six bacterial taxa were validated in T2DM analyses, with four showing directionally consistent effects: Class Clostridia (OR = 0.57, P = 0.045) and Order Clostridiales (OR = 0.57, P = 0.045) were associated with reduced MOD risk, while species Catus (OR = 1.80, P = 0.007) was associated with increased MOD risk, and genus Holdemania (OR = 2.51, P = 0.004) was associated with increased SIRD risk. No significant heterogeneity or pleiotropy was observed across analyses.

Conclusions: Our MR analyses reveal novel causal relationships between gut microbiota and adult-onset T2DM subtypes, though further validation studies are warranted.