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. 2025 Mar 24;25(1):79.
doi: 10.1186/s12902-025-01863-x.

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

Zhichao Ruan  1 , Jiangteng Liu  1 , Jinxi Zhao  2
Affiliations

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

Zhichao Ruan et al. BMC Endocr Disord. .

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.

Keywords: Genetic variants; Gut microbiota; Mendelian randomization; Type 2 diabetes mellitus.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Diagram for key assumptions of mendelian randomization analyses
Fig. 2
Fig. 2
Forest plot of mendelian randomization analysis of gut microbiota and T2DM subtypes
Fig. 3
Fig. 3
Taxonomic network visualization of gut microbiota associated with T2DM subtypes identified through mendelian randomization
Fig. 4
Fig. 4
UpSet plot of gut microbiota associations across six diabetes phenotypes
Fig. 5
Fig. 5
Forest plot of shared gut microbial taxa between type 2 diabetes mellitus and its subtypes
See this image and copyright information in PMC

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