Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study

Abstract

The current body of research points to a notable correlation between an imbalance in gut microbiota and the development of type 2 diabetes mellitus (T2D) as well as its consequential ailment, coronary artery disease (CAD). The complexities underlying the association, especially in the context of diabetic coronary artery disease (DCAD), are not yet fully understood, and the causal links require further clarification. In this study, a bidirectional Mendelian randomization (MR) methodology was utilized to explore the causal relationships between gut microbiota, T2D, and CAD. By analyzing data from the DIAGRAM, GERA, UKB, FHS, and mibioGen cohorts and examining GWAS databases, we sought to uncover genetic variants linked to T2D, CAD, and variations in gut microbiota and metabolites, aiming to shed light on the potential mechanisms connecting gut microbiota with DCAD. Our investigation uncovered a marked causal link between the presence of Oxalobacter formigenes and an increased incidence of both T2D and CAD. Specifically, a ten-unit genetic predisposition towards T2D was found to be associated with a 6.1% higher probability of an increase in the Oxalobacteraceae family's presence (β = 0.061, 95% CI = 0.002-0.119). In a parallel finding, an augmented presence of Oxalobacter was related to an 8.2% heightened genetic likelihood of CAD (β = 0.082, 95% CI = 0.026-0.137). This evidence indicates a critical pathway by which T2D can potentially raise the risk of CAD via alterations in gut microbiota. Additionally, our analyses reveal a connection between CAD risk and Methanobacteria, thus providing fresh perspectives on the roles of TMAO and carnitine in the etiology of CAD. The data also suggest a direct causal relationship between increased levels of certain metabolites -proline, lysophosphatidylcholine, asparagine, and salicylurate -and the prevalence of both T2D and CAD. Sensitivity assessments reinforce the notion that changes in Oxalobacter formigenes could pose a risk for DCAD. There is also evidence to suggest that DCAD may, in turn, affect the gut microbiota's makeup. Notably, a surge in serum TMAO levels in individuals with CAD, coinciding with a reduced presence of methanogens, has been identified as a potentially significant factor for future examination.

Bridging the gap: exploring the causal relationship between metformin and tumors

“…The findings revealed that the intestinal family Oxalobacteraceae significantly increased compared with the control group ( Costabile et al, 2022 ). Another MR analysis demonstrated that an increased presence of the family Oxalobacteraceae was associated with the risk of T2DM ( Zeng et al, 2024 ). Studies have shown that the therapeutic effects and side effects of metformin are closely related to changes in intestinal flora ( Forslund et al, 2017 ; Wu et al, 2017 ).…”

DataSheet7.PDF

“…The findings revealed that the intestinal family Oxalobacteraceae significantly increased compared with the control group (Costabile et al, 2022). Another MR analysis demonstrated that an increased presence of the family Oxalobacteraceae was associated with the risk of T2DM (Zeng et al, 2024). Studies have shown that the therapeutic effects and side effects of metformin are closely related to changes in intestinal flora (Forslund et al, 2017;Wu et al, 2017).…”

DataSheet5.CSV

“…The findings revealed that the intestinal family Oxalobacteraceae significantly increased compared with the control group (Costabile et al, 2022). Another MR analysis demonstrated that an increased presence of the family Oxalobacteraceae was associated with the risk of T2DM (Zeng et al, 2024). Studies have shown that the therapeutic effects and side effects of metformin are closely related to changes in intestinal flora (Forslund et al, 2017;Wu et al, 2017).…”