Gut microbes may reveal why diabetes raises heart disease risk

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.May 13 2026

By combining fecal metagenomics with plasma metabolomics, researchers uncover candidate gut and metabolic markers that may help explain the gut-heart links behind coronary complications in type 2 diabetes.

Study: The gut microbiota and metabolomics in the pathogenesis of type 2 diabetes mellitus combined with coronary atherosclerotic heart disease. Image Credit: FOTOGRIN / Shutterstock

In a recent study published in the journal Scientific Reports, researchers investigated the specific microbial and metabolic signatures of patients with type 2 diabetes mellitus (T2DM) and compared them with those of patients with T2DM combined with coronary atherosclerotic heart disease (T2DM-CAD) to elucidate how intestinal imbalances may be associated with cardiovascular complications.

The study integrated metagenomic sequencing and plasma metabolomics, which together identified eight gut microorganisms with potential diagnostic relevance and eight characteristic metabolites associated with these pathologies. Notably, Bacteroides sp._CAG_875 and the metabolite 12-ketolithocholic acid (12-ketoLCA) emerged as potential candidate biomarkers for distinguishing T2DM-CAD from comparator groups, pending further validation.

T2DM-CAD Gut Microbiome Background

Diabetes is one of the most prevalent chronic health conditions afflicting today’s society. Public health reports suggest that the metabolic condition currently affects more than 370 million people worldwide, with predictive models suggesting these figures will reach 700 million by 2045.

Type 2 diabetes (T2DM) is the most prevalent form of diabetes and is clinically classified as a heterogeneous disorder characterized by insulin resistance and chronic low-grade inflammation. This insulin resistance and inflammation have previously been linked to atherosclerosis (the hardening of the arteries) and coronary atherosclerotic heart disease (CAD), but the biological pathways elucidating these associations remain understudied.

In parallel, clinical research increasingly aims to understand the role of the gut microbiome, the vast community of "commensal" or friendly microorganisms, as the "second genome" that maintains human homeostasis. An imbalance in these microbial communities (“dysbiosis”) has previously been linked to obesity and metabolic dysfunction.

Unfortunately, most studies investigating either the gut microbiome or T2DM-associated blood metabolites have done so in isolation, resulting in a gap in clinical understanding of how these two systems interact in diabetic patients who develop coronary complications.

Integrated Omics Case-Control Study Design

This study aimed to address this knowledge gap by unraveling how interactions between gut bacteria and their small-molecule metabolites may differ between T2DM patients with and without CAD. Its methodology comprised a three-group case-control design involving 30 participants. Participants specifically comprised 10 healthy controls and an equal number of T2DM patients and T2DM-CAD patients, recruited between July and November 2022. Data collection included participants’ demographic and medical histories, as well as their fecal and blood samples.

Participants’ fecal samples were subjected to high-throughput metagenomic sequencing (12 Gb per sample read depth) via the Illumina NovaSeq 6000 platform for gut microbiome characterization. Subsequently, their plasma samples underwent Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) using an ACQUITY UPLC-Xevo TQ-S system to identify and quantify small-molecule metabolites.

Diagnostic biomarker identification was achieved by processing metagenomics and metabolomics data using Random Forest Analysis (RFA). Microbe-metabolite interactions were identified using Spearman correlation, and diagnostic accuracy was determined by calculating the Area Under the Curve (AUC) for Receiver Operating Characteristic (ROC) curves.

Microbial and Metabolite Biomarker Findings

Summary clinical evaluation data statistically confirmed that body mass index (BMI), blood glucose (GLU), triglycerides (TG), C-reactive protein (CRP), and similar baseline diagnostic biomarkers differed significantly among the three sample groups (p < 0.05).

Results from the metagenomic analysis identified a total catalog of 1,909,245 genes, finding that while overall microbial richness and diversity (alpha diversity) remained stable across groups (P > 0.05), the specific species composition shifted substantially.

Furthermore, the data revealed that 17 clinical indicators were significantly correlated with 30 specific gut microbes, including Prevotella disiens (significantly correlated with heart disease indicators) and Sutterella wadsworthensis, thereby highlighting the potential relevance of species-level microbial differences to cardiovascular complications in T2DM.

The study identified Bacteroides sp._CAG_875 as a candidate marker for distinguishing T2DM-CAD, given its promising AUC of 0.90 when comparing controls to T2DM-CAD patients in this small discovery cohort. Similarly, Anaerobutyricum hallii, a species previously known for its role in alleviating diabetes, was identified as a key intestinal microbe in T2DM-CAD patients (AUC = 0.82).

The metabolomic analysis measured 183 metabolites, identifying 42 that were differentially abundant based on a Variable Importance in Projection (VIP) score (> 1.5). Of these, 12-ketolithocholic acid (12-ketoLCA) stood out as a recurring candidate marker across two group comparisons, appearing in both T2DM and T2DM-CAD comparisons with a diagnostic AUC of 0.80.

Finally, linear regression analyses revealed that fructose was positively correlated with the bacteria g-Megamonas and g-Alistipes, which the authors hypothesized may be linked to T2DM-CAD risk through their association with fructose metabolism.

Gut-Heart Axis Clinical Implications

This study is among the few to use an integrated omics analysis to demonstrate that significant shifts in the "gut microbiota-metabolite-host pathway" are closely related to the pathogenesis of T2DM-CAD. The promising ROC performance of Bacteroides sp._CAG_875 and 12-ketoLCA (AUC > 0.80) suggests these molecules could serve as candidate molecular indicators for early disease warning and precise diagnosis if validated in larger, independent cohorts.

While the study is limited by its relatively small sample size and correlation-informed (not causation) results, it highlights the clinical potential of the "gut-heart axis" as a target for future therapeutic interventions to prevent macrovascular complications in diabetic patients.

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