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Deciphering diabetes: how gut microbiota affects disease risk
Last reviewed: 02.07.2025
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In a recent study published in the journal Nature Medicine, a team of scientists examined more than 8,000 metagenomic sequences from people with prediabetes, type 2 diabetes, and normal glycemic status to determine how subtype- and strain-specific microbial features and functions contribute to the pathological mechanisms of type 2 diabetes.
Type 2 diabetes is a rapidly growing global health problem, affecting more than 500 million people worldwide. Pancreatic β-cell mass and function decline over time in patients with type 2 diabetes, with insulin resistance often accompanied by low-grade systemic inflammation.
There is evidence that the gut microbiome plays a critical role in human metabolism and health, often interacting with genetic and environmental factors. Research has also identified distinct gut microbial signatures associated with type 2 diabetes.
However, many of these studies were conducted in small samples or did not control for factors such as obesity or metformin use.
Understanding the role of subtype- and strain-specific gut microbiome functions at the molecular level in type 2 diabetes pathology requires standardized data from a large population.
In this study, the researchers analyzed metagenomic data from 10 cohorts of individuals from Europe, the United States, and China with normal glycemic status, prediabetes, or type 2 diabetes to decipher strain-specific functions and molecular features of the gut microbiota that contribute mechanistically to the pathology of type 2 diabetes.
While previous studies have identified specific microbial species and microbial communities that increase metabolic risks of type 2 diabetes, they did not account for the fact that the microbe’s pathogenic mechanisms are strain-specific. For example, the K12 strain of Escherichia coli is harmless, while the O157 strain is pathogenic.
The researchers obtained more than 8,000 metagenomic sequencing data from six published and four new datasets covering ten cohorts of people with different glycemic status.
Phenotypic data from the cohorts and metagenomic sequences were first processed for standardization, and the final study population consisted of 1,851 patients with type 2 diabetes, 2,770 individuals with prediabetes, and 2,277 participants with normal glycemic status.
The American Diabetes Association diagnostic criteria, which include oral glucose tolerance test, fasting plasma glucose levels, medication use and risk factors such as body mass index, as well as laboratory tests for inflammatory and metabolic factors, were used to harmonize the data set.
The association between type 2 diabetes status and overall gut microbiome configuration was assessed first. Regression models were then used to identify species-level signatures and differences in the distribution of microbial features between groups according to glycemic status.
The researchers also conducted cohort-specific meta-analyses to examine the association between community-level microbial function, such as enzymes and biochemical pathways, and type 2 diabetes.
In addition, sensitive analyses were performed to ensure that the identified microbial signatures associated with type 2 diabetes were not partly due to comorbidities.
The study identified 19 phylogenetically distinct species in dysbiosis in patients with type 2 diabetes. The gut microbiome in patients with type 2 diabetes showed higher abundance of Clostridium bolteae and lower abundance of Butyrivibrio crossotus.
Furthermore, functional changes occurring at the microbial community level due to this dysbiosis have been linked to glucose metabolism disorders and type 2 diabetes pathology.
Other pathways associated with type 2 diabetes that were associated with functional changes at the microbial community level included decreased butyrate fermentation and increased synthesis of bacterial immunogenic structural components.
When analyses were resolved for specific bacterial strains, the study also found that associations between type 2 diabetes pathology and the gut microbiome showed heterogeneity within species.
Strain-specific functions such as horizontal gene transfer, branched-chain amino acid biosynthesis, and those related to inflammation and oxidative stress contributed significantly to this heterogeneity.
Variations in type 2 diabetes risk among individuals were also associated with intra-species diversity for 27 gut microbiota species, including Eubacterium rectale, which showed strain specificity at the population level.
Overall, the study showed that gut microbiome dysbiosis plays a functional role in the pathogenesis of type 2 diabetes, with direct involvement in mechanisms such as glucose metabolism and butyrate fermentation.
Furthermore, the results showed that strain-specific functions are heterogeneously associated with type 2 diabetes pathology, providing new insights into the mechanisms through which the gut microbiome is associated with type 2 diabetes.