In a recent study published in Nature Medicine, a team of scientists examined over 8,000 shotgun metagenomic sequences from individuals with prediabetes, type 2 diabetes, and normal glycemic status to determine how microbial features and functions specific to subspecies and strains contribute to the pathological mechanisms of type 2 diabetes.
Study: Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes. Image Credit: SewCreamStudio/Shutterstock.com
Background
Type 2 diabetes is a rapidly growing global health concern affecting over 500 million people worldwide. The mass and function of the pancreatic β cells in type 2 diabetes patients decline over time, with insulin resistance often being accompanied by systemic low-grade inflammation.
Evidence suggests that the gut microbiome plays a critical role in human metabolism and health and often interacts with genetic factors and the environment. Studies have also identified various gut microbial signatures associated with type 2 diabetes.
However, many of these studies were conducted among small study populations or did not account for confounders or risk factors such as adiposity or the use of the drug metformin.
Standardized data from a large population is required to understand the role of gut microbiome function, specific to subspecies and strains and at the molecular level, in the pathology of type 2 diabetes.
About the study
In the present study, the researchers examined metagenomic data obtained from 10 cohorts of individuals from across Europe, the United States, and China having normal glycemic status, prediabetes, or type 2 diabetes to decipher the strain-specific function and molecular features of gut microbiota that contribute mechanistically to type 2 diabetes pathology.
While previous studies have identified specific gut microbial species and microbial communities that increase the metabolic risk factors for type 2 diabetes, they have not taken into account the fact that the pathogenic mechanisms of a microbe are specific to the strain. For example, the K12 strain of Escherichia coli is harmless, while the O157:H7 strain is pathogenic.
The researchers obtained over 8,000 shotgun metagenomic data from six published and four newly generated datasets spanning ten cohorts of individuals with varying glycemic status.
The phenotypic data from the cohorts and the metagenomic sequences were first processed for standardization, and the final study population consisted of 1,851 type 2 diabetes patients, 2,770 individuals with prediabetes, and 2,277 participants with normal glycemic status.
The American Diabetes Association’s diagnostic criteria, which include oral glucose tolerance test, fasting plasma glucose levels, medication use, and risk factors such as body mass index, and laboratory tests for inflammatory and metabolic factors were used to harmonize the dataset.
The association between type 2 diabetes status and the overall gut microbiome configuration was assessed first. Then, regression models were used to identify signatures at the species level and differences in the distribution of microbial features across the groups based on glycemic status.
The researchers also conducted cohort-specific meta-analyses to investigate the association between microbial function at the community level, such as enzymes and biochemical pathways, and type 2 diabetes.
Additionally, sensitivity analyses were also conducted to ensure that the microbial signatures identified to be associated with type 2 diabetes were not partially influenced by comorbidities.
Results
The study found 19 phylogenetically distinct species that were in dysbiosis in patients with type 2 diabetes. The gut microbiome in patients with type 2 diabetes was found to have a higher abundance of Clostridium bolteae and lower Butyrivibrio crossotus abundance.
Furthermore, the functional changes that occurred at the microbial community level due to this dysbiosis were linked to glucose metabolism perturbations and type 2 diabetes pathology.
Other type 2 diabetes-associated pathways that were linked to functional shifts at the microbial community level included a decrease in butyrate fermentation and increased synthesis of bacterial immunogenic structural components.
When the analyses were resolved for specific bacterial strains, the study also found that the associations between type 2 diabetes pathology and the gut microbiome showed within-species heterogeneity.
Strain-specific functions such as horizontal gene transfer, biosynthesis of branched-chain amino acids, and those related to inflammation and oxidative stress contributed significantly to the heterogeneity.
The variations in type 2 diabetes risk among individuals were also found to be linked to within-species diversity for 27 gut microbial species, including Eubacterium rectale, which showed population-level strain specificity.
Conclusions
Overall, the study found 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 findings reported strain-specific functions that were heterogeneously associated with the pathology of type 2 diabetes, providing novel insights into the mechanisms through which the gut microbiome is associated with type 2 diabetes.
Targeting the gut microbiome: A new approach to treating diabetes