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Type 2 Diabetes Linked to Gut Microbiome Features in Strain-Specific Study

NEW YORK – New research supports the notion that the microbial species, strains, and genes found in individuals' gut microbiomes can provide clues to their risk of developing type 2 diabetes (T2D), while also offering biological insights into the condition.

The new results, appearing in Nature Medicine on Tuesday, "provide evidence for the gut microbiome's potential functional role in the pathogenesis of T2D, and highlight the identification of taxonomic and functional biomarkers for future diagnostic applications," co-senior and co-corresponding authors Dong Wang and Curtis Huttenhower, both from Harvard T.H. Chan School of Public Health and the Broad Institute, wrote in their paper along with their colleagues.

For their analyses, Wang, Huttenhower, and colleagues assessed 8,117 shotgun metagenomic sequence sets, representing gut microbial sequence collections from nearly 6,900 individuals with or without T2D or prediabetes from half a dozen published studies and four newly reported cohorts. The participants were enrolled in the US, Sweden, Finland, Denmark, Germany, France, Israel, and China and were brought together through the Microbiome and Cardiometabolic Disease Consortium.

For their analysis of metagenomic sequences for 1,851 individuals with T2D, 2,770 prediabetes patients, and 2,277 unaffected control participants, the team considered everything from species- and strain-level microbial community members and gut microbiome structure to the functional capabilities of the gut microbe communities.

"Microbial community structure and specific species have previously been linked to metabolic risk factors and T2D," the authors explained, noting that "pathogenic mechanisms are potentially strain specific, meaning that specific microbial strains are causally linked to disease outcomes or that microbial functional processes responsible for host disease development are carried out by a subset of strains in a microbial species."

Using this strain-specific strategy, the investigators tracked down five distinct species found at enhanced or lower-than-usual levels in gut microbial communities from individuals with T2D alone, including two Streptococcus species best known for their role in the oral microbiome, along with 14 species that had dysbiotic features associated with T2D and prediabetes.

Along with follow-up analyses pointing to a confounding role for the drug metformin on the T2D-microbiome associations, the investigators focused in on within-species diversity and strain-specific gene patterns coinciding with T2D risk differences between individuals.

The authors noted that "our examination of strain-specific functional genes builds upon prior mechanistic research in preclinical models, and we hope that it will facilitate future investigations aimed at precisely characterizing the role of gut microorganisms in the development of T2D."

On the functional side of the gut microbiome analyses, the team saw altered activity affecting microbial pathways involved in producing immunogenic bacterial features, glycolysis, and butyrate fermentation. The analyses also revealed T2D-related changes in the representation of bacterial species or strains contributing to processes such as oxidative stress or inflammation and shifts in gut microbiome gene content.

"Although our study does not establish causal linkages and should be interpreted as hypothesis generating, it offers the most comprehensive evidence to date of the gut microbiome's involvement in the pathogenesis of T2D from the population study perspective," the authors noted, adding that the current findings "lay the groundwork for future mechanistic studies."