Gut bacteria alterations impact serum metabolites and may contribute to insulin resistance

A mounting body of scientific evidence suggests a link between the gut microbiome and human metabolic health. Indeed, alteration of microbial composition and function in patients with type 2 diabetes (T2D) appears to be a key feature in the pathogenesis of the disease. However, whether the insulin resistance (IR)-associated serum metabolome may predict metabolic and cardiovascular disorders is unknown.

A recent study, led by Dr. Oluf Pedersen from the Faculty of Health and Medical Sciences at University of Copenhagen in Denmark, has found that dysbiosis of the human gut microbiota impacts the serum metabolome and contributes to the state of IR and metabolic syndrome.

The researchers examined 277 non-diabetic Danish adults and 75 Danish T2D patients with preserved insulin secretion. Analyses included the serum for metabolomics (it provided information about more than 1200 metabolites) and the stool for metagenomics.

People who were insulin-resistant according to the homeostatic model assessment (HOMA-IR) had elevated blood levels of branched-chain amino acids (BCAAs), which have previously been associated with IR and future risk of metabolic and cardiovascular morbidities. The rise of BCAA levels in the blood was related to specific changes in the gut microbiota composition and function, such as enriched biosynthetic potential for BCAAs and deprivation of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus were identified as the main species driving the association between biosynthesis of BCAAs and IR.

In order to test mechanistically whether gut bacteria were causally related to IR, the researchers compared P. copri (n=12) and sham-gavaged (n=12) mice on a high-fat diet. Notably, 3 weeks of P. copri challenge reduced insulin sensitivity, aggravated glucose intolerance and increased circulating levels of BCAAs. These data suggest a potentially causal role of P. copri in mediating the increase in serum BCAA and IR in mice.

“The study…is the first study to integrate serum metabolomics, microbiome and clinical data in a three-pronged analysis. The analysis weight[s] the impact of the different bacterial species [in relation to the disease], and this enabled us to identify the species that was most important for insulin resistance”, said Henrik Bjorn Nielsen, lead author from the Technical University of Denmark.

In conclusion, these findings suggest that imbalances in gut bacteria impact the serum metabolome and contribute to IR. P. copri modulation of serum BCAA levels may open up a potential new way to diminish IR and the associated metabolic and cardiovascular diseases. These results contradicts the findings by a previous study by Reijnders et al. that found an induced gut bacterial imbalance after antibiotic treatment was not associated with metabolism changes and insulin resistance in obese humans.

Reference:

Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016; 535(7612):376-81. doi: 10.1038/nature18646.