Human gut microbes impact host serum metabolome and insulin sensitivity

Abstract

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

“…A decreased BCAA metabolism in fat tissue may contribute to higher BCAA levels in individuals with insulin-resistant obesity [2,[22][23][24]. Intriguingly, a recent study also showed that the gut microbiota can contribute to elevated BCAA levels in insulin-resistant states [25].…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…Examples from T2D research highlight the diverse routes by which human genetics can inform translational medicine: (1) the combination of common-variant GWASs and candidate-gene resequencing has demonstrated that loss-of-function mutations in SLC30A8 (MIM: 611145; encoding a zinc transporter expressed in pancreatic islets) are protective for T2D, leading to efforts by several pharma companies to develop ZnT-8 antagonists; 93 (2) the use of genetic variants as instruments that ''simulate'' variation in environmental and biochemical exposures has clarified the extent to which vitamin D intake, early nutrition, circulating lipid levels, and chronic inflammation play causal roles with respect to the development of T2D [94][95][96][97][98] and has defined the relationship between insulin resistance and the distribution of adipose tissue; 99 (3) the identification of genetic variants associated with individual variation in response to commonly used therapeutic agents has refined our understanding of the mechanisms through which those agents operate 100,101 and, in some instances, has led to therapeutic optimization on the basis of genetic and/or clinical phenotype; 102 and (4) the combination of -omic measurements, longitudinal clinical phenotypes, and GWAS data has highlighted sets of molecules (e.g., branched-chain amino acids) that not only are prospectively associated with T2D progression but could also play a causal role in T2D development and thereby provide valuable clinical tools for stratification and prognostication. 103,104 Auto-immune Diseases Variant and Gene Discovery. In the last 5 years, GWASs have been undertaken for nearly all major immune-mediated diseases (with sample sizes of tens of thousands of case and control individuals for more common immune-mediated diseases studied either by GWASs or by more targeted chips, such as Illumina's Immunochip 105 ), resulting in hundreds of associated loci.…”

The effects of metformin on gut microbiota and the immune system as research frontiers

“…How can a drug acting only within the gut affect systemic carbohydrate metabolism? Specific microbiome profiles are associated with increased glucose intolerance [30]. Alterations in gut microbiota can influence the gut metabolome in a manner that affects the intestinal output of butyrate [24] and acetate [31].…”