Identification of specific gut bacteria and metabolomic signatures related to Myocardial Insulin Resistance in Type 2 Diabetes

Abstract Background In myocardial insulin resistance (mIR), insulin fails to appropriately stimulate myocardial glucose uptake, which can contribute to the development of heart disease. This reversible metabolic abnormality occurs in only a fraction of patients with type 2 diabetes mellitus (T2DM) and may be present even before clinical symptoms or the onset of diabetes. Identifying biomarkers of early-stage mIR is crucial to halt its progression with appropriate treatment and lifestyle interventions. In this context, we explore, for the first time, specific gut bacteria and fecal and plasma metabolic signatures associated with mIR. Methods Forty-two T2DM patients were divided into two groups, mIR patients patients with myocardial insulin sensitivity (mIS), depending on their myocardial glucose uptake measured with 18 F-FDG PET during the hyperglycemic clamp. For each group, fecal microbiota was quantified by Illumina sequencing, and metabolomic profiles in feces and plasma were determined by NMR spectroscopy. Results The Faith’s phylogenetic diversity index was reduced significantly in mIR patients, compared with mIS patients. Linear discriminant analysis effect size (LEfSe) analysis revealed 25 bacterial taxa differing between mIS and mIR groups, and 6 bacteria ( Thermicanus, Lachnobacterium, Desulfovibrio, Desulfuromusa, Desulfosporosinus and Coprobacillus cateniformis ) were significantly decreased in mIR patients at the genus and species levels. Multivariate metabolomic analysis determined that six fecal metabolites (arabinose, β-galactose and ribose, aspartate, histidine and lactate) and six plasma metabolites (creatinine, myo-inositol, threonine, β-galactose, glycerol and choline) were reduced in mIR patients while plasmatic levels of VLDL(CH 3 ) were elevated significantly. Myocardial IR correlated positively with plasmatic VLDL(CH 3 ) and was negatively associated with two bacteria ( Desulfosporosinus and Coprobacillus cateniformis ), five fecal metabolites (arabinose, β-galactose, ribose, aspartate, and histidine) and two plasma metabolites (choline and β-galactose). Conclusions Our pilot study proved that the gut microbiome and the metabolic plasma profile is altered in T2DM patients with mIR. Regression analysis and predictive modelling identified the bacteria Desulfosporosinus and the metabolite galactose as key biomarkers, which could aid in the identification of T2DM patients at risk for myocardial IR and in the design of novel therapeutic strategies to prevent it.