Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes

Abstract

Gut microbiota has recently been proposed as a crucial environmental factor in the development of metabolic diseases such as obesity and type 2 diabetes, mainly due to its contribution in the modulation of several processes including host energy metabolism, gut epithelial permeability, gut peptide hormone secretion, and host inflammatory state. Since the symbiotic interaction between the gut microbiota and the host is essentially reflected in specific metabolic signatures, much expectation is placed on the application of metabolomic approaches to unveil the key mechanisms linking the gut microbiota composition and activity with disease development. The present review aims to summarize the gut microbial-host co-metabolites identified so far by targeted and untargeted metabolomic studies in humans, in association with impaired glucose homeostasis and/or obesity. An alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e., niacin), purines, and phenolic compounds has been associated so far with the obese or diabese phenotype, in respect to healthy controls. Furthermore, anti-diabetic treatments such as metformin and sulfonylurea have been observed to modulate the gut microbiota or at least their metabolic profiles, thereby potentially affecting insulin resistance through indirect mechanisms still unknown. Despite the scarcity of the metabolomic studies currently available on the microbial-host crosstalk, the data-driven results largely confirmed findings independently obtained from in vitro and animal model studies, putting forward the mechanisms underlying the implication of a dysfunctional gut microbiota in the development of metabolic disorders.

Keywords: co-metabolism; gut microbiota; metabolomics; obesity; type 2 diabetes.

FIGURE 1

Products of bile acids co-metabolism associated with obesity and diabetes via metabolomic studies. After the ingestion of food, conjugated BA are secreted into the intestinal lumen, are subjected to deconjugation by the intestinal bacteria, and converted to secondary BA. The main effect of secondary BA is mediated by the FXR activation, which in turn act increasing insulin secretion and sensitivity in the pancreas. Primary BA is also involved in glucose metabolism by TGR-5 activation and glucagon-like peptide-1 (GLP-1) release. Host endogenous processes are in solid lines, while microbial production and metabolite actions are in dotted lines.

FIGURE 2

Products of vitamin, phytochemical and purine co-metabolism associated with obesity and diabetes via metabolomics studies. Intestinal microorganisms catalyze the conversion of dietary choline and carnitine into TMA with a direct effect on the intestinal mucose (increased oxidative stress) and is the substrate for the hepatic production of TMAO (associated with cardiovascular disease risk) and TMA. Choline may escape microbial degradation and convert into betaine and further products [i.e., dimethylglycine (DMG)] by mammalian mitochondrial pathways in the liver and kidney where they have an detrimental osmotic effects. For most of the host microbial co-metabolites associated with the diabese phenotype, the eventual role in glucose and lipid metabolism remains unknown. OGTT, Oral glucose tolerance test; SAH and SAM, S-adenosylmethionine to S-adenosylhomocysteine (methionine cycle).