Modulation of the gut microbiome by novel synthetic glycans for the production of propionate and the reduction of cardiometabolic risk factors

Abstract

BackgroundIncreasing evidence indicates that an altered gut microbiome participates in the development of cardiometabolic syndrome and associated risk factors, such as insulin resistance, dyslipidemia, and obesity, and that targeting the gut microbiome is a promising strategy to lower the risk for cardiometabolic diseases. Part of this reduction is mediated by specific metabolites generated by the gut microbiome. Propionate, a short-chain fatty acid (SCFA) produced from dietary glycans by certain gut microbes is known to exert multiple beneficial metabolic effects. Here, we identify KB39, a novel gut microbiome-targeting synthetic glycan selected for its strong propionate-producing capacity, and demonstrate its effects in vivo to reduce cardiometabolic disease using western diet-fed LDL receptor knock-out mice. MethodsEx vivo fermentation screening of a large library of synthetic glycan ensembles was performed using gut microbiome communities from healthy subjects and overweight patients with type 2 diabetes. A synthetic glycan identified for its high propionate-producing capacity (KB39) was then tested in vivo for effects on systemic, blood and cecal metabolic parameters in Ldlr-/- mice fed a western diet. ResultsEx vivo screening of ~600 synthetic glycans using human gut microbiota from healthy subjects and patients with type 2 diabetes identified a novel glycan (KB39) with high propionate-producing capacity that increased propionate contribution to total SCFA and propionate-producing bacterial taxa compared to negative control. In western diet-fed Ldlr-/- mice, KB39 treatment resulted in an enrichment in propiogenic bacteria and propionate biosynthetic genes in vivo and an increase in absolute and relative amounts of propionate in the cecum. This also resulted in significant decreases in serum total cholesterol, LDL-cholesterol, and insulin levels, as well as reduced hepatic triglycerides and cholesterol content compared to non-treated animals. Importantly, KB39 treatment significantly reduced atherosclerosis, liver steatosis and inflammation, upregulated hepatic expression of genes involved in fatty acid oxidation and downregulated transcriptional markers of inflammation, fibrosis and insulin resistance with only a mild lowering of body weight gain. ConclusionsOur data show that KB39, a novel synthetic glycan supporting a high propionate-producing microbiome, can reduce cardiometabolic risk factors and disease in mice and suggest this approach could be of benefit for the prevention or treatment of cardiometabolic diseases in humans. CLINICAL PERSPECTIVEWhat is new? O_LIA novel synthetic glycan, KB39, was selected from a library of compounds for its high propionate-producing capacity and beneficial effects on the human gut microbiome composition C_LIO_LIKB39 modulates the gut microbiome for high propionate production and significantly reduces cardiometabolic risk factors and disease in a murine model of cardiometabolic diseases C_LI What are the clinical implications? O_LIKB39, delivered orally, could be of benefit for the prevention or treatment of cardiometabolic diseases in humans C_LIO_LIThe efficacy of KB39 in mice compared to the clinical drug fenofibrate justifies further study in humans C_LI