Targeting Microbiome Disruption in Obesity and Type 2 Diabetes

Using transgenic mice overexpressing human IGF-1 receptors in endothelial cells (EC) described as hIGFREO, we discovered a hitherto unrecognised signalling pathway between EC and intestinal enterocytes (IE). This lead to favourable alterations in gut microbiota (GM) and protection against some of the deleterious consequences of high fat diet (HFD) induced obesity/type 2 diabetes mellitus (T2DM), including insulin resistance, glucose intolerance and hypertriglyceridemia. An EC derived small molecule(s) from hIGFREO fed HFD enhanced IE expression of the gene encoding REG3G, a multifunctional antimicrobial peptide important in regulating IE function and the interaction between IE and GM. In pilot studies we have shown that: 1) Transplantation of GM from HFD-fed hIGFREO mice into obese wildtype mice has protective effects on intestinal structure, white adipocyte phenotype, insulin sensitivity and hyperlipidaemia. 2) The secreted metabolome of EC from hIGFREO is different to that of WT revealing protective and potentially therapeutically tractable small molecules for further investigation. 3) Targeted screening of small molecules demonstrated that uridine increased expression of REG3G in Caco2 cells. In the present project using in vivo preclinical and state of the art human gut models, we plan to advance these findings towards clinical translation.