Developing gut microbiome-derived therapies for obesity, insulin resistance, and type 1 diabetes

In this thesis, we investigate the role of the gut microbiome in obesity, insulin resistance and type 1 diabetes. In part I, we used the Amsterdam based GUTDM1-cohort, consisting of 500 individuals with type 1 diabetes, to study endocrine and exocrine dysfunction and the effects of food intake on glycaemic control. We disclose that fibre- and carbohydrate intake are independently associated with glycaemic control and that exocrine pancreatic insufficiency is a prevalent condition in type 1 diabetes. Furthermore, we show the persistence of the insulin prohormone proinsulin in longstanding type 1 diabetes, possibly indicating dormant β-cells. In part II, we study the effect of individual gut-microbiome derived components on metabolic health. We show the improvement in glucose metabolism in individuals with metabolic syndrome upon ingestion of 6-bromotryptophan, a gut microbiome-produced metabolite. We present the protocol of the ongoing PIGER-trial, which aims to diminish fructose-derived ethanol via the ingestion of the probiotic strain Desulfovibrio piger. Finally, we show the safety and gut engraftment of EcNΔClbP, a bio-engineered bacterial strain lacking the carcinogenic protein colibactin, hence providing a platform for future probiotic development. Taken together, this thesis provides novel insights in the pathophysiology and management of type 1 diabetes and explores novel gut microbiome-derived therapeutic agents in obesity, related diseases and type 1 diabetes.