An in vitro investigation of diet-influenced gut bacterial metabolites on the onset of Type 2 diabetes mellitus using a multi-cellular human primary islet model

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Type 2 Diabetes Mellitus (T2DM) is a chronic disease affecting endocrine and metabolic functions due to abnormal pancreatic hormones. The disease aetiology is governed by ineffective insulin secretion from dysfunctional β-cells and excessive glucagon production from α-cells. It is believed that the gut microbiome plays a crucial role in chronic diseases in man including metabolic conditions, particularly through the gut-islet axis, which involves interactions between the gut microbiota and pancreatic islets. Traditional studies into the role of gut microbiome in the pathogenesis of metabolic disease, although being extremely important, are often hampered by being observational in nature or over-reliant on data generated in rodent models, which are very different from humans. In this innovative in vitro study, the complex interactions between gut bacteria, diet, changes in bacterial growth patterns and varying metabolites profiles, and subsequent disease onset were deliberately unlinked, providing a clearer picture of the relationship between gut bacteria metabolites and disease progression. Here, two prominent gut bacterial populations ( Bacteroides thetaiotaomicron and Lactobacillus fermentum ) were isolated from human faecal samples before being manipulated under various dietary conditions to simulate eubiotic and dysbiotic states. The bacterial metabolites were extracted and characterised. Next and for the first time, the impact of metabolites on the onset of T2DM was assessed following long-term exposures in a 3D primary human pancreatic islet model composed of α, β, and δ cells. To evaluate the progression/inhibition of disease, glucose-stimulated insulin, glucagon release and inflammation, were investigated. The data showed that metabolites butyrate and propionate produced by Bacteroides thetaiotaomicron and the co-culture of two bacterial populations in a high-fibre diet significantly improved glucose regulation. Conversely, a high carbohydrate/fat diet led to a characterised unbalanced short-chain fatty acid profiles, notably lower propionate and high acetate levels, which contributed to islet dysfunction and chronic glucotoxicity. This study, along with the overall in vitro approach, highlights the importance of the microbiota–host metabolic axis and identifies potential future applications of targeted metabolite-based interventions that could be useful in the management of T2DM.