Modeling the Diabetic Gut: how microbes fuel metabolic disorders
The prevalence of type II diabetes mellitus [T2DM] continues to increase worldwide. Growing evidence suggests that chronic systemic endotoxinemia due to gut microbiota and an impaired gut barrier plays a key role in the pathogenesis of a metabolic diseases. The gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of trillions of microbes and diverse microbial products to the largest immune system in the body. The gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions; loosening of the junctions induced by stressors, compromises the gut barrier and allows microbes and antigens to leak through and encounter the host immune system, thereby generating systemic endotoxemia. An impaired gut barrier, i.e., ‘leaky gut’, is believed to be a major contributor to the initiation and/or progression of T2DM, obesity, and atherosclerosis. Microbes also control the secretion of glucagon-like peptide-1 (GLP-1) and peptide-2 (GLP-2), from intestinal L-cells which control glucose homeostasis and gut barrier function, respectively. This multidisciplinary proposal seeks to study the importance of a novel molecular mechanism, the stress-polarity pathway comprised of AMPK and GIV, which fortifies the gut barrier against stress-induced collapse; this pathway appears to be necessary and sufficient for the barrier-protective functions of metformin, the widely-prescribed anti-diabetic drug. Using organoid based Gut-in-a dish model we will determine the role of DM-associated microbes and microbial products in gut barrier and in the activation of the SPS- pathway in colonic enteroid-derived monolayers (EDMs) (AIM1). We will assess the impact of microbes, microbial products and nutritional components on the secretion of peptide hormones (PYY, GLP-1/2) that are secreted from the gut lining using intestinal EDMs (AIM2) Insights gained will expose how strengthening the gut barrier is a viable strategy to achieve glycemic control in the most challenging patients, and can serve as the front line of tackling metabolic syndrome and chronic diseases.

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