Neuronal gut-pancreas axis and its effect on pancreatic islet physiology and insulin secretion

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ABSTRACT The physiology of glucose metabolism is intricately linked to the process of digestion. Sensory and gastrointestinal cues trigger and enhance insulin secretion from the endocrine pancreas even before the serum glucose levels rise, thus priming the system for the upcoming glucose intake. Not surprisingly, most effective modern therapeutic approaches for the diabetes treatment are shifting from being pancreas-centric to being gut- centric and include surgical options (various types of bariatric surgeries), as well as pharmacological targeting of glucoregulatory signals from the gut (incretin therapies). Yet, the full complexity of how the gut regulates pancreatic responses is not fully understood. While most research has focused on the endocrine signals from the gut to the pancreas, little is known about direct neuronal links between the two organs. Such a neuronal link has been described in anatomical studies and is termed entero-pancreatic plexus. Despite this anatomical connection, the physiological role of this plexus remains almost entirely unaddressed. The long-term goal of this research project is to understand the contribution of the entero-pancreatic neuronal plexus to the regulation of pancreatic islet function. The objective of this application is to identify and characterize the molecular and functional features of the entero-pancreatic neuronal network and its effect on the function of the endocrine pancreas. Our preliminary data support the existence of the entero-pancreatic neuronal plexus and demonstrate that luminal infusion of carbohydrates into the gut triggers activation of pancreatic neurons within seconds. I therefore hypothesize that activation of entero-pancreatic neuronal plexus by luminal nutrients stimulates insulin secretion from the pancreatic beta cells via cholinergic signaling mechanisms. I propose that manipulation of the gut-pancreas axis holds a therapeutic potential for the treatment or management of the metabolic diseases and introduces a new dimension for understanding of the gut-pancreas interaction and incretin signaling. I will test my hypothesis by pursuing two specific aims. Aim 1 will identify the molecular expression profile of enteric neurons that project to the pancreas using single nuclei RNA sequencing of traced neurons and determine the histological topography and connectivity of these neurons using immunohistochemistry and in-situ hybridization. Aim 2 will investigate entero-pancreatic connection physiologically using in-vivo Ca2+imaging and fluorescent tracking of insulin secretion in exteriorized pancreas, combined with pharmacogenetic and surgical manipulation of neuronal pathways. The findings of this proposal will bring into light neural gut-pancreas axis, which has a far-reaching impact on the fields of gastroenterology and endocrinology.