Direct gut to pancreas neuronal communication in the regulation of metabolism

What you eat plays a major role in health and ill health. Every day the body consumes foods which are broken down in the gut into a complex mixture of molecules. These molecules are sensed in the gut to modulate metabolic functions. They help to regulate digestion but also body wide processes, including how the body regulates glucose, and how it processes fat and protein. New scientific tools are for the first time allowing us to understand how these food components affect metabolism and health on a molecular level.

The pancreas is a particularly important metabolic organ, with critical roles in digestion, and in carbohydrate, fat and protein metabolism. Maintaining good pancreatic function is vital to maintaining health across the life course. The pancreas sits next to the upper part of the small intestine, which is called the duodenum. Almost fifty years ago it was discovered that there are neurons that originate in the wall of the duodenum which extend to the pancreas, suggesting that the gut could signal directly to the pancreas via this pathway to rapidly adjust pancreatic function and metabolism in response to food. However, subsequently, these neurons have been little studied.

Our pilot data shows that a subpopulation of these neurons is involved in the pathway by which specific fats can improve the metabolic response to glucose. However, there are many other neurons in this pathway which are almost completely uncharacterised. We will map the neurons signalling from the gut to the pancreas in a mouse model, and establish the food-related molecules that regulate their function. We will manipulate these neurons in mice to determine the effects they have on metabolism, and whether they can synchronise the activity of different parts of the pancreas to have even greater effects on the body. These studies will determine whether in the future these neurons can be usefully targeted by special diets to improve long term health.

Understanding how the gastrointestinal tract senses and responds to specific foods to drive precise changes in metabolism offers important insight into the physiology of critical body systems, and can identify new strategies for the maintenance of health across the life course. The pancreas is crucial to how the body assimilates nutrients and modulates metabolism following the ingestion of specific foods. Neural regulation is a major pathway controlling pancreatic function. However, there has been little research into direct neuronal communication between the gastrointestinal tract and the pancreas, which is well placed to regulate the acute effects of specific food metabolites. Our data suggest that these gut-to-pancreas neurons can mediate the effects of specific foods on pancreatic hormone release and glucose metabolism. We intend to characterise these neurons and the signals that modulate their activity and thus pancreatic function and whole-body metabolism.

Hypothesis: Direct gut-to-pancreas neuronal signalling regulates the metabolic response to food.

Objectives:
i) Map the expression profiles of gut-to-pancreas neurons and the upstream enteric neurons that regulate them.
ii) Characterise the response of these gut-to-pancreas neurons to specific nutrients and metabolic signals.
iii) Determine the role of specific food-responsive gut-to-pancreas neuronal populations in pancreatic function and the response to food intake.
iv) Establish the effects of gut-to-pancreas neurons on pancreatic networking and metabolism.

These studies will thus map and characterise gut-to-pancreas neurons, establish foods and other factors that modulate their activity, and determine the effect of specific populations of these neurons on pancreatic function, pulsatile insulin release and metabolic profile. These findings will reveal new aspects of vital physiological processes and highlight potential dietary approaches to maintaining health across the life course.