ENTERIC NERVOUS SYSTEM NEURONS AS A TARGET TO TREAT TYPE 2 DIABETES: ROLE OF BACTERIAL BIOACTIVE LIPIDS – ENDIABAC

Type 2 diabetes (T2D) is a major public health problem with 3.5 million of diabetic patients in France, and more than 300 million all over the world. T2D is now considered as an epidemic disease associated with co-morbidities (cardiovascular dysfunction, neuropathy,…) that cost more 13 billion €/per year in France and 44 billion €/per year in the USA. Given the repeated failures of known therapeutic strategies, it is essential to find alternative approaches to win the fight vs T2D. The gut-to-brain axis is one of the first systems of communication disturbed in high-fat diet-induced T2D. Recently, we have revealed a new concept: modifications of mechanical activity of intestinal smooth muscle cells, which are under the influence of enteric nervous system (ENS) neurons, could have a major impact on glycemia. In fact, we have demonstrated that hyper-contractility of the duodenum 1) is associated to an increase of glucose absorption, and 2) generates an afferent signal that informs the brain to block glucose entry in the muscle. Therefore, the modification of the activity of the ENS-contraction couple has repercussions on glycemia by acting via 1) a “local” effect on glucose absorption (an increase of duodenal contraction during fed states positively correlates with glucose absorption leading to hyperglycemia), and 2) a “central” effect on glucose utilization in muscle via a hypothalamic nitric oxide (NO) relay. A dysregulation of these “local” and “central” effects participates to the development of hyperglycemia and insulin resistance observed during T2D. As obese/diabetic mice and human exhibit an alteration of the ENS activity associated to intestinal hyper-contractility, targeting this couple represent a new therapeutic approach to treat T2D. In order to decrease this intestinal hyper-contractility to limit glucose absorption and favor glucose utilization in tissue (liver, adipose tissue, muscle) finding intestinal molecular agents able to modulate the ENS neurons represent an innovative therapeutic strategy. Gut microbes are also able to release various factors (lipopolysaccharides, neurotransmitters, bioactive lipids) to control whole-body homeostasis, and gut dysbiosis is clearly responsible of the establishment of a T2D state. One potential target to modulate the ENS could be bacterial metabolites such as short-chain fatty acids (SCFA) and/or polyunsaturated fatty acid (PUFA)-derived metabolites from dietary PUFA. Our team has recently identified that PUFA could stimulate intestinal sensory neurons to generate visceral hypersensitivity in mice. Whether bioactive fatty acids derived from microbiota have an impact on ENS neurons remains to be determined. This project is supported by preliminary data showing that diabetic mice fed with oligofructose (a prebiotic with anti-diabetic action via the modulation of gut microbiota) present a significant decrease in duodenal contraction associated with improvement of glucose tolerance. The amelioration of the diabetic status was associated with an increase in the levels of a bacterial bioactive lipid recently identified by Partner 1 in the intestine of diabetic mice fed with oligofructose.

Therefore, our objectives will be divided into 3 points:
1) To study the role of gut microbiota in the activity of the ENS-contraction couple,
2) To determine the physiological effect on intestinal glucose absorption and on glucose utilization of gut microbiota through ENS-contraction couple, and
3) To identify bacterial bioactive lipids potentially implicated in this host / microbe communication.
By acting on an integrative physiological system, this project will offer the opportunity to change the therapeutic approach of T2D.