Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice.

OBJECTIVE: The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes. DESIGN: We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human. RESULTS: We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic. CONCLUSIONS: Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

Inflammation and Gut-Brain Axis During Type 2 Diabetes: Focus on the Crosstalk Between Intestinal Immune Cells and Enteric Nervous System.

The gut-brain axis is now considered as a major actor in the control of glycemia. Recent discoveries show that the enteric nervous system (ENS) informs the hypothalamus of the nutritional state in order to control glucose entry in tissues. During type 2 diabetes (T2D), this way of communication is completely disturbed leading to the establishment of hyperglycemia and insulin-resistance. Indeed, the ENS neurons are largely targeted by nutrients (e.g., lipids, peptides) but also by inflammatory factors from different origin (i.e., host cells and gut microbiota). Inflammation, and more particularly in the intestine, contributes to the development of numerous pathologies such as intestinal bowel diseases, Parkinson diseases and T2D. Therefore, targeting the couple ENS/inflammation could represent an attractive therapeutic solution to treat metabolic diseases. In this review, we focus on the role of the crosstalk between intestinal immune cells and ENS neurons in the control of glycemia. In addition, given the growing evidence showing the key role of the gut microbiota in physiology, we will also briefly discuss its potential contribution and role on the immune and neuronal systems.

T-lymphocyte-derived enkephalins reduce Th1/Th17 colitis and associated pain in mice.

BACKGROUND: Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal Th1/Th17-associated inflammation, enkephalins released by colitogenic CD4+ T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in Th1/Th17-associated colitis. METHODS: The anti-inflammatory effects of endogenous opioids were investigated in both Th1/Th17-associated (transfer of CD4+CD45RBhigh T lymphocytes) and Th2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4+ T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4+CD45RBhigh T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred. RESULTS: Peripheral opioid receptor blockade increases the severity of Th1/Th17-induced colitis and attenuates Th2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a Th2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4+CD45RBhigh T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury. CONCLUSIONS: Endogenous opioids, including T-cell-derived enkephalins, promote a Th2-type immune response, which, depending on the context, may either attenuate (Th1/Th17-associated) or aggravate (Th2-associated) intestinal inflammation.

Galanin enhances systemic glucose metabolism through enteric Nitric Oxide Synthase-expressed neurons.

OBJECTIVE: Decreasing duodenal contraction is now considered as a major focus for the treatment of type 2 diabetes. Therefore, identifying bioactive molecules able to target the enteric nervous system, which controls the motility of intestinal smooth muscle cells, represents a new therapeutic avenue. For this reason, we chose to study the impact of oral galanin on this system in diabetic mice. METHODS: Enteric neurotransmission, duodenal contraction, glucose absorption, modification of gut-brain axis, and glucose metabolism (glucose tolerance, insulinemia, glucose entry in tissue, hepatic glucose metabolism) were assessed. RESULTS: We show that galanin, a neuropeptide expressed in the small intestine, decreases duodenal contraction by stimulating nitric oxide release from enteric neurons. This is associated with modification of hypothalamic nitric oxide release that favors glucose uptake in metabolic tissues such as skeletal muscle, liver, and adipose tissue. Oral chronic gavage with galanin in diabetic mice increases insulin sensitivity, which is associated with an improvement of several metabolic parameters such as glucose tolerance, fasting blood glucose, and insulin. CONCLUSION: Here, we demonstrate that oral galanin administration improves glucose homeostasis via the enteric nervous system and could be considered a therapeutic potential for the treatment of T2D.