Journal Article

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

Lucas, Alexandre, Dietrich, Gilles, Muccioli, Giulio G, Knauf, Claude, Fremez, Christophe, Meunier, Etienne, Paquot, Adrien, Everard, Amandine, Lesage, Jean, Laurens, Claire, Cani, Patrice D, Wemelle, Eve, Pomie, Nicolas, Carper, Deborah, Mas Orea, Xavier, Abot, Anne, Moro, Cedric, Fontanie, Maxime, Bessac, Arnaud

2021

Overview

ObjectiveThe 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.DesignWe 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.ResultsWe 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.ConclusionsUsing a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group,CCSD,BMJ Publishing Group LTD
• Subject: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - biosynthesis / 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - pharmacology / Adult / Aged / Animals / Bacteria / Blood glucose / Blood Glucose - metabolism / Brain-Gut Axis / Contraction / Diabetes / diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Experimental - physiopathology / Diabetes Mellitus, Type 2 - physiopathology / Digestive system / Duodenum / Duodenum - innervation / Duodenum - physiology / Enkephalins / Enkephalins - genetics / Enkephalins - metabolism / Enteric nervous system / Enteric Nervous System - drug effects / Enteric Nervous System - physiology / Gastrointestinal Microbiome / Gastrointestinal tract / Glucose / Glucose metabolism / Glucose Tolerance Test / Gut Microbiota / Gut-brain axis / Human health and pathology / Humans / Hyperglycemia / Insulin resistance / Intestinal microflora / Intestine / Isotonic Contraction - drug effects / Life Sciences / Lipids / Male / Metabolism / Metabolites / Mice / Microbiota / Middle Aged / motility disorders / Muscle, Smooth - physiology / Narcotics / Nervous system / Neurons - physiology / Nitric Oxide Synthase Type I - genetics / Nitric Oxide Synthase Type I - metabolism / Oligosaccharides - pharmacology / Opioid receptors (type mu) / Peptides / PPAR gamma - metabolism / prebiotic / Prebiotics / Proenkephalin / Protein Precursors - genetics / Protein Precursors - metabolism / Receptors, Opioid, mu - genetics / Receptors, Opioid, mu - metabolism / RNA, Messenger - metabolism / Signal Transduction / Small intestine / Tissues and Organs / Variance analysis