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

Abstract

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.

Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice

“…Among the potential candidate-mediators, we can mention butyrate, which is produced by D. welbionis J115 T from myo-inositol and known to increase BAT thermogenesis, 38 but also other specific bioactive lipids controlling glucose metabolism and inflammation. 39 40 However, we did not find any increase in the levels of butyrate in the plasma or in the caecal content (online supplemental figure 6).…”

Characterization of the Synergistic Effect between Ligands of Opioid and Free Fatty Acid Receptors in the Mouse Model of Colitis

“…Since 12(S)-HETE is considered as a second messenger that transmits signals from activated MOR, further experiments examined whether MOR is a receptor controlling intestinal contractions and glucose metabolism. The results showed that MOR agonist DAMGO significantly decreased frequency and contraction amplitude of the duodenum of diabetic mice; moreover, this effect was dependent on PPARγ [20].…”

“…Finally, Hasegawa et al [16] suggested that both unsaturated fatty acids and phospholipids can enhance binding of a purified MOR. Additionally, recent studies established that bioactive lipids and MOR cooperate in diabetes [20]. Namely, chronic oral administration of the lipid, 12(S)-hydroxyeicosatetraenoic [12(S)-HETE] reduced duodenal contractions and improved glucose tolerance.…”

High Hydrostatic Pressure Processing of Human Milk Increases Apelin and GLP-1 Contents to Modulate Gut Contraction and Glucose Metabolism in Mice Compared to Holder Pasteurization

“…After a 10 h of fasting, an OGTT (3 g of glucose/kg of body weight) was performed in mice at day 7. Glycaemia was recorded from −30 to 120 min, and insulin and glucagon levels were measured and analyzed at −30, and +15 min as previously described [ 13 ].…”