![]() We then tested the impact of chronic oral administration of 12-HETE on gut hypercontractility and the effects on the duodenal expression of neuronal NO synthase (nNOS). Using lipidomic approaches, we discovered that the improvement in the diabetic state was associated with an increase in the levels of an intestinal lipid, 12-hydroxyeicosatetraenoic acid (12-HETE). We found that prebiotic treatment decreases duodenal hypercontractility by modulating ENS activity. Therefore, in the present study, we have used a prebiotic treatment (ie, oligofructose) to identify novel actors and the molecular mechanisms explaining their antidiabetic properties. 4 7 14 Actually, researchers have not determined the real potential of strategies modulating the gut microbiota using prebiotics to provide novel enterosynes. 8 The discovery of new enterosynes that are able to improve glucose metabolism by modulating the activity of ENS neurons has been highlighted as a promising future source of antidiabetic drugs. The activity of enteric neurons is modulated (1) directly by the bacteria, which are sensed by intrinsic primary afferent neurons 13 or (2) through the release of bioactive molecules whose main representatives are short chain fatty acids (SCFAs). 8 11 A potential explanation for this change is the release of various factors (bioactive peptides/lipids, neurotransmitters, gases and hormones) from bacteria and from the host that are able to decrease hepatic steatosis and adipose tissue inflammation, among other effects. 10 Using nutritional approaches, gut microbiota remodelling with prebiotics and/or probiotics improves glucose metabolism in subjects with T2D. 8 9 Currently, the identification of one bacteria and/or one of its active metabolites is viewed as potential novel therapeutic strategy. Since the beginning of the 2000s, accumulating evidence has revealed key roles for the gut microbiota and its metabolites in controlling glucose metabolism. 5 6 Therefore, the identification of intestinal bioactive molecules that are able to target the ENS, also called enterosynes, 7 represents an innovative therapeutic approach. Thus, enteric NO has the capacity to decrease duodenal contractions and restore the gut-brain axis, subsequently improving insulin sensitivity. 5 Using pharmacological approaches, an oral treatment with gut peptides has been shown to improve glucose metabolism by stimulating the release of nitric oxide (NO) from enteric neurons. 4 In fact, duodenal hypercontractility observed during T2D leads to the genesis of aberrant signalling from the afferent nerves to the hypothalamus, contributing to systemic insulin resistance. Recently, a new concept has emerged: the enteric nervous system (ENS) is considered as new target to treat T2D. 1 2 In addition to the limitation of deleterious effects, future therapeutic strategies should preferentially be administered to patients via the oral route. Although numerous bioactive pharmacological molecules have been approved and used as antidiabetics, the large majority of these molecules has side effects. The identification of new targets to treat type 2 diabetes (T2D) is considered of major importance for public health. Professor Claude Knauf, IRSD, INSERM, Toulouse, Occitanie, France 10 Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université catholique de Louvain, Brussels, Belgium.9 Lille 2 University of Health and Law, Lille, Hauts-de-France, France.8 IPBS, Toulouse, Midi-Pyrénées, France.7 I2MC, INSERM, Toulouse, Occitanie, France.6 Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.4 CNRS, University of Strasbourg, Strasbourg, France.3 European Associated Laboratory (EAL) NeuroMicrobiota, Toulouse, Brussels, France, Belgium.2 Enterosys, CRO, Toulouse, Occitanie, France.1 IRSD, INSERM, Toulouse, Occitanie, France.
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