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Identification of New Enterosynes Using Prebiotics: Roles of Bioactive Lipids and Mu-Opioid Receptor Signalling in Humans and Mi

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Identification of New Enterosynes Using Prebiotics: Roles of Bioactive Lipids and Mu-Opioid Receptor Signalling in Humans and Mi Neurogastroenterology ORIGINAL RESEARCH Gut: first published as 10.1136/gutjnl-2019-320230 on 5 October 2020. Downloaded from Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu- opioid receptor signalling in humans and mice Anne Abot,1,2,3 Eve Wemelle,1,3 Claire Laurens,4,5 Adrien Paquot,6 Nicolas Pomie,2 Deborah Carper,7 Arnaud Bessac,1,8 Xavier Mas Orea,1 Christophe Fremez,2 Maxime Fontanie,2 Alexandre Lucas,7 Jean Lesage,9 Amandine Everard,10 Etienne Meunier,8 Gilles Dietrich,1 Giulio G Muccioli ,6 Cedric Moro,7 Patrice D Cani ,3,10 Claude Knauf 1,3 For numbered affiliations see ABSTRACT end of article. Objective The enteric nervous system (ENS) plays a Significance of this study key role in controlling the gut-br ain axis under normal Correspondence to and pathological conditions, such as type 2 diabetes. What is already known on this subject? Professor Claude Knauf, IRSD, ► Targeting the ‘enteric nervous system (ENS)/ INSERM, Toulouse, Occitanie, The discovery of intestinal actors, such as enterosynes, France; able to modulate the ENS-induced duodenal contraction duodenal contraction’ couple is considered as claude. knauf@ inserm. fr and is considered an innovative approach. Among all the an innovative therapeutic strategy to treat type Professor Patrice D Cani, intestinal factors, the understanding of the role of gut 2 diabetes. Louvain Drug Research Institute, microbes in controlling glycaemia is still developed. ► ENS is under the influence of various molecules WELBIO, Metabolism and from the gut also called enterosynes, which Nutrition, UCLouvain, Université We studied whether the modulation of gut microbiota catholique de Louvain, Avenue by prebiotics could permit the identification of novel have the capacity to decrease duodenal E. Mounier, 73 B1.73.11 enterosynes. contraction. B-1200, Brussels, Belgium; Design We measured the effects of prebiotics on the ► Gut microbiota is well known to have an patrice. cani@ uclouvain. be production of bioactive lipids in the intestine and tested antidiabetic action through hormonal, nervous AA and EW contributed equally. the identified lipid on ENS- induced contraction and and metabolic regulations. PDC and CK contributed glucose metabolism. Then, we studied the signalling What are the new findings? http://gut.bmj.com/ equally. pathways involved and compared the results obtained in ► Modulation of gut microbiota composition by PDC and CK are joint senior mice to human. prebiotics improves glucose homeostasis by authors. Results We found that modulating the gut microbiota acting on ENS/duodenal contraction couple. with prebiotics modifies the actions of enteric ► The mechanism of prebiotic action implies Received 5 November 2019 neurons, thereby controlling duodenal contraction and the presence of an enkephalin/mu- opioid Revised 24 July 2020 subsequently attenuating hyperglycaemia in diabetic Accepted 26 August 2020 receptor and proliferator- activated receptor mice. We discovered that the signalling pathway γ signalling and a bioactive lipid, 12S- on September 26, 2021 by guest. Protected copyright. involved in these effects depends on the synthesis of a hydroxyeicosatetraenoic acid. bioactive lipid 12- hydroxyeicosatetraenoic acid (12- ► The expression of enzymes implicated in enteric HETE) and the presence of mu-opioid receptors (MOR) neurotransmitter synthesis and enkephalin on enteric neurons. Using pharmacological approaches, signalling are altered in the duodenum of we demonstrated the key role of the MOR receptors diabetic human. and proliferator- activated receptor γ for the effects of 12-HETE. These findings are supported by human data How might it impact on clinical practice in the showing a decreased expression of the proenkephalin foreseeable future? and MOR messanger RNAs in the duodenum of patients ► This study is the first showing the alteration of with diabetic. ENS and enkephalin signalling in the duodenum Conclusions Using a prebiotic approach, we identified of diabetic human. Deciphering the mode of enkephalin and 12-HETE as new enterosynes with action of gut microbiota on ENS could represent potential real beneficial and safety impact in diabetic a real safety and innovative therapeutic © Author(s) (or their human. evidence for patients with diabetic. employer(s)) 2020. Re- use permitted under CC BY. Published by BMJ. INTRODUCTION these molecules has side effects.1 2 In addition to the To cite: Abot A, Wemelle E, The identification of new targets to treat type 2 limitation of deleterious effects, future therapeutic Laurens C, et al. Gut Epub ahead of print: [please diabetes (T2D) is considered of major importance strategies should preferentially be administered to 3 include Day Month Year]. for public health. Although numerous bioactive patients via the oral route. doi:10.1136/ pharmacological molecules have been approved Recently, a new concept has emerged: the enteric gutjnl-2019-320230 and used as antidiabetics, the large majority of nervous system (ENS) is considered as new target Abot A, et al. Gut 2020;0:1–10. doi:10.1136/gutjnl-2019-320230 1 Neurogastroenterology to treat T2D.4 In fact, duodenal hypercontractility observed individuals (Tebu-Bio). The donors were patients with diabetes during T2D leads to the genesis of aberrant signalling from the who received antidiabetic treatments or healthy volunteers who Gut: first published as 10.1136/gutjnl-2019-320230 on 5 October 2020. Downloaded from afferent nerves to the hypothalamus, contributing to systemic never received antidiabetic treatments. insulin resistance.5 Using pharmacological approaches, an oral treatment with gut peptides has been shown to improve glucose Mice metabolism by stimulating the release of nitric oxide (NO) from Nine- week-old male C57BL/6J mice (Charles River Labora- enteric neurons. Thus, enteric NO has the capacity to decrease tory, l’Arbresle, France) were housed under specific pathogen- duodenal contractions and restore the gut- brain axis, subse- free conditions in controlled environment (room temperature 5 6 quently improving insulin sensitivity. Therefore, the identifi- of 23°C±2°C, 12 hours daylight cycle) and were provided cation of intestinal bioactive molecules that are able to target the free access to food and water. Experiments were conducted 7 ENS, also called enterosynes, represents an innovative thera- according to the European Community Regulations concerning peutic approach. the protection of experimental animals and were approved Since the beginning of the 2000s, accumulating evidence by the local Animal Care and Use Committee. Mice were fed has revealed key roles for the gut microbiota and its metabo- a high- fat diet (HFD) containing 20% protein, 35% carbohy- 8 9 lites in controlling glucose metabolism. Currently, the iden- drate and 45% fat (Research Diet, New Brunswick, New Jersey, tification of one bacteria and/or one of its active metabolites is USA) supplemented with or without prebiotics (fructooligosac- 10 viewed as potential novel therapeutic strategy. Using nutri- charides (FOS), ORAFTI P95, 0.3 g per mouse per day added tional approaches, gut microbiota remodelling with prebiotics to the tap water, Orafti, Tienen, Belgium) as described in our and/or probiotics improves glucose metabolism in subjects with previous study16 (figure 1A). Oral gavage of 12S- HETE (100 µL, 8 11 T2D. A potential explanation for this change is the release final concentration of 1 µM, Cayman Chemical, Michigan, of various factors (bioactive peptides/lipids, neurotransmitters, USA) or DAMGO ((D- Ala2, NMe-Phe4, Gly- ol5)- enkephalin, gases and hormones) from bacteria and from the host that are a highly selective MOR agonist, 100 µL, final concentration of able to decrease hepatic steatosis and adipose tissue inflamma- 100 nM, Sigma- Aldrich, Michigan, USA) was performed daily 9 12 tion, among other effects. in HFD45%-treated mice during the last week of the HFD45% The activity of enteric neurons is modulated (1) directly by treatment. The same timing was used for intraperitoneal injec- the bacteria, which are sensed by intrinsic primary afferent tion of GW9662 (1 mg/kg/day during the last week). All proto- 13 neurons or (2) through the release of bioactive molecules cols described below were performed at the end of the HFD45% 8 whose main representatives are short chain fatty acids (SCFAs). treatment. The discovery of new enterosynes that are able to improve glucose metabolism by modulating the activity of ENS neurons Measurement of isotonic contractions has been highlighted as a promising future source of antidi- Mice were euthanised under fed conditions. After dissection, abetic drugs.4 7 14 Actually, researchers have not determined the duodenum was washed and incubated with an oxygenated the real potential of strategies modulating the gut microbiota Krebs-Ringer solution, pH 7.4, for 30 min at 37°C, attached to using prebiotics to provide novel enterosynes. Therefore, in the the isotonic transducer (MLT7006 Isotonic Transducer, Hugo http://gut.bmj.com/ present study, we have used a prebiotic treatment (ie, oligof- Basile, Comerio, Italy), and immersed in an organ bath containing ructose) to identify novel actors and the molecular mechanisms the same medium maintained at 37°C. The load applied to the explaining their antidiabetic properties. We found that prebiotic lever was 1 g (10 mN). Isotonic contractions were recorded treatment decreases duodenal hypercontractility by modulating using Labchart software (AD Instruments) following
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