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Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects

International Journal of Obesity (2023)Cite this article

Subjects

Abstract

Objective

To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome.

Methods

Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents.

Results

BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum.

Conclusions

BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

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Fig. 1: Representation of the collection sites in different bariatric surgeries.
Fig. 2: Impact of the treatments on eCBome lipid levels.
Fig. 3: Heatmap representations of log10-transformed abundance of microbial genera in distal jejunum, proximal jejunum and ileum of SHAM HF, SHAM HF-PW, BPD-DS HF and SADI-S HF rats.
Fig. 4: The gut eCBome mediator levels are associated with microbial absolute abundances.
Fig. 5: The gut endocannabinoidome and microbiota are associated with positive effects of the hypoabsorptive bariatric surgeries.

Data availability

The data highlighted in this article will be available upon reasonable request to the corresponding authors.

References

  1. La Sala L, Pontiroli AE. Prevention of diabetes and cardiovascular disease in obesity. Int J Mol Sci. 2020;21:8178.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mukorako P, Lemoine N, Biertho L, Lebel S, Roy MC, Plamondon J, et al. Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats. Int J Obes. 2022;46:297–306.

    Article  CAS  Google Scholar 

  3. Li JV, Ashrafian H, Sarafian M, Homola D, Rushton L, Barker G, et al. Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype. Microbiome. 2021;9:139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. West KA, Kanu C, Maric T, McDonald JAK, Nicholson JK, Li JV, et al. Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery. Gut. 2020;69:1452–9.

    Article  PubMed  Google Scholar 

  5. Paganelli FL, Luyer M, Hazelbag CM, Uh HW, Rogers MRC, Adriaans D, et al. Roux-Y Gastric Bypass and Sleeve Gastrectomy directly change gut microbiota composition independent of surgery type. Sci Rep. 2019;9:10979.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Steinert RE, Rehman A, Souto Lima EJ, Agamennone V, Schuren FHJ, Gero D, et al. Roux-en-Y gastric bypass surgery changes fungal and bacterial microbiota in morbidly obese patients-A pilot study. PloS One. 2020;15:e0236936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Huh YJ, Seo JY, Nam J, Yang J, McDowell A, Kim YK, et al. Bariatric/metabolic surgery induces noticeable changes of microbiota and their secreting extracellular vesicle composition in the gut. Obes Surg. 2019;29:2470–84.

    Article  PubMed  Google Scholar 

  8. Lu C, Li Y, Li L, Kong Y, Shi T, Xiao H, et al. Alterations of serum uric acid level and gut microbiota after Roux-en-Y gastric bypass and sleeve gastrectomy in a hyperuricemic rat model. Obes Surg. 2020;30:1799–807.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dao MC, Belda E, Prifti E, Everard A, Kayser BD, Bouillot JL, et al. Akkermansia muciniphila abundance is lower in severe obesity, but its increased level after bariatric surgery is not associated with metabolic health improvement. Am J Physiol Endocrinol Metab. 2019;317:E446–e59.

    Article  CAS  PubMed  Google Scholar 

  10. Ye Y, Abu El Haija M, Morgan DA, Guo D, Song Y, Frank A, et al. Endocannabinoid Receptor-1 and sympathetic nervous system mediate the beneficial metabolic effects of gastric bypass. Cell Rep. 2020;33:108270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Azar S, Sherf-Dagan S, Nemirovski A, Webb M, Raziel A, Keidar A, et al. Circulating endocannabinoids are reduced following bariatric surgery and associated with improved metabolic homeostasis in humans. Obes Surg. 2019;29:268–76.

    Article  PubMed  Google Scholar 

  12. Guijarro A, Osei-Hyiaman D, Harvey-White J, Kunos G, Suzuki S, Nadtochiy S, et al. Sustained weight loss after Roux-en-Y gastric bypass is characterized by down regulation of endocannabinoids and mitochondrial function. Ann Surg. 2008;247:779–90.

    Article  PubMed  Google Scholar 

  13. Lacroix S, Pechereau F, Leblanc N, Boubertakh B, Houde A, Martin C, et al. Rapid and concomitant gut microbiota and endocannabinoidome response to diet-induced obesity in mice. mSystems. 2019;4:407–19.

    Article  Google Scholar 

  14. Manca C, Boubertakh B, Leblanc N, Deschênes T, Lacroix S, Martin C, et al. Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling. J Lipid Res. 2020;61:70–85.

    Article  CAS  PubMed  Google Scholar 

  15. Hankir MK, Seyfried F, Hintschich CA, Diep TA, Kleberg K, Kranz M, et al. Gastric bypass surgery recruits a gut PPAR-α-Striatal D1R pathway to reduce fat appetite in obese rats. Cell Metab. 2017;25:335–44.

    Article  CAS  PubMed  Google Scholar 

  16. Hutch CR, Trakimas DR, Roelofs K, Pressler J, Sorrell J, Cota D, et al. Oea signaling pathways and the metabolic benefits of vertical sleeve gastrectomy. Ann Surg. 2020;271:509–18.

    Article  PubMed  Google Scholar 

  17. Baraboi ED, Li W, Labbé SM, Roy MC, Samson P, Hould FS, et al. Metabolic changes induced by the biliopancreatic diversion in diet-induced obesity in male rats: the contributions of sleeve gastrectomy and duodenal switch. Endocrinology. 2015;156:1316–29.

    Article  CAS  PubMed  Google Scholar 

  18. Mukorako P, Lopez C, Baraboi ED, Roy MC, Plamondon J, Lemoine N, et al. Alterations of gut microbiota after biliopancreatic diversion with duodenal switch in wistar rats. Obes Surg. 2019;29:2831–42.

    Article  PubMed  Google Scholar 

  19. Turcotte C, Dumais É, Archambault AS, Martin C, Blanchet MR, Bissonnette É, et al. Human leukocytes differentially express endocannabinoid-glycerol lipases and hydrolyze 2-arachidonoyl-glycerol and its metabolites from the 15-lipoxygenase and cyclooxygenase pathways. J Leukoc Biol. 2019;106:1337–47.

    Article  CAS  PubMed  Google Scholar 

  20. Parks DH, Tyson GW, Hugenholtz P, Beiko RG. STAMP: statistical analysis of taxonomic and functional profiles. Bioinformatics. 2014;30:3123–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Depommier C, Vitale RM, Iannotti FA, Silvestri C, Flamand N, Druart C, et al. Beneficial effects of Akkermansia muciniphila are not associated with major changes in the circulating Endocannabinoidome but linked to higher Mono-Palmitoyl-Glycerol levels as new PPARα agonists. Cells. 2021;10:185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Borrelli F, Izzo AA. Role of acylethanolamides in the gastrointestinal tract with special reference to food intake and energy balance. Best Pract Res Clin Endocrinol Metab. 2009;23:33–49.

    Article  CAS  PubMed  Google Scholar 

  23. Gagner M. Hypoabsorption not malabsorption, hypoabsorptive surgery and not malabsorptive surgery. Obes Surg. 2016;26:2783–4.

    Article  PubMed  Google Scholar 

  24. Kapeluto JE, Tchernof A, Masckauchan D, Biron S, Marceau S, Hould FS, et al. Ten-year remission rates in insulin-treated type 2 diabetes after biliopancreatic diversion with duodenal switch. Surg Obes Relat Dis. 2020;16:1701–12.

    Article  PubMed  Google Scholar 

  25. Harris LA, Kayser BD, Cefalo C, Marini L, Watrous JD, Ding J, et al. Biliopancreatic diversion induces greater metabolic improvement than Roux-en-Y gastric bypass. Cell Metab. 2019;30:855–64.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577–85.

    Article  CAS  PubMed  Google Scholar 

  27. Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson-Pérez HE, Stefater MA, et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology. 2011;141:950–8.

    Article  CAS  PubMed  Google Scholar 

  28. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2013;10:575–84.

    Article  PubMed  Google Scholar 

  29. Sinclair P, Brennan DJ, le Roux CW. Gut adaptation after metabolic surgery and its influences on the brain, liver and cancer. Nat Rev Gastroenterol Hepatol. 2018;15:606–24.

    Article  CAS  PubMed  Google Scholar 

  30. Di Marzo V, Silvestri C. Lifestyle and metabolic syndrome: contribution of the endocannabinoidome. Nutrients. 2019;11:1956.

    Article  PubMed  PubMed Central  Google Scholar 

  31. van de Wouw M, Schellekens H, Dinan TG, Cryan JF. Microbiota-Gut-Brain axis: modulator of host metabolism and appetite. J Nutr. 2017;147:727–45.

    Article  PubMed  Google Scholar 

  32. Fujimori K. Prostaglandins as PPARγ modulators in adipogenesis. PPAR Res. 2012;2012:527607.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Donvito G, Piscitelli F, Muldoon P, Jackson A, Vitale RM, D’Aniello E, et al. N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice. Neuropharmacology. 2019;148:320–31.

    Article  CAS  PubMed  Google Scholar 

  34. Takenouchi R, Inoue K, Kambe Y, Miyata A. N-arachidonoyl glycine induces macrophage apoptosis via GPR18. Biochem Biophys Res Commun. 2012;418:366–71.

    Article  CAS  PubMed  Google Scholar 

  35. Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, et al. Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun. 2006;347:827–32.

    Article  CAS  PubMed  Google Scholar 

  36. McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, et al. N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci. 2010;11:44.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kotańska M, Mika K, Szafarz M, Kubacka M, Müller CE, Sapa J, et al. Effects of GPR18 ligands on body weight and metabolic parameters in a female rat model of excessive eating. Pharmaceuticals (Basel). 2021;14:270.

    Article  PubMed  Google Scholar 

  38. Rajaraman G, Simcocks A, Hryciw DH, Hutchinson DS, McAinch AJ. G protein coupled receptor 18: A potential role for endocannabinoid signaling in metabolic dysfunction. Mol Nutr Food Res. 2016;60:92–102.

    Article  CAS  PubMed  Google Scholar 

  39. Foster JR, Ueno S, Chen MX, Harvey J, Dowell SJ, Irving AJ, et al. N-Palmitoylglycine and other N-acylamides activate the lipid receptor G2A/GPR132. Pharmacol Res Perspect. 2019;7:e00542.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol. 2020;26:1242–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lund ML, Egerod KL, Engelstoft MS, Dmytriyeva O, Theodorsson E, Patel BA, et al. Enterochromaffin 5-HT cells - A major target for GLP-1 and gut microbial metabolites. Mol Metab. 2018;11:70–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Amabebe E, Robert FO, Agbalalah T, Orubu ESF. Microbial dysbiosis-induced obesity: role of gut microbiota in homoeostasis of energy metabolism. Br J Nutr. 2020;123:1127–37.

    Article  CAS  PubMed  Google Scholar 

  43. Duan M, Wang Y, Zhang Q, Zou R, Guo M, Zheng H. Characteristics of gut microbiota in people with obesity. PloS One. 2021;16:e0255446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Santacruz A, Marcos A, Wärnberg J, Martí A, Martin-Matillas M, Campoy C, et al. Interplay between weight loss and gut microbiota composition in overweight adolescents. Obesity. 2009;17:1906–15.

    Article  PubMed  Google Scholar 

  45. Rong ZH, Liang SC, Lu JQ, He Y, Luo YM, You C, et al. [Effect of intermittent fasting on physiology and gut microbiota in presenium rats]. Nan Fang Yi Ke Da Xue Xue Bao. 2016;37:423–30.

    PubMed  Google Scholar 

  46. Udayappan SD, Kovatcheva-Datchary P, Bakker GJ, Havik SR, Herrema H, Cani PD, et al. Intestinal Ralstonia pickettii augments glucose intolerance in obesity. PloS One. 2017;12:e0181693.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Million M, Maraninchi M, Henry M, Armougom F, Richet H, Carrieri P, et al. Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii. Int J Obes. 2012;36:817–25.

    Article  CAS  Google Scholar 

  48. Crovesy L, Ostrowski M, Ferreira D, Rosado EL, Soares-Mota M. Effect of Lactobacillus on body weight and body fat in overweight subjects: a systematic review of randomized controlled clinical trials. Int J Obes. 2017;41:1607–14.

    Article  CAS  Google Scholar 

  49. Dione N, Lacroix S, Taschler U, Deschênes T, Abolghasemi A, Leblanc N, et al. Mgll knockout mouse resistance to diet-induced dysmetabolism is associated with altered gut microbiota. Cells. 2020;9:2705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. González-Mariscal I, Krzysik-Walker SM, Kim W, Rouse M, Egan JM. Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice. Mol Cell Endocrinol. 2016;423:1–10.

    Article  PubMed  Google Scholar 

  51. Després JP, Ross R, Boka G, Alméras N, Lemieux I. Effect of rimonabant on the high-triglyceride/ low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-Lipids trial. Arterioscler Thromb Vasc Biol. 2009;29:416–23.

    Article  PubMed  Google Scholar 

  52. Cox HM, Tough IR, Woolston AM, Zhang L, Nguyen AD, Sainsbury A, et al. Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses. Cell Metab. 2010;11:532–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tough IR, Forbes S, Herzog H, Jones RM, Schwartz TW, Cox HM. Bidirectional GPR119 agonism requires peptide YY and glucose for activity in mouse and human colon mucosa. Endocrinology. 2018;159:1704–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Izzo AA, Piscitelli F, Capasso R, Aviello G, Romano B, Borrelli F, et al. Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. Br J Pharmacol. 2009;158:451–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. A C, N C, A I. Postoperative morbidity and weight loss after revisional bariatric surgery for primary failed restrictive procedure: A systematic review and network meta-analysis. Int J Surg. 2022;102:106677.

    Article  PubMed  Google Scholar 

  56. Gagner M. Hypoabsorptive surgery is the best revisional strategy for metabolic and diabetes outcomes. Surg Obes Relat Dis. 2020;16:1454–5.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from IRSC (TB2-138776), FRQS (32559) and the Sentinel North program 3.8 of Université Laval (Canada First Research Excellence Fund). VD is the holder of the Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), which is supported by the Canadian Federal Tri-Agency.

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Authors and Affiliations

  1. Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada

    Paulette Mukorako, Nicolas Flamand, Laurent Biertho, Stéfane Lebel, André Marette, Cristoforo Silvestri, Vincenzo Di Marzo & Denis Richard

  2. Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada

    Paulette Mukorako, Nicolas Flamand, Laurent Biertho, Stéfane Lebel, Natacha Lemoine, Julie Plamondon, Marie-Claude Roy, André Tchernof, André Marette, Cristoforo Silvestri, Vincenzo Di Marzo & Denis Richard

  3. Institute of Nutrition and Functional Foods, Centre NUTRISS, Québec, QC, Canada

    David H. St-Pierre, Thibault V. Varin, André Marette & Vincenzo Di Marzo

  4. Department of Exercise Sciences, Université du Québec à Montréal (UQAM), Québec, QC, Canada

    David H. St-Pierre

  5. School of Nutrition, Faculty of Agriculture and Food Sciences, Québec, QC, Canada

    David H. St-Pierre, André Tchernof & Vincenzo Di Marzo

  6. Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC, Canada

    Nicolas Flamand, Cristoforo Silvestri & Vincenzo Di Marzo

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  1. Paulette Mukorako
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Contributions

PM, DR designed the study; PM, NL, LB, SL, JP, MCR, and NF performed the experiments; PM, TVV, and DSP analyzed the data and arranged the figures; PM, VDM, and CS wrote the first draft of the paper; DR, DSP, NF, AM, AT reviewed the paper. All authors approved the final manuscript.

Corresponding authors

Correspondence to Cristoforo Silvestri, Vincenzo Di Marzo or Denis Richard.

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Competing interests

AT and LB receive research funding from Johnson & Johnson, Medtronic and GI Windows for studies on bariatric surgery. AT acted as a consultant for Bausch Health, Novo Nordisk, and Biotwin. AT and LB are codirectors of the Research Chair in Bariatric and Metabolic Surgery at Université Laval.

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Mukorako, P., St-Pierre, D.H., Flamand, N. et al. Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects. Int J Obes (2023). https://doi.org/10.1038/s41366-023-01307-3

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