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Equipe BADO 2018

Plasticity of gastro-intestinal mucosa in nutritional pathologies and after surgery (PIMS)

Team Le Gall / Bado

Department Hepato-Gastroenterology Department

 

Leader(s)

 

Line-up

 

Presentation

Our team is interested in the contribution of the gastrointestinal tract to nutritional pathologies ranging from overnutrition (obesity) to undernutrition (intestinal insufficiency). Obesity is most often associated with co-morbidities such as type 2 diabetes or non-alcoholic fatty liver disease, and pharmacotherapy for this condition remains inconsistently effective. Today, bariatric surgery, which involves remodeling the gastrointestinal tract, is the only effective treatment for maintaining long term weight loss. While these surgeries are extremely beneficial overall, we have reported that they can sometimes lead to intestinal failure, with severe malnutrition, microvesicular steatosis and acute liver failure (Lancet 2013 et Lancet Gastroenterol Hepatol. 2021). These clinical observations are reminiscent of the short bowel syndrome (SBS), which results from an extensive resection of the small intestine and is the main cause of intestinal failure.

The human, social and economic cost of these nutritional pathologies is constantly rising. Their management therefore requires research efforts to better understand their pathophysiological mechanisms, in order to identify new therapeutic targets and strategies.

To meet this societal need, our team gathers basic scientists specialized in the physiology of the gastrointestinal tract and clinicians (gastroenterologists, digestive surgeons and nutritionists). Together, we are studying the mechanisms of gastrointestinal adaptations in response to obesity, undernutrition/malnutrition and surgical remodeling of the gastrointestinal tract.

We set up unique rat models of bariatric surgeries: vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) (PLoS One 2015, Gastroenterology 2016), one anastomosis gastric bypass (OAGB) (Am J Physiol 2016) and most recently sleeve gastrectomy with transit bipartition (SGTB) (Obesity Surgery 2023) as well as rat models of  short bowel syndrome (Sci. Rep. 2016, Front Cell Infect Microbiol. 2023).

Combining experimental investigations in these preclinical models with clinical studies, we identified differences in intestinal adaptations that contribute to improved glucose homeostasis after RYGB versus VSG bariatric surgeries (Gastroenterology 2016, Nature Commun 2021 ). We also characterized the structural and functional adaptations of the residual intestinal mucosa and microbiota in humans and rats with short bowel syndrome (Sci. Rep. 2016, Microorganisms 2016, Front. Physiol. 2017, Front Cell Infect Microbiol. 2023).

In all these studies, we highlighted the plasticity of the gastro-intestinal epithelial cells and its consequences for intestinal functions (Trends Endocrinol Metab. 2017, Nutr Rev. 2019, Annu. Rev. Nutr. 2020).

 

Intestinal reprogramming and improvement of glucose homeostasis after bariatric surgery.

We set up unique rat models of bariatric surgeries as vertical sleeve gastrectomy (VSG) (PLoS One 2015), Roux-en-Y gastric bypass (RYGB) (PLoS One 2015),  one-anastomosed gastric bypass (OAGB) (Am J Physiol 2016) and most recently Sleeve gastrectomy with transit bipartion (SGTB) (Obesity Surgery 2023) Schematic view of the differential intestinal adaptations after RYGB and VSG leading to improvement of glucose tolerance. In response to RYGB, the intestine became hyperplasic, alimentary glucose transport and blood glucose uptake increased but glucose was sequestered by epithelial cells for their own use. In response to VSG, alimentary glucose transport capacity was reduced and a slight increase in transepithelial glucose transport from blood to the lumen was detected. Both intestinal adaptations contribute to ameliorate sugar tolerance after surgery.

Adapted from Cavin et al. Gastroenterology 2016

 

Intestinal Adaptation in Short bowel Syndrom

Spontaneous adaptations in SBS–IF is characterized by (a) intestinal morphological and (b) functional adaptations, with (a) increased intestinal surface, (b) expression of nutrient transporters and secretion of intestinal hormones (PYY, GLP-1), (c) development of compensatory hyperphagia, and (d) dysbiosis of the intestinal microbiota. Hyperphagia reduces dependence on parenteral nutrition by increasing net nutrient absorption. The increase in enterohormones (PYY, GLP-1, GLP-2) helps improve energy recovery, particularly by the intestinal trophic effect (GLP-2) or by slowing gastrointestinal motility (GLP-1, PYY). Dysbiosis has a putative positive effect of producing SCFAs, which fuel colonocytes.

Adapted from Le Beyec et al. Annual Review of Nutrition 2020

We are now extending our studies to both side of the intestinal epithelium: the mucosa layers containing the immune cells versus the luminal microbiota (ANR iMAT AdMir and BARGAIN). Our goal is to determine the functional consequences of changes in immune cells and microbiota on intestinal epithelial cell function.

 

The intestinal “Menage à Trois”

Both sides of the gastro-intestinal epithelium could contribute to the adaptations in response to surgery readouts. In the mucosa, immune cells directly communicate with epithelial cells. In the outer side, microbiota-produced metabolites feed or signal intestinal epithelial cells

To identify new biomarkers and therapeutic targets for these pathologies, we are now developing “omics” studies of the intestinal mucosa and microbiota in preclinical models and, above all, in patient cohorts.

For example, we have set up the COBILOM. Cohort, a cohort of severely obese patients candidates for bariatric surgery, in whom perioperative samples of intestine, liver and visceral and subcutaneous adipose tissues are taken, and who are followed for at least 3 years. We also have an active file of SGC patients, enabling us to identify new markers predictive of response to the only currently available treatment, Teduglutide (Nutrients 2023, Am J Clin Nutr. 2023).

As the long-term results of bariatric surgery vary greatly from one person to another, we plan to use artificial intelligence to identify new predictive markers of success or failure of surgery and in particular weight regain, very common after 2 to 3 years. We will use histological data from COBILOM biobank. Our objectives are to identify factors linked to weight loss as well as the correction of metabolic syndrome, to better predict weight regain, and to evaluate whether specific predictive factors exist depending on the type of bariatric surgery. This will make it possible to propose personalized measures to improve the long-term results of bariatric surgery.

 

Landmark publications

  • Publication date : 02 February 2023 More

    Analysis of the Efficacy and the Long-term Metabolic and Nutritional Status of Sleeve Gastrectomy with Transit Bipartition Compared to Roux-en-Y Gastric Bypass in Obese Rats
    Obes Surg.

    Authors : Baratte Clement Willemetz Alexandra Ribeiro-Parenti Lara Claire Carette Msika Simon Bado André Sebastien Czernichow Le Gall Maude Poghosyan Tigran

  • Publication date : 01 September 2022 More

    Shortening the Biliopancreatic Limb Length of One Anastomosis Gastric Bypass Maintains Glucose Homeostasis Improvement with Limited Weight Loss
    J Clin Med.

    Authors : Ribeiro-Parenti Lara Hounayda El Jindi Willemetz Alexandra Matthieu Siebert Nathalie Kapel Le Beyec Le Bihan Johanne Bado André Le Gall Maude

  • Publication date : 07 January 2022 More

    Similar Gut Hormone Secretions Two Years After One Anastomosis Gastric Bypass and Roux-en-Y Gastric Bypass: a Pilot Study.
    Obes Surg.

    Authors : David De Bandt Claire Rives-Lange Yvann Frigout Damien Bergerot Anne Blanchard Le Gall Maude Jean-Marc Lacorte Jean-Marc Chevallier Sébastien Czernichow Poghosyan Tigran Claire Carette Le Beyec Le Bihan Johanne

  • Publication date : 01 March 2021 More

    Prevention and treatment of nutritional complications after bariatric surgery
    Lancet Gastroenterol Hepatol.

    Authors : Alexandre Nuzzo Sebastien Czernichow Alexandre Hertig Ledoux Séverine Poghosyan Tigran Didier Quilliot Le Gall Maude Bado André Joly Francisca

  • Publication date : 04 January 2021 More

    Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells
    Nature Communications

    Authors : Ribeiro-Parenti Lara Anne-Charlotte Jarry Jean-Baptiste Cavin Willemetz Alexandra Le Beyec Le Bihan Johanne Aurélie Sannier Benadda Samira Pelletier Anne-Laure Muriel Hourseau Thibaut Léger Bastien Morlet Couvelard Anne Younes Anini Msika Simon Marmuse Jean-Pierre Ledoux Séverine Le Gall Maude Bado André

  • Publication date : 27 October 2020 More

    Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass
    Cell Rep.

    Authors : Yuanchao Ye Marwa Abu El Haija Donald A Morgan Deng Guo Yang Song Aaron Frank Liping Tian Ruth A Riedl Colin M L Burnett Zhan Gao Zhiyong Zhu Shailesh K Shahi Kasra Zarei Couvelard Anne Poté Nicolas Ribeiro-Parenti Lara Bado André Lama Noureddine Andrew Bellizzi Paul Kievit Ashutosh K Mangalam Leonid V Zingman Le Gall Maude Justin L Grobe Lee M Kaplan Deborah Clegg Kamal Rahmouni Mohamad Mokadem

  • Publication date : 06 July 2020 More

    Short Bowel Syndrome: A Paradigm for Intestinal Adaptation to Nutrition?
    Annu Rev Nutr.

    Authors : Le Beyec Le Bihan Johanne Billiauws Lore Bado André Joly Francisca Le Gall Maude

  • Publication date : 30 April 2020 More

    Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model
    Scientific Reports

    Authors : Matthieu Siebert Ribeiro-Parenti Lara Nicholas D. Nguyen Muriel Hourseau Belinda Duchêne Lydie Humbert Nicolas Jonckheere Grégory Nuel Jean-Marc Chevallier Henri Duboc Dominique Rainteau Simon Msika Nathalie Kapel Anne Couvelard Bado André Le Gall Maude

  • Publication date : 16 October 2019 More

    Effect of different bariatric surgeries on dietary protein bioavailability in rats
    Physiol Gastrointest Liver Physiol

    Authors : Tessier R Ribeiro-Parenti Lara Bruneau O Khodorova N Cavin JB Bado André Azzout-Marniche D Calvez J Le Gall Maude Gaudichon C

  • Publication date : 01 April 2019 More

    Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.
    FASEB J.

    Authors : Anne-Charlotte Jarry Nadir Merah Cisse Fanta Florence Cayetanot Marie-Noëlle Fiamma Willemetz Alexandra Dalale Gueddouri Besma Barka Philippe Valet Sandra Guilmeau Bado André Le Beyec Le Bihan Johanne Laurence Bodineau Le Gall Maude

  • Publication date : 01 March 2019 More

    Intestinal plasticity in response to nutrition and gastrointestinal surgery.
    Nutr Rev

    Authors : Le Gall Maude Thenet S Aguanno D Jarry AC1 Genser L Ribeiro-Parenti Lara Joly Francisca Ledoux Séverine Bado André Le Beyec Le Bihan Johanne

  • Publication date : 15 February 2019 More

    Gastric bypass specifically impairs liver parameters as compared with sleeve gastrectomy, independently of evolution of metabolic disorders.
    Surg Obes Relat Dis

    Authors : Ledoux Séverine Sami O Calabrese D Le Gall Maude Flamant Martin Coupaye Muriel

  • Publication date : 01 February 2019 More

    Roux-en-Y Gastric-Bypass and sleeve gastrectomy induces specific shifts of the gut microbiota without altering the metabolism of bile acids in the intestinal lumen
    Int J Obes (Lond).

    Authors : Duboc Henri Nguyen CC Cavin JB Ribeiro-Parenti Lara Jarry AC Rainteau D Humbert L Coffin B Le Gall Maude Bado André Sokol H

  • Publication date : 19 April 2017 More

    Microbiota Is Involved in Post-resection Adaptation in Humans with Short Bowel Syndrome.
    Front Physiol

    Authors : Laura Gillard Camille Mayeur Véronique Robert Isabelle Pingenot Le Beyec Le Bihan Johanne Bado André Patricia Lepage Muriel Thomas Joly Francisca

  • Publication date : 21 June 2016 More

    Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome.
    Sci Rep.

    Authors : Gillard L Billiauws Lore Stan-Iuga B Ribeiro-Parenti Lara Jarry AC Cavin JB Cluzeaud F Mayeur C Thomas M Freund JN Lacorte JM Le Gall Maude Bado André Joly Francisca Le Beyec Le Bihan Johanne

  • Publication date : 15 February 2016 More

    Differences in Alimentary Glucose Absorption and Intestinal Disposal of Blood Glucose After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy
    Gastroenterology.

    Authors : Jean-Baptiste Cavin Couvelard Anne Lebtahi Rachida Robert Ducroc Konstantinos Arapis Eglantine Voitellier Françoise Cluzeaud Laura Gillard Muriel Hourseau Nidaa Mikail Ribeiro-Parenti Lara Nathalie Kapel Marmuse Jean-Pierre Bado André Le Gall Maude

 
 

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    Int Immunopharmacol.

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