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Intestine: nutrition, barrier and diseases

In 2010, the International Federation of the Red Cross reported that worldwide overweight people are 1.5 billion, i.e. more than the 925 million of undernourished people. Obesity is leading to extreme BMI associated with many co-morbidities including type 2 diabetes. The 60% of all deaths are from the non-communicable diseases and exceed now the death caused by infectious agents. More knowledge is required to fight against this tremendous societal burden .

The identified causes of the epidemic of chronic diseases are genetic and environmental risk factors. The intestinal epithelium is a target of environmental changes, since it constitutes an interface between external and internal environment. How intestinal cells sense the changes and trigger the adaptation required to physiological and pathological situations is the central question we are addressing through fundamental and translational approaches.
The role of selective barrier of the intestinal epithelium is ensured by a highly polarized architecture. This occurs despite a constant renewing of the epithelial cells from proliferation of progenitors located in the crypts to differentiation into functional intestinal cells along the villus and apoptosis at the villus tip. Cell-cell junctions are key organizers of the dynamic of epithelial architecture that also act as signaling platforms to regulate cell fate. Our objectives are to analyze the structure of cell-cell junctions, i.e. tight and adherens junctions and desmosomes, in response to stress such as nutrient delivery and to decipher the molecular mechanisms through which junctional complexes regulate barrier function, cell proliferation, differentiation and apoptosis. We recently identified the cellular prion protein and desmosomes as new actors of the intestinal barrier function and built the tools to analyze their involvement in signaling events in health as well as in cancer, inflammation and metabolic diseases. In obese subjects, we are investigating intestinal permeability in links with inflammation, microbiota and metabolic/nutritional status via our involvement in IHU ICAN (K. Clément).

Nutrients are not only absorbed via intestine to fuel the organism but they are also detected in the intestinal lumen to trigger metabolic, endocrine and neuroendocrine functions that contribute to energy homeostasis. Enterocytes, the epithelial absorptive cells, and enteroendocrine cells, secreting hormones including GLP-1 (controlling food intake and insulin secretion), are both able to sense nutrients via plasma membrane or intracellular protein sensors. We have shown that the glucose transporter-detector GLUT2 and the lipid receptor SR-BI are nutrient sensors in enterocytes. Importantly, they are expressed in enteroendocrine cells. We generated cell lines and mouse models with inducible, cell-type specific invalidation of these sensors. Our objectives are to determine the signaling pathways triggered by nutrient sensors leading to nutrient-induced enterohormone secretions occurring directly in enteroendocrine cells, or through enteroendocrine-enterocyte crosstalk and to investigate the relative contribution of nutrient sensors in physiological condition and pathological conditions, i.e. human obesity and metabolic inflammation. Impermeant agonists or antagonists of the detectors might be usefull to treat some metabolic diseases through gut functions.

A controversy emerged on the extensive use, for diabetic patients, of stabilized GLP-1 because of adverse effects on pancreas. Our hypothesis is that endogenous GLP-1 production can be promoted by external factors, including nutrients or detector ligands to favor insulin secretion. The differentiation and function of enteroendocrine cells can modulate gut hormone secretion. In obese subjects, we showed that the number of enteroendocrine L cells in jejunum is regulated by metabolic status and by nutrients. How the nutritional environment, the metabolic status and the microbiota in obesity impact on enteroendocrine cell lineage and function will be addressed in obese subjects undergoing a bypass surgery (K. Clément, iCAN) and in mice fed a lipid- or sugar- enriched diet. Our objectives are to identify the transcription factors that are regulated in precursors to mature secreting cells and their epigenetic modifications by diet and to address the impacts of altered enterohormone secretions on whole body homeostasis. The consequences of obesity and diabetes on the brain-gut axis will be also investigated, looking nutrient sensors in jejunal fragments of obese subjects in links with brain fMRI testing food preference (INSEAD, ICAN).

 Team Leader : Armelle LETURQUE (DR CNRS)


Naïma COMUCE (AJT EPHE), Marielle MOREAU (Eng LVMH), Céline OSINSKI (AI SU).

Doriane AGUANNO (PhD SU), Sarah GHEZZAL (PhD SU), Eva GIL (PhD), Lea LE GLEAU (PhD SU), Ingrid LEMA (Post Doc EPHE), Barbara POSTAL (PhD SU).

Administration : Véronique DALET (Eng UPMC)

Contact details : 33 1 44 27 24 14 , Email:


Selected publications

  • Petit CS, Barreau F, Besnier L, Gandille P, Riveau B, Chateau D, Roy M, Berrebi D, Svrcek M, Cardot P, Rousset M, Clair C, Thenet S. Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with inflammatory bowel disease. Gastroenterology. 2012 Jul;143(1):122-32
  • Baraille F, Ayari S, Carrière V, Osinski C, Garbin K, Blondeau B, Guillemain G, Serradas P, Rousset M, Lacasa M, Cardot P, Ribeiro A. Glucose tolerance is improved in mice invalidated for the nuclear receptor HNF-4 gamma: a critical role for enteroendocrine cell lineage. Diabetes. 2015 Aug;64(8):2744-56
  • Monteiro-Sepulveda M, Touch S, Mendes-Sá C, André S, Poitou C, Allatif O, Cotillard A, Fohrer-Ting H, Hubert EL, Remark R, Genser L, Tordjman J, Garbin K, Osinski C, Sautès-Fridman C, Leturque A, Clément K, Brot-Laroche E. Jejunal T Cell Inflammation in Human Obesity Correlates with Decreased Enterocyte Insulin Signaling. Cell Metab. 2015 Jul 7;22(1):113-24
  • Valleix S, Verona G, Jourde-Chiche N, Nédelec B, Mangione PP, Bridoux F, Mangé A, Dogan A, Goujon JM, Lhomme M, Dauteuille C, Chabert M, Porcari R, Waudby CA, Relini A, Talmud PJ, Kovrov O, Olivecrona G, Stoppini M, Christodoulou J, Hawkins PN, Grateau G, Delpech M, Kontush A, Gillmore JD, Kalopissis AD, Bellotti VD25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile. Nat Commun. 2016 Jan 21;7:10353
  • Schmitt CC, Aranias T,  Viel T,  Chateau D, Le Gall M, Waligora-Duprietc, AJ, Melchior C, Rouxel O, Kapel N, Gourcerol G, Tavitian B, Lehuen A, Brot-Laroche E, Leturque A, Serradas P, Grosfeld A Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis Mol Metab 2016 Nov 2016 1:61-72
  • Beilstein F, Lemasson M, Pène V, Rainteau D, Demignot S, Rosenberg AR. Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles. Gut. 2016 Aug 31. pii: gutjnl-2016-311508

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Link to PubMed

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