Intestine: Nutrition, Barrier & Diseases
Principal investigators :
Armelle Leturque, Ph.D. (Research Director) & Edith Brot-Laroche, Ph.D.
Research team :
Véronique Carrière, Michèle Chabert, Sylvie Demignot, Alexandra Grosfeld, Agnès Ribeiro, Patricia Serradas, Sophie Thenet, Edith Brot-Laroche and Monique Rousset.
UMRS_1138 INSERM/UPMC/UPD Centre de recherche des Cordeliers
[See all of Dr. Leturque’s videos here]
The intestine provides an interface with environmental factors, transferring nutrients to the organism, while maintaining an efficient barrier against toxins and bacteria. Intestine has gained new attention for its roles in metabolic diseases. Effective treatments for reduction of obesity are bariatric surgeries that are often followed by increased gut-hormone secretion. Gut-hormone therapies (GLP-1 analogue and DPPIV inhibitors) are developed to treat type2 diabetic patients. A controversy on the stabilized GLP-1 analogues emerged due to cases of pancreatitis sometimes leading to cancer. There is thus an urge to find strategies to stimulate endogenous GLP-1 secretion by obese and diabetic subjects by a better knowledge of enteroendocrine cell lineage and functions. Furthermore, changes in gut microbiota are reported in metabolic diseases. However, the role of epithelial gut barrier between microbiota and related inflammation remains to be characterized in metabolic diseases. Gathering complementary experiences of the team members, our project aims to 1) identify factors that modify enteroendocrine cell lineage and function and how these changes impact pancreas, intestine, brain and gut microbiota in obesity and diabetes; 2) decipher how the intestinal barrier function is controlled by signaling events driven by junction proteins in response to nutrients and bacterial fractions; 3) characterize proximal gut inflammation in obesity in link with metabolic parameters. Cognitive and translational approaches are conducted to answer these questions.
The intestinal epithelium, whose cells are renewed every week, constitutes a dynamic interface between luminal and internal environments. How intestinal cells adapt to environmental changes and trigger pathways required for adaptation to pathophysiological situations is our central question. Our research project is to investigate intestinal functions, enterohormone cell secretion and differentiation, barrier structure and functions, inflammation response to nutrient and bacteria. Questions are addressed through fundamental and translational approaches.
Armelle Leturque is CNRS Director of Research at the Cordeliers Research Centre in Paris, where she leads a team studying the pathophysiology of absorptive-, endocrine-, and barrier-functions of the gut. She joined the Cordeliers Research Center in 2000 and created a research team. Trained as a physiologist, her main research interest is the nutritional and hormonal mechanisms governing systemic homeostasis. Her team demonstrated that membrane receptors-detectors of sugar impact on the whole metabolism in mammals, and that rate of absorption of sugar-rich meal is tripled when GLUT2 transporter is translocated at apical membrane in rescue of permanent SGLT1. The intestine has the rare property to be renewed within a few days, even in adults and thus adapts to its nutritional environment. Our working hypothesis is that gut absorptive, endocrine and barrier functions, modified by environmental factors, are central in systemic homeostasis. Our current projects aim at understanding the regulations at cellular and molecular levels of gut functions focusing on differentiation of enteroendocrine cells, epithelial equipment in junctional proteins, inflammation by immune cell infiltration and their perturbations in obesity and associated diabetes.
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 Mar 31. pii: db140993. [Epub ahead of print].
Khaldoun SA, Emond-Boisjoly MA, Chateau D, Carrière V, Lacasa M, Rousset M, Demignot S, Morel E. Autophagosomes contribute to intracellular lipid distribution in enterocytes. Mol Biol Cell. 2014 Jan;25(1):118-32.
Michau A, Guillemain G, Grosfeld A, Vuillaumier-Barrot S, Grand T, Keck M, L’Hoste S, Chateau D, Serradas P, Teulon J, De Lonlay P, Scharfmann R, Brot-Laroche E, Leturque A, Le Gall M. Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic β cell development. J Biol Chem. 2013 Oct 25;288(43):31080-92.
Petit, C. S. V., Barreau, F., Besnier, L., Gandille, P., Riveau, B., Chateau, D., Roy, M., Berrebi, D., Svrcek, M., Cardot, P., Rousset, M., Clair, C. and Thenet, S. (2012). Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with inflammatory bowel disease. Gastroenterology 143,122–132.
Ait-Omar A, Monteiro-Sepulveda M, Poitou C, Le Gall M, Cotillard A, Gilet J, Garbin K, Houllier A, Chateau D, Lacombe A, Veyrie N, Hugol D, Tordjman J, Magnan C, Serradas P, Clement K, Leturque A, Brot-Laroche E: GLUT2 accumulation in enterocyte apical and intracellular membranes: a study in morbidly obese human subjects and ob/ob and high fat-fed mice. Diabetes 60:2598-2607, 2011.