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Role of the tight junction-mediated intestinal epithelial barrier in the pathogenesis of type 2 diabetes mellitus and the effect of butyrate treatment using in vivo and in vitro models.


Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease of high prevalence worldwide. Recent studies have pointed to a possible correlation between T2DM and an impairment of the intestinal epithelial barrier associated with endotoxemia, although the causal relationship and the molecular mechanisms are still unclear. Butyrate, a short chain organic acid produced by the intestinal microbiota through the fermentation of nondigestible carbohydrates (fibers), has shown positive effects on the intestinal barrier and metabolic parameters at many pathological situations. The main objectives of the present project are: 1) to investigate the possible temporal relationship between metabolic alterations, the appearance of endotoxemia and the structural and functional alterations of the tight junction (TJ)-mediated epithelial barrier in the small and large intestines using an animal model of T2DM; 2) to determine the possible molecular/cellular mechanisms involved in the modulation of the epithelial barrier at this condition; and 3) to investigate the repercussion of the treatment with sodium butyrate on the metabolic changes and function of the intestinal epithelial barrier mediated by TJ in the animal model employed and under in vitro conditions. As an in vivo model, we will use C57BL/6J mice fed a high-fat diet for different periods of time, namely 15, 30 and 60 days, in order to simulate the different stages of the pathogenesis of type 2 diabetes. As an in vitro model of the intestinal epithelial barrier, we will employ the intestinal epithelial cell line, Caco-2 (colon, human). In both models, the effect of treatment with sodium butyrate (5% of the rodent feed and at concentrations of 0.5 to 2mM diluted in the cell culture medium) will be evaluated. In order to assess the function of the intestinal epithelial barrier in these models, we will use electrophysiological and biochemical methods (measurement of transepithelial electrical resistance and transepithelial flux of extracellular markers), morphological (immunohistochemistry for cellular/tissue localization of TJ proteins, namely occludin, claudins and ZO-1), and molecular biology techniques (Western Blot and qPCR to determine the cell/tissue content and gene expression of TJ proteins, respectively). In parallel, several metabolic parameters (glycemia, insulinemia, lipidemia, and peripheral response to glucose and insulin load) and the plasma and intestinal concentrations of LPS and zonulin (as indicators of the levels of endotoxemia) will be measured in the animals of all experimental groups. We believe that the development of this project will shed light on the cellular mechanisms of TJ-mediated intestinal epithelial barrier regulation and its repercussion in the pathogenesis of type 2 diabetes, which may open new horizons for the treatment and prevention of this metabolic disease. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NASCIMENTO, J. C.; MATHEUS, V. A.; OLIVEIRA, R. B.; TADA, S. F. S.; COLLARES-BUZATO, CARLA B.. High-Fat Diet Induces Disruption of the Tight Junction-Mediated Paracellular Barrier in the Proximal Small Intestine Before the Onset of Type 2 Diabetes and Endotoxemia. Digestive Diseases and Sciences, v. 66, n. 10, p. 3359-3374, . (18/02118-2)
OLIVEIRA, R. B.; CANUTO, L. P.; COLLARES-BUZATO, C. B.. Intestinal luminal content from high-fat-fed prediabetic mice changes epithelial barrier function in vitro. Life Sciences, v. 216, p. 10-21, . (13/15676-0, 18/02118-2)
DE OLIVEIRA, RICARDO BELTRAME; MATHEUS, VALQUIRIA APARECIDA; CANUTO, LEANDRO PEREIRA; DE SANT'ANA, ARIANE; COLLARES-BUZATO, CARLA BEATRIZ. Time-dependent alteration to the tight junction structure of distal intestinal epithelia in type 2 prediabetic mice. Life Sciences, v. 238, . (18/02118-2, 13/15676-0)

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