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Activation of Free Fatty Acid Receptor 4 Affects Intestinal Inflammation and Improves Colon Permeability in Mice.

ABSTRACT: Diet is considered an important trigger in inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of bacterial antigens, consequently influencing the immune system. Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of colitis. Therapeutic activity of GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic colitis: induced by trinitrobenzenesulfonic acid (TNBS), mimicking Crohn's disease, as well as induced by dextran sulfate sodium (DSS), which recapitulates ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by forskolin and veratridine. Administration of FFAR4 agonist GSK137647 attenuated both TNBS-induced and DSS-induced colitis in mice, as indicated by macroscopic parameters and myeloperoxidase activity. The action of FFAR4 agonist GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain fatty acids, attenuates intestinal inflammation.

SUBMITTER: Salaga M

PROVIDER: S-EPMC8399282 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Obesity and its related metabolic syndrome continue to be major public health problems. Monosodium L-glutamate (MSG) may cause metabolic diseases such as obesity. Meanwhile, the Chinese population has undergone rapid transition to a high-fat diet. There is little information available on the effect of MSG and fat alone, or in combination, on free fatty acids (FFAs), lipid metabolism and FFA receptors. Objective:The aim of this study was to evaluate the effects of MSG and fat alone, or in combination, on intestinal luminal FFAs and expression of gastrointestinal FFA receptors. The aim was also to test whether dietary fat and/or MSG could affect expression of genes related to fatty acid metabolism. Design:A total of 32 growing pigs were used and fed with four iso-nitrogenous and iso-caloric diets. Pigs in the four treatments received diets with one of two fat concentrations levels (4.4 and 9.4%) and one of two MSG dose levels (0 and 3%), in which most of the fat were brought by soybean oil. The concentration of short chain fatty acids (SCFAs) in cecum and colon, long chain fatty acids (LCFAs) in ileum, cecum and colon, and FFAs receptors expression in hypothalamus and gastrointestinal tract were determined. Results:MSG and/or fat changed intestinal luminal SCFAs, levels of LCFAs, and showed an antagonistic effect on most of LCFAs. Simultaneously, MSG and/or fat decreased the expression of FFA receptors in hypothalamus and gastrointestinal tract. MSG and/or fat promoted fat deposition through different ways in back fat. Conclusion:Our results support that MSG and/or fat can alter intestinal luminal FFAs composition and concentration, especially LCFAs, in addition, the expression of FFA receptors in ileum and hypothalamus could be decreased. Moreover, MSG and/or fat can promote protein deposition in back fat, and affect the distribution and metabolism of fatty acids in the body tissues and the body's ability to perceive fatty acids; these results provide a reference for the occurrence of fat deposition and obesity caused by high-fat and monosodium glutamate diet.

Project description:Background & aimsThe limited availability of organoid systems that mimic the molecular signatures and architecture of human intestinal epithelium has been an impediment to allowing them to be harnessed for the development of therapeutics as well as physiological insights. We developed a microphysiological Organ-on-Chip platform designed to mimic properties of human intestinal epithelium leading to insights into barrier integrity.MethodsWe combined the human biopsy-derived leucine-rich repeat-containing G-protein-coupled receptor 5-positive organoids and Organ-on-Chip technologies to establish a micro-engineered human Colon Intestine-Chip (Emulate, Inc, Boston, MA). We characterized the proximity of the model to human tissue and organoids maintained in suspension by RNA sequencing analysis, and their differentiation to intestinal epithelial cells on the Colon Intestine-Chip under variable conditions. Furthermore, organoids from different donors were evaluated to understand variability in the system. Our system was applied to understanding the epithelial barrier and characterizing mechanisms driving the cytokine-induced barrier disruption.ResultsOur data highlight the importance of the endothelium and the in vivo tissue-relevant dynamic microenvironment in the Colon Intestine-Chip in the establishment of a tight monolayer of differentiated, polarized, organoid-derived intestinal epithelial cells. We confirmed the effect of interferon-γ on the colonic barrier and identified reorganization of apical junctional complexes, and induction of apoptosis in the intestinal epithelial cells as mediating mechanisms. We show that in the human Colon Intestine-Chip exposure to interleukin 22 induces disruption of the barrier, unlike its described protective role in experimental colitis in mice.ConclusionsWe developed a human Colon Intestine-Chip platform and showed its value in the characterization of the mechanism of action of interleukin 22 in the human epithelial barrier. This system can be used to elucidate, in a time- and challenge-dependent manner, the mechanism driving the development of leaky gut in human beings and to identify associated biomarkers.

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Activation of Free Fatty Acid Receptor 4 Affects Intestinal Inflammation and Improves Colon Permeability in Mice.

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