RESUMO
Acute and chronic colitis affect a huge proportion of the population world-wide. The etiology of colitis cases can be manifold, and diet can significantly affect onset and outcome of colitis. While many forms of acute colitis are easily treatable, chronic forms of colitis such as ulcerative colitis and Crohn's disease (summarized as inflammatory bowel diseases) are multifactorial with poorly understood pathogenesis. Inflammatory bowel diseases are characterized by exacerbated immune responses causing epithelial dysfunction and bacterial translocation. There is no cure and therapies aim at reducing inflammation and restoring intestinal barrier function. Unfortunately, most drugs can have severe side effects. Changes in diet and inclusion of nutritional supplements have been extensively studied in cell culture and animal models, and some supplements have shown promising results in clinical studies. Most of these nutritional supplements including vitamins, fatty acids and phytochemicals reduce oxidative stress and inflammation and have shown beneficial effects during experimental colitis in rodents induced by dextran sulphate sodium or 2,4,6-trinitrobenzene sulfonic acid, which remain the gold standard in pre-clinical colitis research. Here, we summarize the mechanisms through which such nutritional supplements contribute to epithelial barrier stabilization.
Assuntos
Colite Ulcerativa/dietoterapia , Doença de Crohn/dietoterapia , Suplementos Nutricionais , Mucosa Intestinal/efeitos dos fármacos , Animais , Células CACO-2 , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Ácidos Graxos/administração & dosagem , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Compostos Fitoquímicos/administração & dosagem , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Resultado do Tratamento , Ácido Trinitrobenzenossulfônico/toxicidade , Vitaminas/administração & dosagemRESUMO
The gastrointestinal tract is the largest hormone-producing organ in the body due to a specialized cell population called enteroendocrine cells (EECs). The number of EECs increases in the mucosa of inflammatory bowel disease patients; however, the mechanisms responsible for these changes remain unknown. Here, we show that the pro-inflammatory cytokines interferon γ (IFNγ) and tumor necrosis factor α (TNFα) or dextran sulfate sodium (DSS)-induced colitis increase the number of EECs producing chromogranin A (CgA) in the colonic mucosa of C57BL/6J mice. CgA-positive cells were non-proliferating cells enriched with inactive phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and autophagy markers. Moreover, inhibition of Akt and autophagy prevented the increase in CgA-positive cells after IFNγ/TNFα treatment. Similarly, we observed that CgA-positive cells in the colonic mucosa of patients with colitis expressed Akt and autophagy markers. These findings suggest that Akt signaling and autophagy control differentiation of the intestinal EEC lineage during inflammation.
Assuntos
Cromogranina A/metabolismo , Colo/citologia , Citocinas/farmacologia , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Células Neuroendócrinas/efeitos dos fármacos , Células Neuroendócrinas/metabolismo , Animais , Autofagia/efeitos dos fármacos , Western Blotting , Células CACO-2 , Colite/metabolismo , Imunofluorescência , Humanos , Interferon gama/farmacologia , Interleucina-1beta/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) are multifactorial, relapsing disorders of the gastrointestinal tract. However, the etiology is still poorly understood but involves altered immune responses, epithelial dysfunction, environmental factors, and nutrition. Recently, we have shown that the diet supplement corabion has cardioprotective effects due to reduction of oxidative stress and inflammation. Since oxidative stress and inflammation are also prominent risk factors in IBD, we speculated that corabion also has beneficial effects on experimental colitis. Colitis was induced in male mice by administration of 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for a period of 3 or 7 days with or without daily gavage feeding of corabion consisting of vitamin C, vitamin E, L-arginine, and eicosapentaenoic and docosahexaenoic acid. We found that corabion administration attenuated DSS-induced colon shortening, tissue damage, and disease activity index during the onset of colitis. Mechanistically, these effects could be explained by reduced neutrophil recruitment, oxidative stress, production of proinflammatory cytokines, and internalization of the junctional proteins ZO-1 and E-cadherin leading to less edema formation. Thus, corabion may be a useful diet supplement for the management of chronic inflammatory intestinal disorders such as IBD.
Assuntos
Cardiotônicos/uso terapêutico , Colite/tratamento farmacológico , Colite/prevenção & controle , Suplementos Nutricionais , Inflamação/patologia , Estresse Oxidativo , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismo , Animais , Cardiotônicos/farmacologia , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismoRESUMO
The intestinal epithelium forms a stable barrier protecting underlying tissues from pathogens in the gut lumen. This is achieved by specialized integral membrane structures such as tight and adherens junctions that connect neighboring cells and provide stabilizing links to the cytoskeleton. Junctions are constantly remodeled to respond to extracellular stimuli. Assembly and disassembly of junctions is regulated by interplay of actin remodeling, endocytotic recycling of junctional proteins, and various signaling pathways. Accumulating evidence implicate small G proteins of the Ras superfamily as important signaling molecules for the regulation of epithelial junctions. They function as molecular switches circling between an inactive GDP-bound and an active GTP-bound state. Once activated, they bind different effector molecules to control cellular processes required for correct junction assembly, maintenance and remodelling. Here, we review recent advances in understanding how GTPases of the Rho, Ras, Rab and Arf families contribute to intestinal epithelial homeostasis.