PGI2 Inhibits Intestinal Epithelial Permeability and Apoptosis to Alleviate Colitis

Abstract

This study questions reduced prostacyclin production in mucosa from inflammatory bowel disease patients and highlights prostacyclin regulation of the intestinal epithelial barrier. Combining mouse model and human sample analyses, we demonstrated that prostacyclin prevented colitis and occludin down-regulation, inhibited apoptosis, induced occludin membrane location, and reduced intestinal epithelial permeability.BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) that encompass both ulcerative colitis and Crohn's disease are a major public health problem with an etiology that has not been fully elucidated. There is a need to improve disease outcomes and preventive measures by developing new effective and lasting treatments. Although polyunsaturated fatty acid metabolites play an important role in the pathogenesis of several disorders, their contribution to IBD is yet to be understood. METHODS:Polyunsaturated fatty acids metabolite profiles were established from biopsy samples obtained from Crohn's disease, ulcerative colitis, or control patients. The impact of a prostaglandin I 2 (PGI 2 ) analog on intestinal epithelial permeability was tested in vitro using Caco-2 cells and ex vivo using human or mouse explants. In addition, mice were treated with PGI 2 to observe dextran sulfate sodium (DSS)-induced colitis. Tight junction protein expression, subcellular location, and apoptosis were measured in the different models by immunohistochemistry and Western blotting.RESULTS: A significant reduction of PGI 2 in IBD patient biopsies was identified. PGI 2 treatment reduced colonic inflammation, increased occludin expression, decreased caspase-3 cleavage and intestinal permeability, and prevented colitis development in DSS-induced mice. Using colonic explants from mouse and human control subjects, the staurosporine-induced increase in paracellular permeability was prevented by PGI 2 . PGI 2 also induced the membrane location of occludin and reduced the permeability observed in colonic biopsies from IBD patients. CONCLUSIONS:The present study identified Q7 a PGI 2 defect in the intestinal mucosa of IBD patients and demonstrated its protective role during colitis.

Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis

“…The mechanism by which it induces colitis is unclear; however, this model does not require the activation of T and B cells, thus excluding adaptative immunity study, but favoring the study of the contribution of the innate immune system to the development of intestinal inflammation. In addition, the DSS colitogen likely induces epithelial apoptosis and consequent damages, and is, therefore, a useful model to study epithelial-dependent remodeling and inflammation in colitis [ 26 ]. In the present study, we demonstrate that IEC AMPK is an important player in the modulation of the sensitivity to DSS-induced colitis and regulation of mucosal repair after injury, suggesting the potential for targeting AMPK in the treatment of leaky gut disorders.…”

Periodontitis Salivary Microbiota Worsens Colitis

“…These results indicated that periodontitis salivary microbiota exacerbated colitis from the aspects of gut microbiota and metabolome. However, recent studies have suggested that prostaglandins may have a protective effect on the gut (Miyoshi et al 2017; Pochard et al 2021), suggesting the increase of inflammation-related metabolites may reflect a protective adaptation of suffered tissues. Further investigation about the role of these substances in the disease is warranted.…”

Polyunsaturated Fatty Acid-Derived Lipid Mediators That Regulate Epithelial Homeostasis

“…40) Furthermore, prostaglandin I 2 (PGI 2 )-IP signaling in intestinal epithelial cells suppressed epithelial permeability, maintained occludin expression, and inhibited epithelial apoptosis. 41) Thromboxanes, another prostanoid produced by COXs, are involved in the regulation of epithelial homeostasis via TP receptor. In the skin, TP is expressed in epidermal keratinocytes and dorsal root ganglion (DRG) neurons.…”

“…LTB 4 promoted skin homing of neutrophils and CD8 + T cells, contributing to pathogenesis of dermatitis. [54][55][56] LTB 4 also medi- Epidermis ・Enhances TSLP production 24,25) ・Suppresses CXCL1 induction 29) ・Promotes wound healing 49) ・Activates mast cells 30) ・Mediates dendritic cells 31) ・Regulates T cell differentiation [32][33][34][35] Intestine ・Inhibits necroptosis 37) ・Causes malabsorption 39) PGD 2 Intestine ・Suppresses IL13Rα expression 40) PGI 2 Intestine ・Inhibits permeability 41) 15d-PGJ 2 Breast epithelium ・Induces apoptosis 50) TXA 2 Epidermis ・Induces pruritus 42,51) ・Mediates γδT cell 43) 12-HHT Epidermis ・Promotes migration 45) ・Mediates barrier function 46) Cornea ・Promotes migration 47) Intestine ・Mediates barrier function 48) ・Enhances proliferation 52) Epidermis ・Enhances CCL27 production 57) ・Promotes homing of immune cells [54][55][56] LTD 4…”