Homoectoine Protects Against Colitis by Preventing a Claudin Switch in Epithelial Tight Junctions

• Published in: Digestive diseases and sciences 2019-02, Vol.64 (2), p.409-420
• Main Authors: Castro-Ochoa, Karla F., Vargas-Robles, Hilda, Chánez-Paredes, Sandra, Felipe-López, Alfonso, Cabrera-Silva, Rodolfo I., Shibayama, Mineko, Betanzos, Abigail, Nava, Porfirio, Galinski, Erwin A., Schnoor, Michael
• Format: Article
• Language: English
• Subjects: Acids; Amino Acids, Diamino - pharmacology; Animals; Biochemistry; Caco-2 Cells; Claudin-1 - drug effects; Claudin-1 - genetics; Claudin-1 - metabolism; Claudin-2 - drug effects; Claudin-2 - genetics; Claudin-2 - metabolism; Colitis; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Colon; Cytokines; Dextran; Dextran Sulfate - toxicity; Disease Models, Animal; Edema; Electric Impedance; Epithelium - drug effects; Gastroenterology; Gastrointestinal diseases; Hepatology; Humans; In Vitro Techniques; Inflammation; Inflammatory bowel disease; Interferon-gamma - pharmacology; Male; Medicine; Medicine & Public Health; Metabolism; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Oncology; Original Article; Oxidative stress; Oxidative Stress - drug effects; Permeability; Permeability - drug effects; Prevention; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Sulfates; Tight Junctions - drug effects; Tight Junctions - metabolism; Transplant Surgery; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-018-5309-8

Background Inflammatory bowel diseases (IBD) are multifactorial disorders affecting millions of people worldwide with alarmingly increasing incidences every year. Dysfunction of the intestinal epithelial barrier is associated with IBD pathogenesis, and therapies include anti-inflammatory drugs that enhance intestinal barrier function. However, these drugs often have adverse side effects thus warranting the search for alternatives. Compatible solutes such as bacterial ectoines stabilize cell membranes and proteins. Aim To unravel whether ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and homoectoine (4,5,6,7-tetrahydro-2-methyl-1H-(1,3)-diazepine-4-carboxylic acid), a synthetic derivative of ectoine, have beneficial effects during dextran sulfate sodium (DSS)-induced colitis in mice. Methods/Results We found that the disease activity index was significantly reduced by both ectoines. DSS-induced edema formation, epithelial permeability, leukocyte recruitment and tissue damage were reduced by ectoine and homoectoine, with the latter having stronger effects. Interestingly, the claudin switch usually observed during colitis (decreased expression of claudin-1 and increased expression of the leaky claudin-2) was completely prevented by homoectoine, whereas ectoine only reduced claudin-2 expression. Concomitantly, only homoectoine ameliorated the drop in transepithelial electrical resistance induced by IFN-γ and TNF-α in Caco-2 cells. Both ectoines inhibited loss of ZO-1 and occludin and prevented IFN-γ/TNF-α-induced increased paracellular flux of 4 kDa FITC-dextran in vitro. Moreover, both ectoines reduced expression of pro-inflammatory cytokines and oxidative stress during colitis. Conclusion While both ectoine and homoectoine have protective effects on the epithelial barrier during inflammation, only homoectoine completely prevented the inflammatory claudin switch in tight junctions. Thus, homoectoine may serve as diet supplement in IBD patients to reach or extend remission.