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Early Life Stress Triggers Persistent Colonic Barrier Dysfunction and Exacerbates Colitis in Adult IL-10/ Mice

Lennon, E. M. DVM*; Maharshak, Nitsan MD†,‡; Elloumi, H. PhD; Borst, L. DVM, PhD*; Plevy, S. E. MD; Moeser, Adam J. DVM, PhD*,§

doi: 10.1097/MIB.0b013e3182802a4e
Original Basic Science Articles

Background: It has become increasingly evident that disease flares in the human inflammatory bowel diseases are influenced by life stress. It is known that life stress can trigger disturbances in intestinal barrier function and activate proinflammatory signaling pathways, which are important contributors to intestinal inflammation and clinical disease; however, the exact mechanisms of stress-induced inflammatory bowel disease exacerbations remain to be elucidated. Here, we presented a model of early life stress–induced exacerbation of colitis in interleukin (IL)-10−/− mice.

Methods: C57Bl/6 wild-type and IL-10−/− mice were exposed to neonatal maternal separation (NMS) stress on postnatal days 1 to 18 and reared under normal conditions until 10 to 12 weeks of age. At this time, histopathology, colitis scores, intestinal barrier function, proinflammatory cytokine expression, and mast cell activity were evaluated.

Results: NMS increased the severity of colitis IL-10−/− mice indicated by greater colitis scores and colonic proinflammatory cytokine concentrations. NMS and IL-10−/− increased colonic permeability; however, NMS alone did not induce colitis. Increased mast cell activation and colonic tryptase release were observed in IL-10−/− mice exposed to NMS, indicating mast cell activation.

Conclusions: This study demonstrates that colitis in IL-10−/− mice can be exacerbated by NMS stress. The precise mechanisms of enhanced colitis severity in NMS IL10−/− mice are unclear but persistent defects in intestinal barrier function likely play a contributing role. NMS serves as a novel model to investigate the mechanisms by which early life stress influences the development and course of inflammatory bowel disease in adulthood.

Article first published online 26 February 2013

*Department of Population Health and Pathobiology, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina

Departments of Medicine, Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

§Center for Comparative Medicine and Translational Research (CCMTR), North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina.

Reprints: Adam J. Moeser, DVM, PhD, Department of Population Health and Pathobiology, North Carolina State University, College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC 27607 (e-mail: ajmoeser@ncsu.edu).

Supported by the NIH K08 DK084313 (A.J.M.), R01 DK54452 (S.E.P.), and P30 DK34987 (A.J.M. and S.E.P., Immunotechnologies Core and Histology Core). N. Maharshak is supported by the Crohn’s and Colitis Foundation of America Research Fellowship Award and the American Physicians Fellowship for Medicine in Israel. E. M. Lennon is supported by the Ruth L. Kirschstein National Research Service Award T32 RR024394 as part of North Carolina State University's Comparative Medicine and Translational Research Training Program.

E. M. Lennon and N. Maharshak contributed equally to this paper.

The authors have no conflicts of interest to disclose.

Received July 06, 2012

Accepted July 09, 2012

© Crohn's & Colitis Foundation of America, Inc.
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