Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease.
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Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 ("T/I" mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 ("T/I-het" dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for development of therapies to prevent reproductive complications and/or growth failure in humans with IBD.
Published Version (Please cite this version)10.1371/journal.pone.0152764
Publication InfoHale, LP; MacIver, Nancie Jo; Nagy, E; Rodriguiz, Ramona M; & Wetsel, William Christopher (2016). Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease. PLoS One, 11(4). pp. e0152764. 10.1371/journal.pone.0152764. Retrieved from http://hdl.handle.net/10161/11956.
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Associate Professor of Pediatrics
My laboratory is broadly interested in how large changes in nutritional status (e.g. malnutrition or obesity) influence T cell immunity. Malnutrition can lead to immunodeficiency and increased risk of infection, whereas obesity is associated with inflammation that promotes multiple diseases including autoimmunity, type 2 diabetes, and cardiovascular disease. We have identified the adipocyte-secreted hormone leptin as a critical link between nutrition and immunity. Leptin is
Associate Professor in Psychiatry and Behavioral Sciences
RESEARCH INTERESTS Last Updated: 31 December 1997 My laboratory uses genetically-modified mice to study the roles that certain genes and gene products play in the expression of abnormal neuroendocrine, neurological, and psychiatric responses. Traditionally, an identification of neuroendocrine dysfunction has involved biochemical analyses of hormonal responses, those for neurological disorders have relied upon behavioral and postmortem analyses, and those for psychiatric co
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