title: Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease.
abstract: 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.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Eniko
authors.initials: E
authors.lastname: Nagy
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Nancie J
authors.initials: NJ
authors.lastname: MacIver
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Hale
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000503:physiopathology*; D051379:Mice; D012098:Reproduction