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.





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Nagy, Eniko, Ramona M Rodriguiz, William C Wetsel, Nancie J MacIver and Laura P Hale (2016). Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease. PLoS One, 11(4). p. e0152764. 10.1371/journal.pone.0152764 Retrieved from

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Nancie Jo MacIver

Adjunct Associate Professor in the Department 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 secreted from adipocytes in proportion to adipocyte mass and is therefore decreased in malnutrition and increased in obesity.  We have found that leptin is a critical regulator of effector T cell glucose metabolism and thereby drives effector T cell activation.  From these initial findings, we have established further lines of investigation, as summarized here.

(1) Determining molecular mechanisms of T cell dysfunction in malnutrition – Our goal is to identify metabolic and epigenetic mechanisms by which malnutrition and decreased leptin alter T cell function leading to increased susceptibility to infection and protection against autoimmune diseases.  We study this using a mouse model of autoimmunity, experimental autoimmune encephalomyelitis (EAE).

(2) Elucidating mechanisms of T cell inflammation in obesity-induced type 2 diabetes – Our goal is to identify molecular and metabolic mechanisms by which obesity alters the Teff/Treg balance, resulting in inflammation and subsequent insulin resistance leading to type 2 diabetes.  With our collaborators from UNC Chapel Hill, we are also identifying immunometabolic changes in obese animals and humans that correlate with increased susceptibility to influenza.

(3) Determining the role of insulin and IGF-1 in regulating T cell function and metabolism – Our goal is to identify how insulin influences both T cell glucose uptake and T cell differentiation/cytokine production and determine the role of insulin signaling in T cells in the setting of obesity-associated diabetes.  We hypothesize that insulin has a direct role in T cell function through its abiltiy to alter T cell glucose metabolism, influence T cell cytokine production, and impact the pathophysiology of obesity-associated type 2 diabetes. 


Laura Pope Hale

Professor of Pathology

The Hale laboratory employs techniques of cellular and molecular biology to study mechanisms responsible for the generation of both normal immune responses and immune-mediated diseases. Research in the laboratory is mainly focused on inflammatory bowel disease (IBD), an immune-mediated disorder that is hypothesized to result from the abnormal immune response of a genetically susceptible host to the antigens derived from enteric bacteria. Development of optimal treatments for disease requires a detailed understanding of mechanisms of disease pathogenesis. Thus current work in the laboratory is aimed at understanding triggers of intestinal inflammation and mechanisms of inflammation-associated neoplasia, in addition to developing novel therapies for IBD treatment. Ongoing research also includes investigating mechanisms that determine the immunogenicity of oral antigens, to develop novel adjuvants for oral vaccines. This work has relevance for pathogenesis and treatment of infectious diseases affecting the gastrointestinal tract, as well as for inflammatory bowel disease.

Dr. Hale is an expert in pathologic evaluation of colitis and immunodeficiency in both humans and mice and is board-certified in Anatomic and Clinical Pathology.

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