The Role of Estrogen Signaling in a Mouse Model of Inflammatory Bowel Disease: A Helicobacter Hepaticus Model

Abstract

The pathogenesis of inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, is due in part to interactions between the immune system, genetics, the environment, and endogenous microbiota. Gonadal sex hormones (GSH), such as estrogen, are thought to be involved in the development of IBD as variations in disease severity occur during pregnancy, menopause, or oral contraceptives use. In certain strains of mice, infection with Helicobacter hepaticus triggers IBD-like mucosal inflammation that is more severe in female mice than in males, suggesting a role for GSH in this model. To determine the role of estrogen signaling in microbiota-induced intestinal inflammation, estrogen receptor (ER) α and β knock-out (KO) mice, ER agonists, and adoptive transfers were utilized. We demonstrate that, when signaling is limited to ERβ on a non-CD4+ cell subset, disease is less severe and this correlates with decreased expression of pro-inflammatory mediators.

Age, Gender, and Women’s Health and the Patient

“…The positive role of estrogen in maintaining intestinal barrier function may be through maintenance of tight junctions and/or influence on inflammatory response. 102…”

Actual Usage and Quality of Experimental Colitis Models in Preclinical Efficacy Testing

“…However, female mice develop a more severe disease when inoculated with H. hepaticus than male mice, which seems to contradict the aforementioned studies. 27 Female mice secrete higher levels of IL-6 and IL-12 than male mice in chronic DSS and TNBS models. Interventions acting on the cytokine signaling system may therefore have a different efficacy in male versus female mice.…”

“…25,26 Estrogen-deficient mice infected with the bacteria Helicobacter hepaticus and treated with placebo developed a much more severe inflammation than estrogen-deficient mice treated with 17b-estradiol. 27 Specifically, it is suggested that signaling through the estrogen-b-receptor seems to decrease disease severity. However, female mice develop a more severe disease when inoculated with H. hepaticus than male mice, which seems to contradict the aforementioned studies.…”

Inflammatory Bowel Disease

“…Although estrogen signaling through nuclear estrogen receptors (ERs) is generally considered to promote immunity, correlating with enhanced immune responses against infectious agents in female patients, 19 divergent estrogen effects have been reported in other disease settings. Several genetic and bacterial models of IBD in mice display a similar female bias for severe intestinal inflammation 20, 21 and studies of estrogen signaling in these systems have revealed cell-specific mechanisms of estrogen-mediated immunomodulation. Exogenous estrogen treatment in Th1-linked experimental colitis has been shown to reduce tissue inflammatory and injury indices, and suppress proinflammatory cytokine expression and mast cell protease levels in an ER-dependent manner.…”

“…22 Helicobacter hepaticus inoculation of ER knockout mice further revealed that functional ERβ signaling in the absence of ERα is sufficient to dampen intestinal inflammation and proinflammatory cytokine expression in bacterially-induced IBD. 20 Estrogen signaling through intestinal epithelial cell ERβ supports tight junction development and decreases intestinal permeability, thereby reinforcing the primary cellular mucosal barrier to omnipresent gut microbes. 23 Furthermore, ERβ mRNA levels are reduced in colonic biopsies from IBD patients and IL-10 knockout (IL-10 −/− ) mice, with increased colonic permeability preceding the onset of colitis in this genetic mouse model.…”