Estrogen-Mediated Effects Underlie Gender Bias in Inflammatory Bowel Disease

The gastrointestinal tract is continuously exposed to a myriad of food antigens and symbiotic microflora, thus modulation of the inflammatory response is tightly regulated to prevent aberrant immune activation and chronic inflammation. However, in individuals with a genetic and environmental predisposition (eg, altered microbiota, viral or bacterial infection, chemical additives, or pollutants), regulation of intestinal inflammation is impaired. This condition leads to a chronic relapsing immune activation against luminal antigens, also known as inflammatory bowel disease (IBD). 1Kaser A. Zeissig S. Blumberg R. S. Inflammatory bowel disease. Annu Rev Immunol. 2010; 28: 573-621Crossref PubMed Scopus (1477) Google Scholar IBD consists of 2 main types, Crohn's disease (CD) and ulcerative colitis (UC), and typically is characterized by debilitating symptoms such as bloody diarrhea, weight loss, and fatigue. 2Baumgart D. Sandborn W. J. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007; 369: 1641-1657Abstract Full Text Full Text PDF PubMed Scopus (1408) Google Scholar Currently, IBD is emerging as a growing health care problem in industrialized countries, with a prevalence of 0. 5% in the general Western population. 3Kaplan G. G. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1191) Google Scholar This was equal to almost 3. 5 million patients in the United States and Europe, with a direct health care cost of more than US 10 billion annually and an invaluable impact on the emotional, financial, and social state of the patients and their families. 3Kaplan G. G. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1191) Google Scholar Symptoms of IBD fluctuate considerably over time and often flare at times of hormonal changes, such as puberty, pregnancy, and menopause, 2Baumgart D. Sandborn W. J. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007; 369: 1641-1657Abstract Full Text Full Text PDF PubMed Scopus (1408) Google Scholar suggesting a potential involvement of steroid hormones such as 17β estradiol (estrogen), prolactin, and testosterone in the pathogenesis of this disease. As reported for several other chronic inflammatory diseases, 4Rubtsova K. Marrack P. Rubtsov A. V. Sexual dimorphism in autoimmunity. J Clin Invest. 2015; 125: 2187-2193Crossref PubMed Scopus (128) Google Scholar IBD also shows a gender bias, with females slightly more prone to develop CD, whereas males are more likely to develop UC. 5Ananthakrishnan A. N. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015; 12: 205-217Crossref PubMed Scopus (884) Google Scholar Until now, the molecular and cellular mechanisms underlying this gender bias were unclear, although sex-specific differences in the immune system together with hormonal influence on the inflammatory response were thought to play a major role. Data from Goodman et al6Goodman W. A. Havran H. L. Quereshy H. A. Kuang S. De Salvo C. Pizarro T. T. Estrogen receptor α loss-of-function protects female mice from DSS-induced experimental colitis. Cell Mol Gastroenterol Hepatol. 2018; 5: 630-633Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar published in this issue of Cellular and Molecular Gastroenterology and Hepatology disclosed some of the mechanisms responsible for the gender-dependent differences observed in experimental models of intestinal inflammation. In their current work, Goodman et al6Goodman W. A. Havran H. L. Quereshy H. A. Kuang S. De Salvo C. Pizarro T. T. Estrogen receptor α loss-of-function protects female mice from DSS-induced experimental colitis. Cell Mol Gastroenterol Hepatol. 2018; 5: 630-633Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar showed that genetic silencing of the estrogen receptor-α (ERα) in female mice resulted in protection from chemical-induced intestinal inflammation (dextran sodium sulfate DSS). On the contrary, this gender difference was reversed in the case of ERβ knockout mice because DSS-treated ERβ-deficient female mice showed increased signs of intestinal inflammation compared with male mice. 6Goodman W. A. Havran H. L. Quereshy H. A. Kuang S. De Salvo C. Pizarro T. T. Estrogen receptor α loss-of-function protects female mice from DSS-induced experimental colitis. Cell Mol Gastroenterol Hepatol. 2018; 5: 630-633Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Biological effects of estrogens are mediated by at least 2 related members of the steroid-receptor superfamily: ERα and ERβ. ERα and ERβ are nuclear receptors that homodimerize and translocate to the nucleus after ligand binding, and regulate transcription of target genes through either binding to estrogen-response elements in the DNA or by tethering to and influencing the functions of other transcription factors. 7Jia M. Dahlman-Wright K. Gustafsson J. Å. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 557-568Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar The nature of the ER interactome not only will determine the distinct role of ERs in a specific tissue, but also will determine different roles of the same receptor in different tissues. In this way, ERs can modulate several physiological and biological processes ranging from lipid and glucose homeostasis cell proliferation and growth, to immunity, reproduction, and brain development. 7Jia M. Dahlman-Wright K. Gustafsson J. Å. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 557-568Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar Thus, it is not surprising that defective ER signaling has been linked to a variety of diseases such as cancer, metabolic and cardiovascular disease, neurodegeneration, inflammation, and osteoporosis. 7Jia M. Dahlman-Wright K. Gustafsson J. Å. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab. 2015; 29: 557-568Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar Goodman et al6Goodman W. A. Havran H. L. Quereshy H. A. Kuang S. De Salvo C. Pizarro T. T. Estrogen receptor α loss-of-function protects female mice from DSS-induced experimental colitis. Cell Mol Gastroenterol Hepatol. 2018; 5: 630-633Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar investigated if sex-specific differences in ERα or ERβ gene expression may underlie differences in male vs female responses to DSS treatment. However, knockout of each individual ER isoform results in compensatory up-regulation of the other receptor, both in male and female mice, making it unlikely to contribute to sex-based differences. 6Goodman W. A. Havran H. L. Quereshy H. A. Kuang S. De Salvo C. Pizarro T. T. Estrogen receptor α loss-of-function protects female mice from DSS-induced experimental colitis. Cell Mol Gastroenterol Hepatol. 2018; 5: 630-633Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar ERα and ERβ gene expression also was comparable between male and female UC colon samples, suggesting that sex-based differences in ER-mediated effects are most likely not caused by differences in gene expression. It is possible that despite equivalent gene expression, protein expression of ERα/ERβ may be different in males and females, as has been previously shown in the case of colon cancer tissues. 8Foley E. F. Jazaeri A. A. Shupnik M. A. Jazaeri O. Rice L. W. Selective loss of estrogen receptor beta in malignant human colon. Cancer Res. 2000; 60: 245-248PubMed Google Scholar Alternatively, the signaling downstream of ERα/ERβ may results in differential patterns of gene expression in males and females, ultimately leading to enhanced colitis in males. Analysis of gene expression from inflamed colonic tissues identified alteration of typical estrogen-responsive genes such as Socs3, Ctsd, and Fos as being up-regulated in colon tissues of DSS-treated ERα-knockout male mice compared with ERα-knockout females. In line with these data, similar gene expression profiles of Socs3, Ctsd, and Fos were found in colonic biopsy specimens from male and female patients suffering from UC. Overall, these data support the idea that in case of epithelial damage as in DSS colitis and UC, ERβ engagement may result in protection in female mice, but not in males. Interestingly, in a previous study, Goodman et al had shown that male mice but not females were protected by ERβ signaling in an experimental model of Crohn's-like ileitis. 9Goodman W. A. Garg R. R. Reuter B. K. Mattioli B. Rissman E. F. Pizarro T. T. Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol. 2014; 7: 1255-1265Crossref PubMed Scopus (23) Google Scholar This discrepancy may explain an important connection between sex-specific risk to develop UC or CD and protective functions of ERβ signaling in men and women. ERβ is expressed abundantly in the colonic epithelium, where it has an established role in maintaining colonic architecture, tight-junction formation, and barrier function. 10Looijer-van Langen M. Hotte N. Dieleman L. A. Albert E. Mulder C. Madsen K. L. Estrogen receptor-beta signaling modulates epithelial barrier function. Am J Physiol Gastrointest Liver Physiol. 2011; 300: G621-G626Crossref PubMed Scopus (116) Google Scholar, 11Wada-Hiraike O. Imamov O. Hiraike H. Hultenby K. Schwend T. Omoto Y. Warner M. Gustafsson J. A. Role of estrogen receptor beta in colonic epithelium. Proc Natl Acad Sci U S A. 2006; 103: 2959-2964Crossref PubMed Scopus (203) Google Scholar Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, 12Pierdominici M. Maselli A. Varano B. Barbati C. Cesaro P. Spada C. Zullo A. Lorenzetti R. Rosati M. Rainaldi G. Limiti M. R. Guidi L. Conti L. Gessani S. Linking estrogen receptor β expression with inflammatory bowel disease activity. Oncotarget. 2015; 6: 40443-40451Crossref PubMed Scopus (48) Google Scholar pointing to ERβ as a critical regulator of colonic architecture and function. Importantly, ERβ functions as a dominant-negative regulator of ERα functions. 13Maruyama K. Endoh H. Sasaki-Iwaoka H. Kanou H. Shimaya E. Hashimoto S. Kato S. Kawashima H. A novel isoform of rat estrogen receptor beta with 18 amino acid insertion in the ligand binding domain as a putative dominant negative regular of estrogen action. Biochem Biophys Res Commun. 1998; 246: 142-147Crossref PubMed Scopus (128) Google Scholar Therefore, ERβ's protective role in the colon may be owing to direct targets of ERβ-mediated gene transcription, or via indirect effects on the inhibition of ERα-mediated targets. However, a clear understanding of the molecular mechanisms by which ERβ signaling protects female colonic mucosa while it worsens intestinal inflammation in males still is missing. So far, there is no actual cure for IBD, making patients dependent on lifelong symptomatic medical treatment aimed to reduce and/or delay recurrence of intestinal inflammation. Managing IBD is therefore an important priority in gastroenterology, requiring a multidisciplinary approach that combines the optimization of current symptomatic therapies with the development of novel treatments to ultimately cure this devastating disease. Targeting of ER may be a novel approach to IBD treatment during the acute phase of inflammation. Further understanding of the different molecular and cellular mechanisms involved in the gender response and in the engagement of the 2 ER receptors during intestinal inflammation will be of vital importance to improve gender-specific treatment for patients suffering from IBD. Estrogen Receptor α Loss-of-Function Protects Female Mice From DSS-Induced Experimental ColitisCellular and Molecular Gastroenterology and HepatologyVol. 5Issue 4PreviewMales are at greater risk than females for developing ulcerative colitis (UC) and experiencing worse clinical disease1–3; the molecular basis for this sex bias remains unclear. An important regulatory mechanism of colonic homeostasis is via noncanonical estrogen receptor (ER) signaling. Very low levels of circulating estrogen are required to bind transmembrane and cytosolic ERs, such that immune responses in both sexes are subject to regulation by estrogen. Estrogen receptor β (ERβ) is expressed abundantly in the human colon, 4, 5 where it has a critical role in maintaining barrier function and colonic architecture. Full-Text PDF Open Access