Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), as do most chronic inflammatory disorders, displays unique features and confers different risk factors in male and female patients. Importantly, sex-based differences in IBD exist for epidemiological incidence and prevalence among different age groups, with men and women developing distinct clinical symptoms and disparity in severity of disease. In addition, the presentation of comorbidities in IBD displays strong sex differences. Notably, particular issues exclusive to women's health, including pregnancy and childbirth, require specific considerations in female patients with IBD of childbearing age that can have a substantial influence on clinical outcomes. This Review summarizes the latest findings regarding sex-based differences in the epidemiology, clinical course, comorbidities and response to current therapies in patients with IBD. Importantly, the latest basic science discoveries in this area of investigation are evaluated to provide insight into potential mechanisms underlying the influence of sex on disease pathogenesis, as well as to design more personalized and efficacious care, in patients with IBD.

Fig. 1 |. Sex-specific risk of Crohn’s disease throughout the lifespan.

During early childhood, boys have a higher risk than girls of developing Crohn’s disease. However, around the time of puberty, the risk of Crohn’s disease in girls increases substantially, potentially owing to shifting hormone levels. The majority of population-based studies of Western cohorts show an increased risk of Crohn’s disease among women compared with men.

Fig. 2 |. IBD comorbidities showing differential prevalence between male and female patients.

IBD comorbidities often manifest in sex-specific ways. Male patients carry a higher risk of malignant neoplasias, colitis-associated colorectal cancer and extraintestinal manifestations, such as primary sclerosing cholangitis, urolithiasis and primary ankylosing spondylitis (left). Female patients carry a higher risk of cardiovascular disease, anaemia, nutrient deficiencies, apical periodontitis and oral cancer (right).

Fig. 3 |. Men with ulcerative colitis and women with Crohn’s disease show reductions in quality of life parameters.

Quality of life is diminished in patients with severe IBD symptoms. Female patients with Crohn’s disease and male patients with ulcerative colitis are most likely to report increased anxiety and depression, disability and interference with professional productivity, including greater rates of unemployment. In addition, there is a high rate of voluntary childlessness among women with Crohn’s disease, potentially due to lack of information about how their disease might influence their unborn child. The intensity of the colour of each bar reflects the impact of each parameter.

Fig. 4 |. Potential mechanisms contributing to sex differences in IBD.

This schematic shows the potential mechanisms underlying sex-based differences in IBD according to basic research. Based on its role in other inflammatory disorders, as well as its clear link to IBD, the microbiota might contribute to sex-based differences in IBD by several different mechanisms, including differences in commensal composition between male mice and female mice, the ability of the microbiota in male mice to induce testosterone that has protective effects, and the induced protection in female mice after faecal transplantation from male donors. Oestrogen (E2) has also been shown to have immunoprotective effects during experimental colitis by inducing regulatory T (T_reg) cell expansion and function in male mice in an oestrogen receptor (ER)-β-dependent manner. In addition, decreased ERβ has been observed in both epithelial and T_reg cells from female mice prone to ileitis and/or colitis, which can promote intestinal epithelial barrier dysfunction and worsening of disease. Interestingly, decreased expression of ERα in male mice results in exacerbation of intestinal inflammation, but has the opposite effect in female mice, suggesting that skewing towards ERβ signalling induces global protection from colitis. Finally, increasing evidence indicates that differential transcription (for example, by DNA methylation) of genes located on chromosome X can regulate molecules that can also affect downstream sex-based differences in the pathogenesis of IBD. T_H1 cell, T helper 1 cell.