Genetic Link Uncovered Between Endometriosis and Gut Disorders

Unpicking the link between endometriosis and gut issues

Living with endometriosis can be debilitating. The chronic condition – where tissue that is similar to the endometrium grows outside of the uterus – can manifest a whole host of symptoms, including severe pain in the pelvic region, heavy bleeding, fertility issues, pain during sex and mental health issues.

Many women diagnosed with endometriosis also experience gastrointestinal (GI) symptoms that are associated with GI disorders, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Observational studies have started to unpick this link, but there are many questions that remain unanswered. Are these symptoms the effect of one disease on the other? Do GI disorders and endometriosis share etiologies? Could the symptoms be a side effect of pharmacological treatments? Or, have previous observational studies fallen victim to the effect of bias?

Endometriosis affects ~ 190 million women and girls of reproductive age globally. Professor Grant Montgomery, NHMRC leadership fellow at the Institute for Molecular Bioscience, University of Queensland (UQ), explains why the journey to a diagnosis is often convoluted: “Sufferers can find it difficult to distinguish the source of their pain leading to confusion or misdiagnosis and years of delay in treatment during which time the endometriosis can progress to more severe disease.” Montgomery’s research explores the genes and pathways that underpin and increase the risk for common disorders, including endometriosis.

Diving deeper into the mechanism underpinning the observed link between endometriosis and GI disorders could help patients in reaching an appropriate diagnosis and undertaking an effective treatment plan. This was the focus for Dr. Sally Mortlock, research fellow and senior research officer at UQ, and Montgomery, in their latest Cell Press study.

Increased incidence of GI disorders in women with endometriosis

The researchers conducted a comprehensive analysis of observational, genetic and pharmaceutical data obtained from the UK BioBank, the Australian Longitudinal Study on Women’s Health (ALSWH) and the Australian Pharmaceutical Benefits Scheme (PBS).

“We analyzed medical data from 188,000 women in the UK Biobank and found that women with endometriosis were twice as likely to have an IBS diagnosis compared to women without the disease and 1.4 times more likely to have a diagnosis of gastro-esophageal reflux disease (GORD),” Mortlock describes.

GI disorders and endometriosis also share genetic risk factors, Mortlock explains: “We identified evidence that genetic predisposition to IBS also contributes to endometriosis risk. [When] investigating regions of the genome contributing to the risk of both diseases, we identified genes and biological pathways that may be involved in the development of both diseases.”

“This genetic finding supports the clinical observation of an increased incidence of gastrointestinal disorders in women with endometriosis,” Montgomery says.

“Using data from the ALSWH and the PBS, we observed higher use of prescription medications for GI disorders in women with endometriosis and higher use of hormone therapies in women with GI disorders, supporting the co-occurrence of these diseases,” she adds.

Drug repurposing and contraindications for endometriosis

Some of the shared genetic risk regions for both endometriosis and GI disorders are targets for authorized drugs. Mortlock and colleagues believe that their analyses could create new opportunities for repurposing pharmaceuticals to address common symptoms across endometriosis and GI disorders. PDE4B’s encoded protein, for example, is a target of the drug pentoxifylline, which has been trialed for endometriosis and GI disorders separately. “Studies suggest the drug is effective at reducing pain in patients with IBS, but more trials are needed to assess its effectiveness on endometriosis symptoms,” says Mortlock.

Repurposing existing drugs could be beneficial for enhancing endometriosis treatment symptoms. However, Mortlock and colleagues’ study also brings to light the issue of drug contraindications. Many women with endometriosis take non-steroidal anti-inflammatory drugs (NSAIDs) to manage their pain, Mortlock says: “NSAIDs can contribute to the risk of developing GI complications such as peptic ulcer disease (PUD). Clinicians should consider this when prescribing NSAIDs for the management of endometriosis symptoms, especially when women with endometriosis are at higher risk of developing these GI disorders.”

Endometriosis subtypes are a key focus area

Mortlock and colleagues hope that their study raises awareness of the link between GI disorders, so that women experiencing GI symptoms can be correctly diagnosed and their condition managed appropriately.

Their future research will work to identify potential subtypes of endometriosis, using datasets that have more detailed clinical and symptom data. Mortlock explains that this is a priority because one of the key limitations in this study is the varied symptom profiles and lesions in endometriosis patients. “Our recent work with the International Endometriosis Genetics Consortium suggests subtypes of endometriosis likely exist and this may influence the occurrence of comorbid conditions such as GI disorders,” she concludes.

Dr. Sally Mortlock was speaking to Molly Campbell, Senior Science Writer for Technology Networks.

Reference: Yang F, Wu Y, Hockey R et al. Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management. Cell Press. 2023. doi: 10.1016/j.xcrm.2023.101250