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LONDON, ON - In a study involving 542 Crohn’s disease patients, researchers at Lawson Health Research Institute examined whether a patient’s DNA can be used to identify their risk of severe disease. They found that patients with a genetic variant in a gene called FXR (farnesoid X-receptor) are much more likely to need surgery and to need it earlier in their care journey. Surprisingly, they found that women with the genetic variant are at an even higher risk than men.

Crohn’s disease is an often debilitating condition that affects one in every 150 Canadians. The condition is characterized by intestinal inflammation caused by unnecessary attacks from the body’s immune system. It’s a disease that can behave and progress differently from one person to the next, with some requiring surgery to remove affected parts of the intestine.

“While medications are prescribed to manage Crohn’s disease, physicians have to balance the risk of side effects with the risk of undertreating severe cases of the disease,” explains Dr. Aze Wilson, Associate Scientist at Lawson Health Research Institute and Gastroenterologist at London Health Sciences Centre (LHSC). “In order to personalize treatment, it would be great to have a tool for identifying which patients will have the most severe cases of illness.”

Dr. Wilson and her colleagues became interested in the FXR gene because of its role in intestinal health. The FXR gene is a part of human DNA that controls how we process drugs and has also been linked to how well our intestines work. The research team suspected that variation in the gene could lead to poorer outcomes in Crohn’s disease patients. 

“Given the importance of FXR to intestinal health, we wanted to see whether it plays a role in disease severity and we discovered that it does,” says Dr. Wilson. “Our findings suggest that genetic testing could be used to identify patients at a high risk of poor outcomes. This would allow physicians to tailor treatments to give patients the best chance at success.”

The team also discovered that women who carried the genetic variant were at the highest risk of needing surgery and the highest risk of early surgery, even when compared to men with the genetic variant. Struck by this finding, they conducted further testing using laboratory-based cell models. They found that estrogen (a female sex hormone) in combination with the genetic variant reduced the function of FXR even further. 

“Differences between men and women with Crohn’s disease are not often considered in research or clinical practice. We apply treatments in the same way to both sexes, which may not be the best approach,” explains Dr. Wilson. “We identified a group of women who may benefit from a different approach to care. The study highlights the need for evaluating the effect of biological sex on disease and the interaction it may have with our DNA.”

Looking forward, the team hopes to further explore the effect of this genetic variant on intestinal health using laboratory-based cell models. They also hope to assess the value of genetic testing as a tool for informing treatment decisions made by patients and their physicians. 

“One of our larger goals as a research group is to develop a personalized care plan for patients with Crohn’s disease and ulcerative colitis – one that integrates genetic information and other biomarkers to improve how care is delivered to these patient populations,” notes Dr. Wilson. 

The study, “Genetic variation in the farnesoid X-receptor predicts Crohn’s disease severity in female patients,” is published in Nature’s Scientific Reports.  

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Dr. Aze Wilson, Associate Scientist at Lawson Health Research Institute and Gastroenterologist at London Health Sciences Centre (LHSC)

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LONDON, ONTARIO - A new study from Lawson Health Research Institute and Western University illustrates how the gut microbiome interacts with an oral medication in prostate cancer patients, suggesting bacteria in the gut play a role in treatment outcomes. The findings, published in Nature Communications, highlight how the drug abiraterone acetate is metabolized by bacteria in the gut to reduce harmful organisms while promoting those that fight cancer. The team suspects this is one of many examples of how the microbiome influences our response to medications. 

“Research is beginning to uncover the ways in which the human microbiome influences cancer development, progression and treatment,” explains Brendan Daisley, a PhD candidate at Western’s Schulich School of Medicine & Dentistry who is conducting research at Lawson. “Our study highlights a key interaction between a cancer drug and the gut microbiome that results in beneficial organisms with anti-cancer properties.”

Traditional prostate cancer therapies are designed to deprive the body of hormones called androgens, which are responsible for prostate cancer growth. 

“Unfortunately, traditional androgen deprivation therapies are not always effective,” explains Dr. Joseph Chin, Lawson Associate Scientist, Professor at Schulich Medicine & Dentistry and Urologist at London Health Sciences Centre (LHSC). "In those cases, alternative therapies are explored.”

Abiraterone acetate is a highly effective therapy used in the treatment of prostate cancer that has been resistant to other treatments. While abiraterone acetate also works to reduce androgens in the body, it does so through a different mechanism and, unlike traditional therapies, it is taken orally. 

“When drugs are taken orally, they make their way through the intestinal tract where they come into contact with billions of microorganisms,” says Dr. Jeremy Burton, Lawson Scientist, Associate Professor at Schulich Medicine & Dentistry and lead researcher on the study. “While it’s long been a mystery why abiraterone acetate is so effective, our team wondered if the gut microbiome plays a role.”

The team’s study included 68 prostate cancer patients from LHSC, including those being treated with abiraterone acetate and those being treated with traditional androgen deprivation therapies. The research team collected and analyzed patient stool samples, and conducted further experiments in their laboratory at St. Joseph’s Health Care London.

They discovered that patients’ gut microbiomes changed drastically after taking abiraterone acetate. Bacteria in the gut metabolized the drug leading to a significant increase in a bacterium called Akkermansia muciniphila. Referred to as a ‘next-generation probiotic,’ this bacterium’s relevance has recently been explored in several large cancer studies. It’s been shown to facilitate a better response to cancer immunotherapy drugs and it can elicit a wide range of other positive health benefits as well. The increase in Akkermansia muciniphila also led to an increased production of vitamin K2 which is known for anti-cancer properties that can inhibit tumour growth. 

The team also observed the impact of androgen depletion on the microbiome. Both abiraterone acetate and traditional androgen deprivation therapies led to a decrease in organisms that utilize androgen. 

“These findings clearly demonstrate that the gut microbiome is playing a role in treatment response,” notes Dr. Burton.

The team hopes to further explore drug-microbiome interactions with a goal of harnessing the microbiome to improve treatment outcomes for a variety of diseases. In another study, they are exploring whether fecal microbiota transplants from a healthy donor can change the microbiome of melanoma patients to increase organisms like Akkermansia muciniphila and improve response to immunotherapy. They also plan to study whether analysis of a patient’s microbiome can be used to predict their response to specific therapies.

“While more research is needed, we may one day be able to analyze a patient’s microbiome to determine the best course of treatment or even influence the microbiome to improve outcomes,” says Dr. Burton. “This could lead to a new frontier in personalized medicine.”

The study was made possible through the generous support of The W. Garfield Weston Foundation, St. Joseph’s Health Care Foundation and the Canadian Urologic Oncology Group. 

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Brendan Daisley, a PhD candidate at Western University’s Schulich School of Medicine & Dentistry who is conducting research at Lawson Health Research Institute

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Dr. Jeremy Burton (left) and Brendan Daisley (right) are conducting research on microbiome-drug interactions at Lawson Health Research Institute and Western University

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