Gene variant may leave gut vulnerable to Crohn’s

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A genetic variation previously linked to obesity, cholesterol levels, blood pressure, and schizophrenia also is associated with Crohn’s disease.

In addition, the genetic variant is associated with changes in the composition of the gut microbiome—which is made up of potentially billions of microbes that help people digest food, synthesize nutrients, and perform myriad other essential functions—in healthy people, overweight people, and people with Crohn’s disease.

The chronic inflammatory condition of the gastrointestinal tract is estimated to cost the US $6 billion annually.

“We knew from previous studies that there is reduced diversity of the gut microbiome in patients with Crohn’s disease,” says co-senior and corresponding author Richard Duerr, a professor in University of Pittsburgh’s School of Medicine, and co-director and scientific director of the UPMC Inflammatory Bowel Disease Center. “But that left us with a question: Does Crohn’s disease alter the composition of the gut microbiota, or do pre-existing changes in the gut microbiota confer risk for Crohn’s disease?

“Our study found that there is a reduction in the abundance of hundreds of minor species of gut bacteria in healthy, overweight, and Crohn’s disease-affected people who carry this genetic variant, suggesting that the genetic variant may increase risk for disease by altering the gut habitat. This is an important step toward understanding how the disease works so we can develop therapies or a cure in the future.”

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The team focused their analysis on 10,523 blood samples from people with inflammatory bowel disease (half had been diagnosed with Crohn’s disease) and 5,726 samples from healthy people. They discovered that a variation in the SLC39A8 gene is associated with Crohn’s disease. The findings appear in the journal Gastroenterology.

“This finding is another important example of how a particular genetic variant can have a role in the development and course of many diseases. Our study of this variant suggests that therapies effective in treating one disease also may benefit the treatment of some patients with other illnesses,” says co-senior author Dermot McGovern, director of Translational Medicine in the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, and director of Precision Medicine at Cedars-Sinai.

Taking it a step further, the team identified healthy people, overweight people, and Crohn’s disease-affected people with the genetic variant and analyzed their gut microbiomes. That is how they discovered that the genetic variant is not just linked to Crohn’s and other conditions, but also to a reduction in hundreds of species of gut bacteria.

“Many of these species are believed to play roles in protecting the intestine against Crohn’s disease, and also in preserving a lean body physiology,” says Braun. “So, this may be an example where the gene increases risk for disease via its effect on types of bacteria we need to preserve our health.”

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The findings have sparked additional questions and potential research avenues, but therapies are still quite a ways off, says Duerr, also a professor in the Pitt Graduate School of Public Health Department of Human Genetics.

“This study illustrates the remarkable interaction between our proper genome and our symbiome—the organisms and environment inside and outside of us that influence our well-being—in the setting of inflammatory bowel disease,” says Mark T. Gladwin, chair of medicine professor of internal medicine at Pitt. “Insights from this study are likely to guide the development of microbiome modulating therapies that hold the promise to alleviate patient suffering.”

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Helmsley Charitable Trust, among others, funded the work. Additional support for this research came from numerous grants to the individual researchers, as listed in the publication.

Source: University of Pittsburgh