Assessing patients’ genetics has become key to prescribing personalized interventions in a variety of diseases — most notably cancer, in which targeted treatments for specific genetic variants have significantly improved prognoses. However, the genetics revolution has yet to reach Crohn’s disease, a condition that affects more than 1 million Americans, says Johns Hopkins gastroenterologist Joanna Melia.

            “Although we know a fair amount about the genetics of inflammatory bowel diseases, including Crohn’s, we don’t often use genetics clinically to inform prognosis or treatment decisions,” she says. “If we knew a patient was a carrier of a particular mutation that predisposes them to more severe Crohn’s and we had a targeted therapy, that would be an opportunity for personalized medicine.”

            New research led by Melia is bringing this goal closer to fruition. In a study recently published in Inflammatory Bowel Diseases, Melia and her colleagues connected a genetic mutation in a subset of patients with Crohn’s to aberrant bile acid metabolism caused by dysregulation in a gut hormone known as FGF19. The research may mean that doctors could treat patients with drugs already on the market.

            Previous research has shown that about one-tenth of people with Crohn’s have mutations in a gene called ZIP8, a key metal transporter that regulates manganese homeostasis. Patients bearing a mutated form of ZIP8 are more likely to have stricturing and penetrating ileal disease, the most difficult form of Crohn’s to treat. Because of competition for trace metals between gut microbes and host cells, researchers have hypothesized that ZIP8 mutations could affect the microbiota. Colon mucosal biopsies and stool analyses have provided mixed results; however, researchers had yet to analyze the microbiome of the ileum in patients with ZIP8 mutations, Melia explains.

            The researchers took advantage of data from a previous study that profiled the genetics and ileal microbiome of hundreds of newly diagnosed, treatment-naïve pediatric patients with Crohn’s. Their results showed that in patients with mutated ZIP8, the ileal microbiome was depleted in bacteria sensitive to bile acids, suggesting an overabundance of bile acid in the ileum caused by perturbed bile acid signaling. In a mouse model carrying a similar ZIP8 mutation, the researchers demonstrated that this excess of bile acid was caused by a decrease in signaling by the mouse analog of FGF19. Data from another study of adult patients with Crohn’s confirmed FGF19 dysregulation in ZIP8 mutation carriers with ileocolonic Crohn’s disease. This dysregulation not only leads to problems in the ileum from increased bile acids, Melia says, but also increased immune activity that could be responsible for Crohn’s-related inflammation.

            Melia explains that the manganese regulated by ZIP8 plays an important role in catalyzing protein glycosylation — her lab and others have found distinct glycosylation differences in individuals with ZIP8 mutations compared with those without these mutations. Thus, it may be possible to treat patients who have Crohn’s with ZIP8 mutations with existing drugs already U.S. Food and Drug Administration-approved to treat other glycosylation disorders.

            “It’s exciting that a safe and well-tolerated medical therapy for Crohn’s patients with ZIP8 mutations is potentially closer than we’ve thought,” she says.

 

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