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Longitudinal Irritable Bowel Syndrome Omics Study Points to Possible Treatment Target

NEW YORK – A prospective multi-omic study of irritable bowel syndrome (IBS) that encompassed a broad range of analyses and sample types has uncovered metabolic pathway shifts that appear to line up with the disease and its symptoms.

"[W]e identified the host-microbial pathway of purine metabolism, which may play an important role in the pathophysiology of IBS," the authors reported in their study, published in Cell on Thursday, noting that the work "provides multiple new therapeutic targets for future investigation." Co-senior authors Purna Kashyap, a researcher at the Mayo Clinic in Rochester, and Dan Knights, an investigator at the University of Minnesota, led the work.

The researchers used RNA sequencing, metagenomic sequencing, mass spectrometry-based metabolomics, array-based DNA methylation profiling, and other approaches to assess a wide range of host and gut microbial features in stool samples collected monthly for six months from dozens of individuals with or without IBS, including patients with constipation or diarrhea symptoms.

Together with blood and gut biopsy samples, the collection made it possible to search for host and microbial pathways that are altered during IBS flare-ups or in the presence of specific symptoms.

Based on nearly a dozen data types — from host mucosal tissue transcriptomes, metabolomes, methylome profiles, and microbial profiles to symptoms, cytokine features, and physiology — the longitudinal study flagged three main pathway patterns, the team reported, particularly related to purine metabolism.

In individuals with IBS who suffered from constipation, for example, the integrated analyses revealed lower-than-usual levels of short-chain fatty acids such as propionate, butyrate, and acetate in the gut, reflected in fecal samples. On the other hand, the investigators saw a rise in tryptamine and primary bile acid levels in stool samples from individuals with IBS and diarrhea.

They noted that both the constipation and diarrhea disease subtypes were marked by so-called purine starvation — metabolic shifts that included a drop in levels of a host and microbial metabolite called hypoxanthine in fecal samples, accompanied by enhanced colonic tissue expression of a xanthine oxidase enzyme that helps convert hypoxanthine and xanthine to uric acid.

"This illustrates the relevance of employing multi-omics measurements in humans to identify potential disease mechanisms that may depend on human-specific responses in gene expression," the authors wrote. "Hypoxanthine is an appealing drug target given the availability of the xanthine oxidase inhibitor allopurinol, which is used to treat gout, and thiopurines, which are used to optimize inflammatory bowel disease therapy."

Along with already available drugs used to treat other conditions, the authors noted, additional drugs that are still being developed may offer opportunities to target purine metabolism pathway components such as xanthine oxidase more specifically or effectively. They may also target components of other host pathways that bubbled up from the genomic, metabolomic, metagenomic, and transcriptome data.

"[O]ur integrated longitudinal multi-omics study highlights how we can leverage human studies to advance our understanding of diseases with both host and microbial components to identify targets for improved treatment," the authors concluded.

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