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Study Uncovers Microbiome, Metabolic Features Tied to IBD Treatment Response

NEW YORK – A team from the Massachusetts General Hospital, the Broad Institute, and elsewhere has identified gut microbial and blood serum features that correspond with better or worse response to biologic therapies for inflammatory bowel disease (IBD).

"[W]ith the increasing number of mechanisms of action available, we need to be able to make smart and informed decisions for our patients that get them the right drug early on in the disease," co-senior and co-corresponding author Ashwin Ananthakrishnan, a gastroenterology researcher at Massachusetts General Hospital, explained in an email, noting that "it is possible and indeed likely that microbial determinants of treatment may differ by mechanism of action."

Starting with blood and fecal samples collected over time from nearly 200 individuals with moderate to severe Crohn's disease or ulcerative colitis from Mass General Hospital's Prospective Registry in IBD Study, the researchers used a combination of metagenomic sequencing, serum metabolomics, and serum proteomics to search for biomarkers coinciding with remission after treatment with biologic therapy, particularly anti-cytokine or anti-integrin therapy.

The team's ­prospective analysis, published in Cell Host and Microbe on Thursday, highlighted specific sets of immune or gut microbiome features associated with clinical remission after 14 weeks or a year of treatment with each of the drug types, compared to the samples collected before these therapies began for the 77 ulcerative colitis patients and 108 Crohn's disease cases included in the study. Nearly half of the participants had clinical remission within the first 14 weeks of treatment, while another 22 patients reached remission within 52 weeks of follow up.

"With availability of multiple therapeutic mechanisms of action, identifying determinants of overall likelihood to improve with treatment, as well as the more nuanced response to a given treatment class, is of high priority in the management of IBD," the authors wrote, noting that their multi-omics approach for finding potential response markers identified "unique microbial signatures that may preferentially favor response to a specific therapeutic class."

When it came to the therapies targeting the tumor necrosis factor (TNF) inflammatory cytokine or interleukin (IL)-12 or IL-23 cytokines, for example, the researchers found that treatment responses were more common in the patients with relatively rich gut microbial communities prior to treatment. They also saw an over-representation of microbes linked to dihydroxylation processes that convert primary bile acids to secondary bile acids in the IBD patients who responded well to these treatments — results supported by their tandem mass spectrometry-based serum metabolite analyses.

Similarly, IBD remission after anti-cytokine treatment appeared to coincide with the presence of microbial diversity-linked immune proteins circulating in the blood, the team reported, which could be detected based on telltale proteomic signatures in blood serum samples.

On the other hand, the investigators detected a distinct set of gut microbial, blood serum proteomic, and metabolomic patterns in the IBD patients who responded to, or reached remission on, an anti-integrin treatment called vedolizumab that targets leukocyte trafficking processes.

Such results suggest that features found in the stool and blood may help for predicting responses to existing therapies, while providing a better look at disease pathology and progression, the authors explained, which may ultimately point to potentially targetable pathways for new drug development or probiotic tools for preventing inflammation.

"If replicated and confirmed in larger cohorts, this is an important advance towards the goal of precision medicine and personalized therapeutics in IBD," Ananthakrishnan said.

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