Metabolomic Insights Discover Biomarker for Ulcerative Colitis

The Challenge: Find Biomarkers and Therapeutic Targets for IBD

Inflammatory bowel disease (IBD) mainly comprises ulcerative colitis (UC) and Crohn’s disease and is a complex and multifactorial disease with unknown etiology. Currently, the specific components of the microbiome that contribute to intestinal health or IBD are not well defined. Precisely how microbiota-derived metabolites can lead to IBD has not been extensively explored. A research team sought to define what metabolites in the microbiome influence IBD development and progression.¹

Metabolon Insight: Metabolomics Identifies Metabolites that Contribute to IBD

Metabolon helped identify and characterize novel microbial-derived metabolites that contribute to IBD or intestinal health. The Metabolon Global Discovery Panel analyzed serum and colonic tissue metabolites from healthy and colitic mice.

The Solution: Microbiota-Derived Indole Metabolites Promote Intestinal Health

Global metabolomic profiling by mass spectrometry was performed on serum and colonic tissue from healthy and colitic mice. Guided by an unbiased metabolomic approach, Metabolon detected a depletion of indole and indole-derived metabolites in both serum and colons of colitic mice.

The researchers then translated these findings to human subjects. They quantified various indole metabolites in human serum samples from healthy controls, subjects with active UC, and subjects with UC in remission. This analysis demonstrated that serum indole-3-propionic acid (IPA), an indole metabolite, was decreased by nearly 60% in subjects with active UC compared with healthy controls. Moreover, this IPA deficiency normalized in UC patients in remission.

Given the observation that indole metabolites are significantly decreased in active colitis, the therapeutic potential of IPA was tested in mice. Therapeutic administration of oral IPA was protective in mice with colitis. Animals that received IPA not only exhibited fewer physical signs of disease but also had significantly less damage to crypt structure and restricted inflammatory infiltration. These results indicate that therapeutic normalization of IPA during active colitis attenuates disease and promotes gastrointestinal health.

The team also found that exposing human intestinal epithelial cells and human intestinal organoids to IPA upregulates IL-10R1 at the RNA and protein levels. Therefore, they identified IL-10R1 as a direct target of IPA. This suggests that microbial-derived IPA could promote anti-inflammatory effects since IL-10R1 has been shown to attenuate excessive production of proinflammatory mediators. This work defines a novel role for indole metabolites in anti-inflammatory pathways mediated by IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics for IBD.

The Outcome: Indole Metabolites can be Used as Therapeutic Agents or as a Biomarker to Assess Intestinal Health

The researchers showed that indole metabolites were depleted in the microbiome of mice and humans with colitis. These findings present new insight into our understanding of host-microbial communication.

The results have revealed for the first time, that IPA can be used as both a biomarker for active UC as well as an indicator of disease remission in human UC. Moreover, the researchers showed that IPA could be utilized as a novel therapeutic agent for colitic mice. In the future, oral administration of IPA could also be used to treat humans with UC. Therefore, this study provides strong evidence for the role of microbiota-derived IPA in promoting intestinal health.

Translational research tools like the Global Discovery Panel offer the ability to analyze serum and colonic metabolomic profiles of individuals with other intestinal diseases. This panel will ultimately allow the identification of novel biomarkers (metabolites) that might otherwise go undetected and can be used as therapeutic targets or to assess intestinal disease progression and severity.