Gut Microbial Enzymes Identified That Diminish Efficacy of 5-ASA in IBD
Key findings
- The objective of this study was to identify gut microbial enzymes responsible for inactivating 5-aminosalicylic acid (5-ASA) into its clinically ineffective form, N-acetyl 5-ASA
- A multi-omics workflow was applied to data from a multicenter U.S. cohort of 79 individuals with inflammatory bowel disease (45 users of 5-ASA) who reported on medications, diet, and symptoms, and provided serial stool and blood samples for a year
- 12 previously uncharacterized microbial acetyltransferases were identified and biochemically validated to be associated with the generation of N-acetyl 5-ASA
- Four bacterial enzymes were linked to approximately three-fold greater risk of 5-ASA treatment failure, defined as the need for initiation of corticosteroid therapy, and that result was validated in a prospective, independent cohort
- The methodology used in this study is generalizable to other drugs and chemicals, which could position the microbiome as a biomarker of treatment response, and/or lead to novel adjuvant therapies
Mesalamine, also called 5-aminosalicylic acid (5-ASA), is the most common anti-inflammatory therapy for ulcerative colitis and is often prescribed for Crohn's disease. Unfortunately, over half of patients fail to respond or eventually lose response.
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Nearly 40 years ago, researchers observed the conversion of 5-ASA to its inactive form, N-acetyl 5-ASA, in human stool cultures. It's long been theorized gut bacteria are responsible for this transformation, and now Mass General Brigham researchers have identified specific enzymes involved. In Nature Medicine, they present evidence that 5-ASA is inactivated by gut commensal acetyltransferases, which normally condense short-chain acyl-CoAs as part of intracellular energy storage.
The authors are Raaj S. Mehta, MD, MPH, attending physician in the Division of Gastroenterology and investigator in the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital, and instructor in Medicine at Harvard Medical School, Jared R. Mayers, MD, PhD, fellow in the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, and colleagues.
Methods
The team used data from the Integrative Human Microbiome Project Inflammatory Bowel Disease Multi'omics Database (IBDMDB), a multicenter U.S. cohort of 132 individuals with and without IBD who reported on medications, diet, and symptoms, and provided serial stool and blood samples for a year.
79 participants with Crohn's disease or ulcerative colitis yielded 1,036 metagenomes, 440 metatranscriptomes, and 508 metabolomes. 45 of the participants were users of 5-ASA, and 34 were not.
5-ASA–Metabolizing Enzymes
The researchers started with individual metatranscriptome- and metabolome-based analyses to identify microbial genes implicated in 5-ASA inactivation. When they pooled the data they identified 12 previously uncharacterized microbial acetyltransferases associated with the generation of N-acetyl 5-ASA.
The enzymes belong to two protein superfamilies: thiolases and acyl-CoA N-acyltransferases. In vitro, characterization of representatives from both families confirmed the ability of these enzymes to acetylate 5-ASA.
Predicting Treatment Failure
Three microbial thiolases and one acyl-CoA N-acyltransferase were associated with a significantly increased risk of 5-ASA treatment failure, which the team defined as the need to initiate corticosteroid therapy. The odds ratios were 2.58 to 3.24, depending on the gene.
The team validated the results in the Study of a Prospective Adult Research Cohort with IBD (SPARC IBD). Among 208 users of 5-ASA who were steroid-free at study entry, 60 initiated corticosteroid use. Consistent with the IBDMDB analysis, carriage of three or all four of the newly identified microbial acetyltransferase genes was associated with treatment failure (OR, 2.77; 95% CI, 1.03–7.43).
Pooled analysis of the IBDMDB and SPARC IBD results suggested a more than three-fold increased risk of drug failure (OR, 3.12; 95% CI, 1.41–6.89).
Therapeutic Implications
Patients for whom 5-ASA therapy fails are typically progressed to riskier immunosuppressive treatments. The ability to escalate therapy only when necessary (e.g., when 5-ASA–modifying thiolase sequences are present in the gut microbiome) would represent an exciting advance in precision medicine for IBD.
In addition, it may be possible to develop microbiome-specific inhibitors of enzymes to enhance 5-ASA efficacy.
More broadly, since the study methodology is generalizable to other endpoints, chemicals, and microbiome multi-omics, it could improve the ability to understand the gut microbial metabolism of other drugs and suggest new avenues for targeted or adjuvant therapies.
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