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Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease.

ABSTRACT: For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 controls and patients with IBD. This associated 12 previously uncharacterized microbial acetyltransferases with 5-ASA inactivation, belonging 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. A cross-sectional analysis within the discovery cohort and subsequent prospective validation within the independent SPARC IBD cohort (n = 208) found three of these microbial thiolases and one acyl-CoA N-acyltransferase to be epidemiologically associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a longstanding challenge in IBD management, outline a method for the discovery of previously uncharacterized gut microbial activities and advance the possibility of microbiome-based personalized medicine.

SUBMITTER: Mehta RS

PROVIDER: S-EPMC10928503 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease.

Mehta Raaj S RS Mayers Jared R JR Zhang Yancong Y Bhosle Amrisha A Glasser Nathaniel R NR Nguyen Long H LH Ma Wenjie W Bae Sena S Branck Tobyn T Song Kijun K Sebastian Luke L Pacheco Julian Avila JA Seo Hyuk-Soo HS Clish Clary C Dhe-Paganon Sirano S Ananthakrishnan Ashwin N AN Franzosa Eric A EA Balskus Emily P EP Chan Andrew T AT Huttenhower Curtis C

Nature medicine 20230223 3

For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 ...[more]

PMID: 36823301

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Project description:BackgroundAcute interstitial nephritis (AIN) is an important cause of kidney injury accounting for up to 27% of unexplained renal impairment. In up to 70% of cases, drugs, including aminosalicylates, are reported as the underlying cause. Following two recent paediatric cases of suspected mesalazine induced AIN within our own department, we performed a systematic review of the literature to address the following question: In patients with inflammatory bowel disease (IBD), is interstitial nephritis associated with 5-aminosalicylate (5-ASA) treatment? Our primary objective was to identify the number of cases reported in the literature of biopsy-proven 5-ASA induced interstitial nephritis, in children and adults with IBD. We also aimed to identify which variables influence the onset, severity and recovery of 5-ASA interstitial nephritis.MethodsEmbase and PubMed databases were searched from inception to 07/10/20. Search terms had three main themes: "inflammatory bowel disease", "interstitial nephritis" and "aminosalicylates". Studies were included if they reported an outcome of AIN, confirmed on biopsy, suspected to be secondary to a 5-ASA drug in those with IBD. A narrative synthesis was performed.ResultsForty-one case reports were identified. Mesalazine was the most frequently reported aminosalicylate associated with AIN (95%). The median duration of treatment before AIN was diagnosed was 2.3 years (Interquartile Range (IQR) 12-48 months). The median rise in creatinine was 3.3 times the baseline measurement (IQR 2.5-5.5). Aminosalicylate withdrawal and steroids were the most frequently used treatments. Despite treatment, 15% of patients developed end-stage renal failure.ConclusionsAIN is a serious adverse drug reaction associated with aminosalicylates, with mesalazine accounting for most reports. The current guidance of annual monitoring of renal function may not be sufficient to identify cases early. Given the severity of AIN and reports in the literature that early treatment with steroids may be beneficial, we would recommend at least 6 monthly monitoring of renal function. PROSPERO registration number CRD42020205387.

Project description:Background: Diet has been linked to gut dysbiosis and the onset, course, and response to treatment of patients with IBD and metabolic disease. Methods: This single-centre prospective case-control study investigated the relationship between dietary intake, metabolic profile, and stool microbial composition in 57 individuals with IBD in clinical remission and 24 healthy individuals (HC). Participants' baseline anthropometric measurements, serum metabolic parameters, lipid profiles, and oral and stool samples for microbiota testing were collected. Their dietary intake and physical activity were documented. A partially corrected correlation was performed to examine the associations between variables and p-values adjusted for multiple comparisons using the Benjamini-Hochberg equation (adj-p). Results: In participants with IBD, the intake of saturated fat correlated positively, and the intake of dietary fibre correlated negatively with anthropometric indices (saturated fat and BMI: r = 0.37, adj-p = 0.04, fibre and BMI: r = -0.45, adj-p = 0.01). Higher anthropometric indices were associated with poorer glucose control and a less favourable serum lipid profile (BMI and insulin: r = 0.48, p < 0.01, WHR and triglycerides: r = 0.57, p < 0.01). The stool microbiota of participants in the IBD group was less diverse and more similar to their oral microbiota than was observed in the HC group (Mann-Whitney U test p = 0.03). Within the IBD group, a higher intake of added sugar and processed meat and a higher serum insulin level was associated with lower stool microbial alpha diversity (processed meat intake and Shannon's diversity: r = -0.43, adj-p = 0.02; added sugar and Shannon's diversity: r = -0.39, adj-p = 0.03; insulin and Shannon's diversity: r = -0.45, adj-p = 0.02). Neither the dietary intake nor stool microbial composition correlated with the risk of disease flaring. Conclusions: Our findings suggest that dietary intake is associated with the metabolic health and gut microbial composition of IBD patients.

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Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease.

Publications

Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease.

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