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

Mehta, Raaj S.; Mayers, Jared R.; Zhang, Yancong; Bhosle, Amrisha; Glasser, Nathaniel R.; Nguyen, Long H.; Ma, Wenjie; Bae, Sena; Branck, Tobyn; Song, Kijun; Sebastian, Luke; Ávila-Pacheco, Julián; Seo, Hyuk-Soo; Clish, Clary B.; Dhe‐Paganon, Sirano; Ananthakrishnan, Ashwin N.; Franzosa, Eric A.; Balskus, Emily P.; Chan, Andrew T.; Huttenhower, Curtis

doi:10.1038/s41591-023-02217-7

Cited by 64 publications

(24 citation statements)

References 74 publications

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“… 38 Another possible mechanism is drug metabolism by the microbiome, highlighted by a recent report revealing that microbiome metabolism of 5-ASA stratifies mesalamine responders from non-responders. 44 Here, we do not observe a direct antimicrobial effect of SAS or a differential role for microbiome metabolism of SAS accounting for clinical response. Instead, our study now reveals a mechanism by which SAS acts as a xenobiotic on F. prausnitzii to modulate transcription of genes associated with butyrate production and boost production of butyrate in vivo .…”

Section: Discussioncontrasting

confidence: 55%

The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis

Lima,

Pires,

Rupert

et al. 2024

Cell Reports Medicine

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Section: Discussioncontrasting

confidence: 55%

The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis

Lima,

Pires,

Rupert

et al. 2024

Cell Reports Medicine

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“…49,75,76 However, conventional medicines treatments are often struggle to effectively target the gut microbiota, alleviate the diseases related to the gut microbiota and difficult to fundamentally solve the cause of some metabolic diseases, and even cause undesirable side effects such as flora disturbance. 77,78 The interplay between medicines and the composition of gut microbiota challenges prior concepts of medicine specificity and reveals broader physiological impacts. Numerous clinical studies have long demonstrated the effects of antibiotics on the gut microbiota, where they might reduce beneficial bacteria, leading to a decrease in microbial diversity, causing everything from short-term gastrointestinal disturbances to increased long-term risks of conditions like IBD and obesity.…”

Section: Current Issues and Limitations Of Traditional Medicinesmentioning

confidence: 99%

“…Recent research indicate that most human diseases were associated with changes in the composition of gut microbiota 49,75,76 . However, conventional medicines treatments are often struggle to effectively target the gut microbiota, alleviate the diseases related to the gut microbiota and difficult to fundamentally solve the cause of some metabolic diseases, and even cause undesirable side effects such as flora disturbance 77,78 …”

Section: Probiotics Prebiotics and Postbiotics Therapy Emerges As Alt...mentioning

confidence: 99%

Probiotics, prebiotics, and postbiotics in health and disease

Ji,

Jin,

Liu

et al. 2023

MedComm

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The gut microbiota and its homeostasis play a crucial role in human health. However, for some diseases related to the gut microbiota, current traditional medicines can only relieve symptoms, and it is difficult to solve the root causes or even cause side effects like disturbances in the gut microbiota. Increasing clinical studies and evidences have demonstrated that probiotics, prebiotics, and postbiotics can prevent and treat various diseases, but currently they can only be used as dietary supplements rather than medicines, which restricts the application of probiotics in the field of medicine. Here, this review analyzes the importance of gut microbiota in human health and the current problems of traditional medicines, and systematically summarizes the effectiveness and mechanisms of probiotics, prebiotics, and postbiotics in maintaining health and treating diseases based on animal models and clinical trials. And based on current research outcomes and development trends in this field, the challenges and prospects of their clinical application in maintaining health, alleviating and treating diseases are analyzed. It is hoped to promote the application of probiotics, prebiotics, and postbiotics in disease treatment and open up new frontiers in probiotic research.

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“…Indeed, a multi-omics work-flow consisting of gut microbiome metagenomics, metabolomics and metatranscriptomics identified 12 previously uncharacterised microbial acetyltransferases capable of acetylating 5-ASA which belong to two protein superfamilies, namely thiolases and acyl-CoA N-acetyltransferases [ 31 ] . The presence of three thiolases and one acyl-CoA N-acetyltransferase in the human gut microbiome was associated with an increased risk of treatment failure of 5-ASA based on the analysis of the discovery cohort and the SPARC IBD cohort (Study of a Prospective Adult Research Cohort with IBD) [ 31 ] . While this relationship needs to be confirmed with larger cohorts of patients, it does pave the way toward future “personalised microbiome-based medicine”.…”

Section: Non-specific Anti-inflammatory and Immunosuppressive Therape...mentioning

confidence: 99%

“…While this relationship needs to be confirmed with larger cohorts of patients, it does pave the way toward future “personalised microbiome-based medicine”. Indeed, the authors suggest that 5-ASA-modifying thiolase sequences in the gut microbiome of a patient could be used as a biomarker of treatment efficacy and that microbiome-specific inhibitors of enzymes such as thiolases could be developed to enhance 5-ASA treatment efficacy [ 31 ] .…”

Section: Non-specific Anti-inflammatory and Immunosuppressive Therape...mentioning

confidence: 99%

Interplay between inflammatory bowel disease therapeutics and the gut microbiome reveals opportunities for novel treatment approaches

O’Reilly,

Mills,

Rea

et al. 2023

Microbiome Res Rep

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Inflammatory bowel disease (IBD) is a complex heterogeneous disorder defined by recurring chronic inflammation of the gastrointestinal tract, attributed to a combination of factors including genetic susceptibility, altered immune response, a shift in microbial composition/microbial insults (infection/exposure), and environmental influences. Therapeutics generally used to treat IBD mainly focus on the immune response and include non-specific anti-inflammatory and immunosuppressive therapeutics and targeted therapeutics aimed at specific components of the immune system. Other therapies include exclusive enteral nutrition and emerging stem cell therapies. However, in recent years, scientists have begun to examine the interplay between these therapeutics and the gut microbiome, and we present this information here. Many of these therapeutics are associated with alterations to gut microbiome composition and functionality, often driving it toward a “healthier profile” and preclinical studies have revealed that such alterations can play an important role in therapeutic efficacy. The gut microbiome can also improve or hinder IBD therapeutic efficacy or generate undesirable metabolites. For certain IBD therapeutics, the microbiome composition, particularly before treatment, may serve as a biomarker of therapeutic efficacy. Utilising this information and manipulating the interactions between the gut microbiome and IBD therapeutics may enhance treatment outcomes in the future and bring about new opportunities for personalised, precision medicine.

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

Cited by 64 publications

References 74 publications

The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis

The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis

Probiotics, prebiotics, and postbiotics in health and disease

Interplay between inflammatory bowel disease therapeutics and the gut microbiome reveals opportunities for novel treatment approaches

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