Vancomycin relieves mycophenolate mofetil-induced gastrointestinal toxicity by eliminating gut bacterial ?-glucuronidase activity.
Ontology highlight
ABSTRACT:
SUBMITTER: Taylor MR
PROVIDER: S-EPMC6685722 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Vancomycin relieves mycophenolate mofetil-induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity.
Taylor Michael R MR Flannigan Kyle L KL Rahim Hannah H Mohamud Amina A Lewis Ian A IA Hirota Simon A SA Greenway Steven C SC
Science advances 20190807 8
Mycophenolate mofetil (MMF) is commonly prescribed and has proven advantages over other immunosuppressive drugs. However, frequent gastrointestinal side effects through an unknown mechanism limit its use. We have found that consumption of MMF alters the composition of the gut microbiota, selecting for bacteria expressing the enzyme β-glucuronidase (GUS) and leading to an up-regulation of GUS activity in the gut of mice and symptomatic humans. In the mouse, vancomycin eliminated GUS-expressing ba ...[more]
Similar Datasets
Project description:BackgroundGlobally, enteric-coated mycophenolate sodium (EC-MPS) is replacing mycophenolate mofetil (MMF) in maintenance immunosuppressant regimens. The predominant reason for conversion is the purported improvement in gastrointestinal (GI) quality of life. This paper considers the level of bias associated with studies comparing EC-MPS and MMF for GI-related improvement and provides insight into whether conversion is supported by evidence.MethodsUsing a pre-determined protocol, a literature search was conducted. Full-text review, data extraction and risk of bias analysis was conducted by two independent authors using the Cochrane domain-based evaluation of risk of bias. The review was reported according to the preferred reporting items for systematic reviews and meta-analyses.ResultsTwenty-nine studies were included in risk of bias analysis. Of these, only three were deemed a low risk of bias. Across these three studies, there were no statistically significant differences in the proportion of GI-related adverse events nor was there a significant difference in the GI-related quality of life between EC-MPS- and MMF-treated patients in these data.ConclusionThere was a high risk of bias across the 29 studies investigating conversion from MMF to EC-MPS for potential improvement in GI-related quality of life. The consolidated results of the three studies with low risk of bias suggest no evidence to convert patients stabilised on MMF. If a patient experiences GI-related adverse events whilst taking MMF, other methods should be explored before conversion to EC-MPS.
| S-EPMC6277323 | biostudies-literature
Project description:Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.
| S-EPMC7933434 | biostudies-literature
Project description:Immunosuppressive (IS) therapy is indicated to treat progressive sarcoidosis, but randomized controlled trials to guide physicians in the use of steroid sparing agents are lacking. The aim of this retrospective study was to examine the role of mycophenolate mofetil (MMF) as an alternative therapy in the treatment of sarcoidosis.A retrospective chart review of all patients who had been prescribed MMF between January 2008 and October 2011 was conducted. Patients with insufficient data or who had another IS therapy initiated concomitantly with MMF, including prednisone, were excluded. Physiological data obtained at the time MMF therapy was initiated as well as six and twelve months before and after therapy was extracted. Longitudinal analyses of the effect of MMF on changes in pulmonary function at MMF start, 6 months, 12 months pre and post MMF therapy were conducted.37/76 patients met our inclusion/exclusion criteria. There were no statistically significant changes in PFT measurements pre and post MMF therapy. We did find a trend (p = 0.07) towards improvement in DLCO 12 months pre and post MMF in patients who were started on MMF due to intolerance to previous IS therapy compared to those who were unresponsive to their previous IS therapy. We also noted a reduction in prednisone dose in those treated with MMF.MMF appears to offer no extra benefit to sarcoidosis patients unresponsive to previous steroid-sparing agents, but may be beneficial in patients intolerant to their previous steroid-sparing agent. Additional studies investigating the efficacy of MMF as the initial steroid-sparing agent are needed to further clarify the role of MMF in sarcoidosis.
| S-EPMC4254196 | biostudies-other
Project description:Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial β-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The β-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF.ImportanceNeuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.
| S-EPMC11302255 | biostudies-literature
Project description:PurposeTo evaluate mycophenolate mofetil as a single noncorticosteroid immunosuppressive treatment for noninfectious ocular inflammatory diseases.DesignRetrospective cohort study.MethodsCharacteristics of patients with noninfectious ocular inflammation treated with mycophenolate mofetil at 4 subspecialty clinics from 1995 to 2007 were abstracted by expert reviewers in a standardized chart review of every eye at every visit. Main outcomes measured were control of inflammation, corticosteroid-sparing effects, and discontinuation of mycophenolate mofetil (including the reasons for discontinuation). Survival analysis was used to estimate the incidence of outcomes, and to identify risk factors for each.ResultsAmong 236 patients (397 eyes) treated with mycophenolate mofetil monotherapy, 20.3%, 11.9%, and 39.8% had anterior uveitis, intermediate uveitis, and posterior uveitis or panuveitis respectively; 14% had scleritis; 7.6% had mucous membrane pemphigoid; and 6.4% had other ocular inflammatory diseases. By Kaplan-Meier estimation, complete control of inflammation--sustained over consecutive visits spanning at least 28 days--was achieved in 53% and 73% of patients within 6 months and 1 year respectively. Systemic corticosteroid dosage was reduced to 10 mg of prednisone or less, while maintaining sustained control of inflammation, in 41% and 55% of patients in 6 months and 1 year respectively. Twelve percent of patients discontinued mycophenolate mofetil within the first year because of side effects of therapy.ConclusionsGiven sufficient time, mycophenolate mofetil was effective in managing ocular inflammation in approximately half of the treated patients. Treatment-limiting side effects were observed in 12% of patients and typically were reversible.
| S-EPMC2826576 | biostudies-literature
Project description:Background: Only a subset of patients with systemic sclerosis (SSc) demonstrate improvement in modified Rodnan skin score (mRSS) during mycophenolate mofetil (MMF) treatment. Here we investigated the molecular and cellular effects in skin associated with MMF therapy in subjects who demonstrated or lacked clinical improvement. Methods: Clinical and skin gene expression data were obtained genome-wide from baseline and longitudinal (6-, 12-, 24-, and 36-mo) biopsies in 33 MMF-treated subjects with SSc. Clinical improvement was defined as mRSS reduction ≥ 25%. An inflammatory signature score was calculated for each patient sample using single-sample gene set enrichment analysis (ssGSEA). Cell type specific changes during treatment were characterized. Results: Eleven subjects with SSc completed at least 24 months of MMF therapy and were termed ‘completers’. Two distinct gene expression patterns were observed that corresponded to MMF treatment status. Three subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in activated dendritic cells. MMF cessation at 24 months resulted in an inflammatory signature rebound paralleling mRSS increase. Three subjects that remained on MMF showed persistent inflammatory signature reductions with decreasing or stable mRSS. The remaining six completers either did not fulfill minimum mRSS (n=5), and/or lacked a baseline inflammatory signature (n=4). Conclusions: An elevated inflammatory skin gene expression signature is associated with clinical improvement during MMF therapy. Inflammation returned upon MMF discontinuation with concomitant mRSS increase. These data summarize MMF’s molecular effects in skin and support MMF therapy for longer than 24 months in patients who demonstrate clinical response.
2017-01-01 | GSE76885 | GEO
Project description:To evaluate effectiveness and safety of mycophenolate mofetil (MMF) monotherapy in paediatric autoimmune uveitis.We reviewed medical records of patients, 18 years of age or younger, with autoimmune uveitis treated with MMF at our practice from 2005 to 2009. The dose and duration of MMF therapy, inflammation status, visual acuity, previous immunomodulatory therapies, and adverse effects were recorded. In addition, the following subgroups were defined: (1) Durable Disease Control: patients whose uveitis remained quiescent for at least 2 years on MMF monotherapy, with no more than two flare-ups successfully treated with an increase in MMF dosage and/or a short course (<1 month) of corticosteroids; (2) Short-term Inflammation Control: patients whose uveitis remained quiescent for less than 2 years, with no more than one flare-up successfully treated with an increase in MMF dosage and/or a short course of corticosteroids, or who initially achieved inflammation control but discontinued MMF because of significant adverse effects.A total of 38 out of 52 patients (73.1%) obtained inflammation control following 2 months of MMF monotherapy, achieving ≤ 0.5+ grading in anterior chamber cell/flare and vitreous haze. In the cross-sectional analysis, 25 patients (48.1%) met the criteria for Durable Disease Control, and 13 others (25.0%) qualified for Short-term Inflammation Control. Visual acuity remained stable or improved in 94.2% of the study population. Six patients (11.5%) discontinued MMF because of significant adverse effects, the most common of which was gastrointestinal disturbances.MMF monotherapy appears to be an effective and safe treatment in paediatric autoimmune uveitis.
| S-EPMC3171236 | biostudies-other
Project description:Mycophenolate mofetil (MMF) has been widely prescribed for neuromyelitis optica spectrum disorders (NMOSD) although some patients experience severe gastrointestinal (GI) side effects following MMF administration. Our study investigated the potential mechanisms of this toxicity in NMOSD patients. We constructed MMF-induced colitis mouse model and produced a multi-omic dataset in which microbiome and metabolome analysis from the mouse GI tract to decipher the mechanisms of MMF GI toxicity. Further, 17 female NMOSD patients treated with MMF were prospectively enrolled and grouped according to the diarrhea symptom as non-diarrhea NMOSD group (NM) and diarrhea NMOSD group (DNM) as well as healthy controls (HC, 12 female). The gut microbiota was analyzed using 16S rRNA sequencing of stool samples. In the mouse model, we found that vancomycin administration drastically altered the colon content metabolomes and microbiomes and prevented MMF-induced body weight loss, cecal and colon tissue injury. Bacteroidetes and Firmicutes converted phenyl-beta-D-glucuronide (MPAG) to mycophenolic acid (MPA) that could result in damaged intestinal tissue. We also demonstrated that the alpha diversity in the DNM group was increased and this was accompanied by increased Firmicutes and Proteobacteria abundance. Collectively, these results reveal that alterations of the gut microbiome and metabolome contribute to MMF-induced colitis. Modifying of the gut microbiome and metabolome may alleviate MMF-induced GI toxicity in NMOSD patients.
2024-06-18 | MTBLS4392 | MetaboLights
Project description:ObjectivesTo investigate safety and efficacy of MMF in patients with severe or MTX-refractory juvenile localized scleroderma.MethodsConsecutive juvenile localized scleroderma patients undergoing systemic treatment were included in a retrospective longitudinal study. Patients treated with MMF because they were refractory or intolerant to MTX (MMF-group) were compared with responders to MTX (MTX-group). Disease activity was assessed by Localized Scleroderma Cutaneous Assessment Tool and thermography. Disease course was established on the number of relapses and treatment changes. Relapse-free survival was examined by Kaplan-Meier analysis.ResultsMMF and MTX groups included 22 and 47 patients, respectively. No significant difference in demographics, follow-up duration and treatment before diagnosis was observed between groups. The most represented clinical subtypes in the MMF-group were pansclerotic morphea and mixed subtype (P = 0.008 and P = 0.029, respectively), and linear scleroderma of the face in the MTX-group (P = 0.048). MMF was started because of MTX resistance (18 patients), relapse during MTX tapering/withdrawal (3 patients) and anaphylaxis to MTX (1 patient). After mean 9.4 years of follow-up, 90.9% of patients on MMF and 100% of those on MTX had inactive disease. No significant difference in relapse-free survival between the groups was found (P = 0.066, log-rank test), although MMF likely induced more persistent remission. MMF was well tolerated and combination of MMF and MTX did not increase its efficacy.ConclusionThe present study adds strong evidence on the efficacy and tolerance of MMF in severe and/or MTX-refractory juvenile localized scleroderma. Further controlled studies are needed to prove its efficacy as first line treatment.
| S-EPMC7937018 | biostudies-literature
Project description:MMF, the most commonly used adjuvant immunosuppressant in pediatric heart transplantation, has frequent GI adverse events. SNPs in inosine 5'-monophosphate dehydrogenase I (IMPDH1) may contribute to MMF GI intolerance. Phased haplotypes may have more utility than individual SNPs in candidate gene association studies for complex traits. This study defined common IMPDH1 haplotypes and investigated whether these haplotypes influence MMF GI intolerance in 59 pediatric heart recipients. Genotypes were assessed by Taqman analysis of IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294, and rs2228075, and haplotypes were inferred using Arlequin 3.01 software. GI intolerance was defined as diarrhea, vomiting, nausea, or abdominal pain requiring MMF dose holding for > 48 h or MMF discontinuation. GI intolerance occurred in 21 patients (35.6%). Ten IMPDH1 haplotypes were identified in this population. In univariable analyses, one haplotype was strongly associated with MMF GI intolerance with 59.1% of carriers of this haplotype experiencing MMF GI intolerance compared to 21.6% of non-carriers (p = 0.005). In this study, we identify a common IMPDH1 haplotype associated with MMF GI intolerance in a population of pediatric heart transplant patients. This haplotype of interest did not demonstrate stronger association with MMF GI intolerance than an individual IMPDH1 SNP.
| S-EPMC2955782 | biostudies-literature