Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor, Michael R.; Flannigan, Kyle L.; Rahim, Hannah; Mohamud, Amina; Lewis, Ian A.; Hirota, Simon A.; Greenway, Steven C.

doi:10.1101/561274

Cited by 12 publications

(25 citation statements)

References 65 publications

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“…The resulting free MPA undergoes partial re‐absorption 75 . MMF administration in mice leads to an enrichment of GUS expressing bacteria, 76 which has been associated with severe gastrointestinal toxicity, whereas mice lacking GUS expressing bacteria showed no adverse reaction 77 . These findings identified MPA as the responsible agent for gastrointestinal toxicity and suggest that treatment‐induced microbial changes contribute to drug toxicity.…”

Section: Clinical Implications Of Dysbiosis In Sotmentioning

confidence: 96%

The gut microbiome in solid organ transplantation

Arassi

Zeller

Karcher

et al. 2020

Pediatric Transplantation

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Allogeneic transplantation is an important, albeit rarely curative therapy for a large number of end-stage organ diseases and haematopoietic disorders. The introduction of potent immunosuppressants and anti-infective prophylaxis has continuously and substantially improved transplant outcome and patient survival. However, rejections, infections, and immunosuppressant-specific adverse effects remain a serious threat to allograft function and patient health. Therefore, innovative and individualized therapeutic interventions to alleviate treatment toxicity and improve patient mortality remain an unmet need. This is particularly pressing in paediatric patients, for whom transplant-related complications are more frequent than for adults and transplant dysfunction is more detrimental due to children's longer life expectancy and dependence on a functioning graft. Recently, accumulating evidence has suggested the human

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Section: Clinical Implications Of Dysbiosis In Sotmentioning

confidence: 96%

The gut microbiome in solid organ transplantation

Arassi

Zeller

Karcher

et al. 2020

Pediatric Transplantation

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“…We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs beyond irinotecan (10)(11)(12).…”

mentioning

confidence: 99%

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Bhatt

Pellock

Biernat

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

142

104

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Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immunedeficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage. microbiome | chemotherapy | cancer | gastrointestinal toxicity I rinotecan (CPT-11) is essential for treating colorectal and pancreatic cancers and is frequently administered as a mixture with 5-fluorouracil and/or oxaliplatin. Ongoing clinical trials seek to extend irinotecan to other forms of cancer. However, irinotecan causes both myelosuppression and gastrointestinal (GI) side effects, including mucositis and late-onset diarrhea, which are often dose limiting: 88% of irinotecan patients develop diarrhea, with 30% experiencing acute grade 3 to 4 diarrhea (1-3). This toxicity is frequently refractory to antimotility drugs. Thus, treating irinotecaninduced diarrhea is a significant clinical need (4, 5).The irinotecan prodrug is activated in vivo to SN38, a potent topoisomerase I inhibitor (6) that retards the growth of rapidly proliferating cells in tumors and the intestinal epithelium, which renews every 5 d. SN38 is detoxified through the addition of glucuronic acid (GlcA) to form SN38-G, a compound marked for elimination via the GI tract. Gut commensal bacterial β-glucuronidase (GUS) proteins remove GlcA from SN38-G. Reactivated SN38 inflicts epithelial damage, resulting in bleeding diarrhea and acute weight loss in animal models (7). We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs be...

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“…Many human target drugs are reported to be metabolited to its inactive form by gut human microbiome 51, 52 or impact the gut bacteria 51–53 . Gut bacteria genes that metabolite 41 human targeted drugs, 6 non-traditional antibacterial therapeutic and key enzymes experimented validated for 12 human diseases were mapped to our oral SGB genomic contents ( Supplementary Tables 6 ).…”

Section: Resultsmentioning

confidence: 99%

“…7a). More specificly, there are total 2696 SGBs containβ-glucuronidase enzyme that can metabolite anti-cancer drug Gemcitabine (2’, 2’-difluorodeoxycytidine) into its inactive form 52 . 456 SGBs have agmatine gene for anti T2D drug Metformin and 225 SGBs have tyrosine decarboxylase (TyrDC) for anti-parkinson drug L-dopa 51 .…”

Section: Resultsmentioning

confidence: 99%

Over 50000 metagenomically assembled draft genomes for the human oral microbiome reveal new taxa

Zhu

Liang

Chen

et al. 2019

Preprint

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21The oral cavity of each person is home for hundreds of bacterial species. While 22 taxa for oral diseases have been well studied using culture-based as well as 23 amplicon sequencing methods, metagenomic and genomic information remain 24 scarce compared to the fecal microbiome. Here we provide metagenomic shotgun 25 data for 3346 oral metagenomics samples, and together with 808 published 26 samples, assemble 56,213 metagenome-assembled genomes (MAGs). 64% of the 27 3,589 species-level genome bins contained no publicly available genomes, others 28 with only a handful. The resulting genome collection is representative of samples 29 around the world and across physiological conditions, contained many genomes 30 from Candidate phyla radiation (CPR) which lack monoculture, and enabled 31 discovery of new taxa such as a family within the Acholeplasmataceae order. 32 New biomarkers were identified for rheumatoid arthritis or colorectal cancer, 33 which would be more convenient than fecal samples. The large number of 34 metagenomic samples also allowed assembly of many strains from important 35 oral taxa such as Porphyromonas and Neisseria. Predicted functions enrich in 36 drug metabolism and small molecule synthesis. Thus, these data lay down a 37 genomic framework for future inquiries of the human oral microbiome. 38 39The human microbiome has been implicated in a growing number of diseases. 40The majority of microbial cells is believed to reside in the large intestine 1 and cohorts 41 with fecal metagenomic data contain over 1000 individuals 2, 3 . For the oral 42 microbiome, hundreds of metagenomic shotgun-sequenced samples have been 43 available from the Human Microbiome Project (HMP) and for rheumatoid arthritis 4-6 . 44A number of other diseases studied by Metagenome-wide association studies (MWAS) 45 using gut microbiome data also indicated potential contribution from the oral 46 microbiome in disease etiology 7-12 . Although the MWAS on rheumatoid arthritis was 47 the oral microbiome is believed to be well covered by culturing 13 , and analyses by 54 16S rRNA gene amplicon sequencing or polymerase chain reaction (PCR) are 55 common. Recently published large-scale metagenomic assembly efforts mostly 56 included fecal metagenomic data [14][15][16] . It is not clear how much is really missing for 57 the oral microbiome. The saliva, in particular, seems to have more bacterial species 58 per individual than the fecal microbiome 17 . 59After getting contigs using assembly algorithms suitable for metagenomic 60 data 18 , a central idea used by metagenomic binning algorithms is that genes or contigs 61 that co-vary in abundance among many samples belong to the same microbial 62 genome 8,[19][20][21] . Large cohorts are therefore prerequisites for high-quality assembly. 63Here we present 3346 new oral metagenomic samples, and 56,213 64 metagenome-assembled genomes (MAGs) which represent 3,589 species-level clades, 65revealing new taxa as well as substantially complementing the genomic content of 66 known species. This ...

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Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Cited by 12 publications

References 65 publications

The gut microbiome in solid organ transplantation

The gut microbiome in solid organ transplantation

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Over 50000 metagenomically assembled draft genomes for the human oral microbiome reveal new taxa

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