An Atlas of β-Glucuronidases in the Human Intestinal Microbiome

Pollet, Rebecca M.; D’Agostino, Emma H.; Walton, William G.; Xu, Yongmei; Little, Michael S.; Biernat, Kristen A.; Pellock, S.J.; Patterson, Loraine M.; Creekmore, Benjamin C.; Isenberg, Hanna N.; Bahethi, Rohini R.; Bhatt, Aadra P.; Liu, Jian; Gharaibeh, Raad Z.; Redinbo, Matthew R.

doi:10.1016/j.str.2017.05.003

Cited by 206 publications

(307 citation statements)

References 50 publications

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“…Thus, glucuronidation enables the quantification of molecules that would otherwise elude measurement. However, glucuronide moieties are labile and many bacteria express glucuronidase enzymes that hydrolyze them, reducing the signal at WWTPs (Pollet 2017, Jacox 2017. Thus, we hypothesized glucuronides present at upstream sites might be underrepresented or absent in WWTP samples.…”

Section: Upstream Sampling Enables Detection Of Human Associated Biommentioning

confidence: 99%

24-hour multi-omics analysis of residential sewage reflects human activity and informs public health

Matus¹,

Duvallet

Soule

et al. 2019

Preprint

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High-throughput molecular analysis of sewage is a promising tool for precision public health. Here, we combine sewer network and demographic data to identify a residential catchment for sampling, and explore the potential of applying untargeted genomics and metabolomics to sewage to collect actionable public health data. We find that wastewater sampled upstream in a residential catchment is representative of the human microbiome and metabolome, and we are able to identify glucuronidated compounds indicative of direct human excretion, which are typically degraded too quickly to be detected at treatment plants. We show that diurnal variations during 24-hour sampling can be leveraged to discriminate between biomarkers in sewage that are associated with human activity from those related to the environmental background. Finally, we putatively annotate a suite of human-associated metabolites, including pharmaceuticals, food metabolites, and biomarkers of human health and activity, suggesting that mining untargeted data derived from residential sewage can expand currently-used biomarkers with direct public health or policy relevance. process sewage non-stop through one day, and for Herbie from Cambridge Public Works for providing his good humor and professional insights during our many sampling trips. We thank the generous sponsorship of the Kuwait Foundation for Advancement of Sciences, and the MIT Center for Microbiome Informatics and Therapeutics provided support for computational resources. We thank the WHOI FT-MS facility for sample analysis and Krista Longnecker for training in metabolomics data analysis and discussions throughout the study.

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Section: Upstream Sampling Enables Detection Of Human Associated Biommentioning

confidence: 99%

24-hour multi-omics analysis of residential sewage reflects human activity and informs public health

Matus¹,

Duvallet

Soule

et al. 2019

Preprint

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show abstract

“…The relationship between the intestinal microbiome and the host metabolome is important to understand drug and xenobiotic metabolism, and mode of action [1,2]. Intestinal bacteria express enzymes, like β-glucuronidases, that may activate (and sometimes reactivate) certain drugs [3], and intestinal bacteria can alter how the host metabolizes drugs and xenobiotics [4,5]. Changes in the composition of the intestinal bacteria can influence the host due to the role intestinal microbiota play in drug metabolism [6], food metabolism [7], and gut barrier function [8].…”

Section: Introductionmentioning

confidence: 99%

Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

et al. 2019

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Persistent organic pollutants (POPs) are important environmental chemicals and continued study of their mechanism of action remains a high priority.POPs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), and polychlorinated biphenyls (PCBs), are widespread environmental contaminants that are agonists for the aryl hydrocarbon receptor (AHR). Activation of the AHR modulates the gut microbiome community structure and function, host immunity, and the host metabolome. In the current study, male C57BL6/J mice were exposed, via the diet, to 5 µg/kg body weight (BW) TCDF or 24 µg/kg BW of TCDF every day for 5 days. The functional and structural changes imparted by TCDF exposure to the gut microbiome and host metabolome were explored via 16S rRNA gene amplicon sequencing, metabolomics, and bacterial metatranscriptomics. Significant changes included increases in lipopolysaccharide (LPS) biosynthesis gene expression after exposure to 24 µg/kg BW of TCDF. Increases in LPS biosynthesis were confirmed with metabolomics and LPS assays using serum obtained from TCDF-treated mice. Significant increases in gene expression within aspartate and glutamate metabolism were noted after exposure to 24 µg/kg BW of TCDF. Together, these results suggest that after exposure to 24 µg/kg BW of TCDF, the gut microbiome increases the production of LPS and glutamate to promote localized gut inflammation, potentially using glutamate as a stress response.

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“…The gut bacteria Bacteroides spp. and Roseburia spp., both enriched in the presence of MMF and eliminated by vancomycin, encode for GUS enzymes and have demonstrated GUS activity in vitro(30)(31)(32)(33). It was expected that MPAG would apply a positive selective pressure to bacteria encoding MPAG-compatible GUS enzymes since the resultant GA can be used as a carbon source during anaerobic metabolism(34).…”

mentioning

confidence: 99%

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

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has proven advantages over other immunosuppressive drugs but gastrointestinal (GI) side effects frequently limit its use. The pathways involved in the metabolism of the prodrug MMF and the bioactive derivative mycophenolic acid (MPA) are well characterized but the mechanism responsible for toxicity is unknown. Here we extend our previous observation that an intact gut microbiome is required for MMF-induced toxicity and demonstrate that gut bacterial metabolism is responsible for the GI inflammation and weight loss associated with MMF exposure. In mice consuming MMF, the introduction of vancomycin alone was sufficient to prevent or reverse MMF-induced weight loss and colonic inflammation. MMF induced the expansion of bacteria expressing b-glucuronidase (GUS) in the cecum and proximal colon. GUS activity, which is responsible for the catabolism of glucuronidated MPA (MPAG) to free MPA, was increased in the presence of MMF and eliminated by vancomycin. Vancomycin eliminated multiple Bacteroides spp. that flourished in the presence of MMF and prevented the breakdown of MPAG without negatively affecting serum MPA levels. Human data suggests that increased stool GUS activity can be associated with MMF-related toxicity. Our work provides a mechanism for the GI toxicity associated with MMF and a future direction for the development of therapeutics.3

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An Atlas of β-Glucuronidases in the Human Intestinal Microbiome

Cited by 206 publications

References 50 publications

24-hour multi-omics analysis of residential sewage reflects human activity and informs public health

24-hour multi-omics analysis of residential sewage reflects human activity and informs public health

Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

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

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