Gut microbial β-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics

Joshua B Simpson; Morgan E Walker; Joshua J Sekela; Samantha M Ivey; Parth B Jariwala; Cameron M Storch; Mark E Kowalewski; Amanda L Graboski; Adam D Lietzan; William G Walton; Kacey A Davis; Erica W Cloer; Valentina Borlandelli; Yun-Chung Hsiao; Lee R Roberts; David H Perlman; Xue Liang; Hermen S Overkleeft; Aadra P Bhatt; Kun Lu; Matthew R Redinbo

doi:10.1016/j.chom.2024.04.018

Gut microbial β-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics

Cell Host Microbe. 2024 May 13:S1931-3128(24)00138-0. doi: 10.1016/j.chom.2024.04.018. Online ahead of print.

Authors

Joshua B Simpson¹, Morgan E Walker¹, Joshua J Sekela¹, Samantha M Ivey¹, Parth B Jariwala¹, Cameron M Storch¹, Mark E Kowalewski², Amanda L Graboski³, Adam D Lietzan⁴, William G Walton¹, Kacey A Davis², Erica W Cloer⁵, Valentina Borlandelli⁶, Yun-Chung Hsiao⁷, Lee R Roberts⁸, David H Perlman⁸, Xue Liang⁸, Hermen S Overkleeft⁶, Aadra P Bhatt⁹, Kun Lu⁷, Matthew R Redinbo¹⁰

Affiliations

¹ Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA.
² Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
³ Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
⁴ Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
⁷ Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA.
⁹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA. Electronic address: redinbo@unc.edu.

PMID: 38754417
DOI: 10.1016/j.chom.2024.04.018

Abstract

Hormones and neurotransmitters are essential to homeostasis, and their disruptions are connected to diseases ranging from cancer to anxiety. The differential reactivation of endobiotic glucuronides by gut microbial β-glucuronidase (GUS) enzymes may influence interindividual differences in the onset and treatment of disease. Using multi-omic, in vitro, and in vivo approaches, we show that germ-free mice have reduced levels of active endobiotics and that distinct gut microbial Loop 1 and FMN GUS enzymes drive hormone and neurotransmitter reactivation. We demonstrate that a range of FDA-approved drugs prevent this reactivation by intercepting the catalytic cycle of the enzymes in a conserved fashion. Finally, we find that inhibiting GUS in conventional mice reduces free serotonin and increases its inactive glucuronide in the serum and intestines. Our results illuminate the indispensability of gut microbial enzymes in sustaining endobiotic homeostasis and indicate that therapeutic disruptions of this metabolism promote interindividual response variabilities.

Keywords: FDA-approved drugs; X-ray crystallography; hormones; interindividual response variability; metabolism; metagenomics; metaproteomics; multi-omics; neurotransmitters; β-glucuronidase.