%0 Journal Article
%T Gut microbial β-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics.
%A Simpson JB
%A Walker ME
%A Sekela JJ
%A Ivey SM
%A Jariwala PB
%A Storch CM
%A Kowalewski ME
%A Graboski AL
%A Lietzan AD
%A Walton WG
%A Davis KA
%A Cloer EW
%A Borlandelli V
%A Hsiao YC
%A Roberts LR
%A Perlman DH
%A Liang X
%A Overkleeft HS
%A Bhatt AP
%A Lu K
%A Redinbo MR
%J Cell Host Microbe
%V 32
%N 6
%D 2024 Jun 12
%M 38754417
%F 31.316
%R 10.1016/j.chom.2024.04.018
%X 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.