PDF(Pubmed)
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.
摘要：
激素和神经递质对体内平衡至关重要，它们的破坏与从癌症到焦虑症的各种疾病有关。肠道微生物β-葡糖醛酸酶（GUS）酶对内源性葡糖醛酸的差异再激活可能会影响疾病发作和治疗的个体差异。使用多元，在体外，和体内方法，我们表明,无菌小鼠体内有活性的内生物活性物质水平降低,不同的肠道微生物Loop1和FMNGUS酶驱动激素和神经递质的再激活.我们证明了一系列FDA批准的药物通过以保守的方式拦截酶的催化循环来防止这种再活化。最后,我们发现，在常规小鼠中抑制GUS会减少血清和肠道中游离的5-羟色胺，并增加其非活性的葡糖苷酸。我们的结果阐明了肠道微生物酶在维持内生体内稳态中的不可或缺性，并表明这种代谢的治疗性破坏促进了个体间的反应变异性。
