Jaskiw George E, Obrenovich Mark E, Kundrapu Sirisha, Donskey Curtis J
Psychiatry Service, Veterans Affairs Northeast Ohio Healthcare System (VANEOHS), Cleveland, Ohio.
School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Pathog Immun. 2020 Dec 29;5(1):382-418. doi: 10.20411/pai.v5i1.394. eCollection 2020.
The gut microbiome (GMB) generates numerous small chemicals that can be absorbed by the host and variously biotransformed, incorporated, or excreted. The resulting metabolome can provide information about the state of the GMB, of the host, and of their relationship. Exploiting this information in the service of biomarker development is contingent on knowing the GMB-sensitivity of the individual chemicals comprising the metabolome. In this regard, human studies have lagged far behind animal studies. Accordingly, we tested the hypothesis that serum levels of chemicals unequivocally demonstrated to be GMB-sensitive in rodent models would also be affected in a clinical patient sample treated with broad spectrum antibiotics.
We collected serum samples from 20 hospitalized patients before, during, and after treatment with broad-spectrum antibiotics. We also collected samples from 5 control patients admitted to the hospital but not prescribed antibiotics. We submitted the samples for a non-targeted metabolomic analysis and then focused on chemicals known to be affected both by germ-free status and by antibiotic treatment in the mouse and/or rat.
Putative identification was obtained for 499 chemicals in human serum. An aggregate analysis did not show any time x treatment interactions. However, our literature search identified 10 serum chemicals affected both by germ-free status and antibiotic treatment in the mouse or rat. Six of those chemicals were measured in our patient samples and additionally met criteria for inclusion in a focused analysis. Serum levels of 5 chemicals (p-cresol sulfate, phenol sulfate, hippurate, indole propionate, and indoxyl sulfate) declined significantly in our group of antibiotic-treated patients but did not change in our patient control group.
Broad-spectrum antibiotic treatment in patients lowered serum levels of selected chemicals previously demonstrated to be GMB-sensitive in rodent models. Interestingly, all those chemicals are known to be uremic solutes that can be derived from aromatic amino acids (L-phenylalanine, L-tyrosine, or L-tryptophan) by anaerobic bacteria, particularly species. We conclude that judiciously selected serum chemicals can reliably detect antibiotic-induced suppression of the GMB in man and thus facilitate further metabolome-based biomarker development.
肠道微生物群（GMB）产生许多可被宿主吸收、经各种生物转化、整合或排泄的小分子化学物质。由此产生的代谢组可提供有关GMB状态、宿主状态及其关系的信息。利用这些信息服务于生物标志物开发取决于了解构成代谢组的各个化学物质对GMB的敏感性。在这方面，人体研究远远落后于动物研究。因此，我们检验了以下假设：在啮齿动物模型中明确证明对GMB敏感的化学物质的血清水平，在接受广谱抗生素治疗的临床患者样本中也会受到影响。
我们收集了20例住院患者在接受广谱抗生素治疗前、治疗期间和治疗后的血清样本。我们还从5例入院但未使用抗生素的对照患者中收集了样本。我们将样本送去进行非靶向代谢组学分析，然后聚焦于已知在小鼠和/或大鼠中受无菌状态和抗生素治疗影响的化学物质。
在人血清中推定鉴定出499种化学物质。汇总分析未显示任何时间×治疗交互作用。然而，我们的文献检索确定了10种在小鼠或大鼠中受无菌状态和抗生素治疗影响的血清化学物质。在我们的患者样本中对其中6种化学物质进行了测量，并且它们还符合纳入聚焦分析的标准。在我们接受抗生素治疗的患者组中，5种化学物质（对甲酚硫酸盐、苯酚硫酸盐、马尿酸盐、吲哚丙酸和硫酸吲哚酚）的血清水平显著下降，但在我们的患者对照组中未发生变化。
患者接受广谱抗生素治疗会降低先前在啮齿动物模型中证明对GMB敏感的特定化学物质的血清水平。有趣的是，所有这些化学物质都是已知的尿毒症溶质，可由厌氧细菌，特别是某些物种从芳香族氨基酸（L-苯丙氨酸、L-酪氨酸或L-色氨酸）衍生而来。我们得出结论，明智选择的血清化学物质能够可靠地检测出人类中抗生素诱导的GMB抑制，从而有助于进一步开展基于代谢组的生物标志物开发。
