Changes in the Serum Metabolome of Patients Treated With Broad-Spectrum Antibiotics

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 Clostridial 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.