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

Abstract

Background: 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.Methods: 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.Results: 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.Conclusions: 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.

Host microbiome depletion attenuates biofluid metabolite responses following radiation exposure

“…Mice provided with a broad-spectrum β-lactam antibiotic, imipenem, over 4 days showed perturbation in urinary metabolites involved in amino acid metabolism, TCA cycle, and purine and pyrimidine metabolism, however these levels recovered after the mice stopped receiving the antibiotic [13]. Humans receiving β-lactam antibiotic alone or in addition to other medications showed correlating changes in blood metabolites (e. g., hippuric acid, indole propionate, indoxyl sulfate, cresol sulfate) as had been recorded in murine models [15]. Hippuric acid and indoxyl sulfate were two top metabolites associated with the host microbiota in urine and serum in germ free mice [6] and depleted in the urine of mice given a cocktail of neomycin, streptomycin, and bacitracin [43].…”

“…Microbiota derived metabolites (indole-3-carboxaldehyde and kynurenic acid) have been implicated in host radioprotection [8], although radiation enteritis and intestinal injury can also be lessened in germ free mice or through administering antibiotics [9][10][11], which is why antibiotics will likely be supplied as a first defense countermeasure in a nuclear emergency [12]. Furthermore, in addition to antibiotic administration [13][14][15][16], radiation exposure can have effects on the host microbiome that can affect downstream metabolic analyses [17][18][19]. From a biodosimetry perspective, it will be necessary to develop a radiation biosignature capable of dose reconstruction irrespective of the natural variation in the human microbiome [20] or antibiotic regimens [21].…”

Effects of Uremic Clearance Granules on p38 MAPK/NF-κB Signaling Pathway, Microbial and Metabolic Profiles in End-Stage Renal Disease Rats Receiving Peritoneal Dialysis

“… 47 Hippurate was a uremia toxin that can be produced by anaerobic bacteria, especially Clostridium, using aromatic amino acids such as L-phenylalanine, L-tyrosine, or L-tryptophan. 48 Therefore, it is reasonable to speculate that UCG could slow down the accumulation of toxins in ESRD by regulating phenylalanine metabolism.…”