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. 2020 Jun 11;10(6):242.
doi: 10.3390/metabo10060242.

Antibiotic-Induced Changes in Microbiome-Related Metabolites and Bile Acids in Rat Plasma

Véronique de Bruijn  1   2 , Christina Behr  1 , Saskia Sperber  1 , Tilmann Walk  3 , Philipp Ternes  3 , Markus Slopianka  3 , Volker Haake  3 , Karsten Beekmann  2 , Bennard van Ravenzwaay  1
Affiliations

Antibiotic-Induced Changes in Microbiome-Related Metabolites and Bile Acids in Rat Plasma

Véronique de Bruijn et al. Metabolites. .

Abstract

Various environmental factors can alter the gut microbiome's composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were compared to distinguish between microbiome-derived or -associated and systemic changes in the plasma metabolome. The resulting changes in the plasma metabolome were compared to the effects of a third reference compound, roxithromycin, which is readily bioavailable. A community analysis revealed that the oral administration of vancomycin and roxithromycin in particular leads to an altered microbial population. Antibiotic-induced changes depending on the administration routes were observed in plasma metabolite levels. Indole-3-acetic acid (IAA) and hippuric acid (HA) were identified as key metabolites of microbiome modulation, with HA being the most sensitive. Even though large variations in the plasma bile acid pool between and within rats were observed, the change in microbiome community was observed to alter the composition of the bile acid pool, especially by an accumulation of taurine-conjugated primary bile acids. In-depth investigation of the relationship between microbiome variability and their functionality, with emphasis on the bile acid pool, will be necessary to better assess the potential adverseness of environmentally induced microbiome changes.

Keywords: antibiotics; bile acids; metabolomics; microbiome.

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Conflict of interest statement

The authors declare no conflict of interest, there is no connection between BASF SE and the subject of this manuscript.

Figures

Figure 1
Figure 1
Principal coordinate analysis (PCoA) of the gut microbial community showing the treatment-related effect of oral administration of roxithromycin, streptomycin and vancomycin versus the feeding control and the vehicle control (0.5% carboxymethylcellulose (CMC) in drinking water).
Figure 2
Figure 2
O-PLS-DA score plots. Individual models were generated by comparing samples from each antibiotic treatment and application route to all controls. (a) roxithromycin p.o. (b) roxithromycin i.p. (c) streptomycin p.o. (d) vancomycin i.p. (e) vancomycin p.o. (f) streptomycin i.p. Rats were either orally or parenterally dosed with vancomycin, streptomycin and roxithromycin (n = 5 per group). The control group received no treatment, the gavage control group received 0.5% CMC in drinking water and the intraperitoneal and subcutaneous control group were injected with a saline solution (n = 10 per group). Each dot represents a single plasma sample. The different days are represented by different point shapes. tp1, scores for first predictive component; to1, scores for first orthogonal component; p.o., per os (by mouth); i.p., intraperitoneal; s.c., subcutaneous.
Figure 3
Figure 3
Hierarchical clustering analysis (HCA) of plasma metabolic profiles of antibiotic-treated male Crl/Wi(Han) rats compared to vehicle control animals. Animals were orally or parenterally dosed with roxithromycin, streptomycin or vancomycin for 28 days daily. Plasma samples were drawn on days 7, 14 and 28 (indicated by 7d, 14d, 28d). Coloring is based on the t-values. Input values are normalized against the respective vehicle control, and depicted in the axis label as antibiotic_vs_vehicle control_study day. rox, roxithromycin; str, streptomycin; van, vancomycin; con_po, per os vehicle control; con_ip, intraperitoneal vehicle control; con_sc, subcutaneous vehicle control. * additional: phosphatidylcholine (C18:2,C18:2).
Figure 4
Figure 4
Plasma bile acid levels of male Crl/Wi(Han) rats treated orally or parenterally with vancomycin, streptomycin or roxithromycin. Input values are log10-transformed fold-changes relative to the feeding control. p_ indicates primary bile acid s_ secondary bile acid. The black horizontal line in each boxplot represents the group median value. p.o., per os (by mouth); i.p., intraperitoneal; s.c., subcutaneous.
Figure 5
Figure 5
Relative cholic acid levels (normalized to the median value of the feeding controls) in plasma of male Crl/Wi(Han) rats in the different control groups (n = 10 per group) on days 7, 14 and 28. Values from the same animals are connected. p.o., per os (by mouth); i.p., intraperitoneal; s.c., subcutaneous.
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References

    1. Zhang Y.-J., Li S., Gan R., Zhou T., Xu N.-P., Li H.-B. Impacts of Gut Bacteria on Human Health and Diseases. Int. J. Mol. Sci. 2015;16:7493–7519. doi: 10.3390/ijms16047493. - DOI - PMC - PubMed
    1. Xu J., Gordon J.I. Honor thy symbionts. Proc. Natl. Acad. Sci. USA. 2003;100:10452–10459. doi: 10.1073/pnas.1734063100. - DOI - PMC - PubMed
    1. Behr C., Kamp H., Fabian E., Krennrich G., Mellert W., Peter E., Strauss V., Walk T., Rietjens I.M.C.M., Van Ravenzwaay B. Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats. Arch. Toxicol. 2017;91:3439–3454. doi: 10.1007/s00204-017-1949-2. - DOI - PubMed
    1. Lindon J., Holmes E., Bollard M.E., Stanley E.G., Nicholson J. Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers. 2004;9:1–31. doi: 10.1080/13547500410001668379. - DOI - PubMed
    1. Ramirez T., Daneshian M., Kamp H., Bois F., Clench M.R., Coen M., Donley B., Fischer S.M., Ekman E.R., Fabian E., et al. Metabolomics in Toxicology and Preclinical Research. ALTEX. 2013;30:209–225. doi: 10.14573/altex.2013.2.209. - DOI - PMC - PubMed

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