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.2009 Mar 10;106(10):3698-703.
doi: 10.1073/pnas.0812874106. Epub 2009 Feb 20.

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

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Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

William R Wikoff et al. Proc Natl Acad Sci U S A..

Abstract

Although it has long been recognized that the enteric community of bacteria that inhabit the human distal intestinal track broadly impacts human health, the biochemical details that underlie these effects remain largely undefined. Here, we report a broad MS-based metabolomics study that demonstrates a surprisingly large effect of the gut "microbiome" on mammalian blood metabolites. Plasma extracts from germ-free mice were compared with samples from conventional (conv) animals by using various MS-based methods. Hundreds of features were detected in only 1 sample set, with the majority of these being unique to the conv animals, whereas approximately 10% of all features observed in both sample sets showed significant changes in their relative signal intensity. Amino acid metabolites were particularly affected. For example, the bacterial-mediated production of bioactive indole-containing metabolites derived from tryptophan such as indoxyl sulfate and the antioxidant indole-3-propionic acid (IPA) was impacted. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes. Multiple organic acids containing phenyl groups were also greatly increased in the presence of gut microbes. A broad, drug-like phase II metabolic response of the host to metabolites generated by the microbiome was observed, suggesting that the gut microflora has a direct impact on the drug metabolism capacity of the host. Together, these results suggest a significant interplay between bacterial and mammalian metabolism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The microbione exerts a broad effect on mammalian biochemistry. (Upper) The experimental workflow for the metabolomics studies performed. (Lower) Major differences are observed in the profiles of GF and conv plasma obtained employing + ESI. PCA analysis of the profiling data from XCMS (Left) shows an excellent separation between sample groups. As shown in the Venn diagram (Right), most species are observed in both GF and conv samples, but a significant number are unique to a given sample set, with ≈3-fold more ions unique to the conv sample.
Fig. 2.
Fig. 2.
The diversity of indole-containing compounds in serum is affected by the microbiome. (Upper) Various indole-containing molecules arise only in the presence of the microbiome and ultimately enter the plasma by means of different routes. (Lower) Differences in the plasma levels of indole-containing compounds attributed to the action of the microbiome. The integrated signal intensities plotted on they axes are reduced by a factor of 1,000.
Fig. 3.
Fig. 3.
Sulfate profiling based on constant neutral loss scanning of 80m/z in − ESI mode for conv (Upper) and GF (Lower) pooled plasma samples. Them/z values for several species are listed above their respective peak. Identified sulfates include: phenyl sulfate (a), indoxyl sulfate (b),p-cresol sulfate (c), equol sulfate (d), and methyl equol sulfate (e).
Fig. 4.
Fig. 4.
Differences in the plasma levels of various glycine-conjugated compounds attributed to the action of the microbiome. Potential metabolic pathways leading to the formation of hippuric acid as well as 3 other glycine conjugates arising from the presence of the microbiome are provided. The integrated signal intensities plotted on they axes are reduced by a factor of 1,000.
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