Original Article

Microbe-Microbe and Microbe-Host Interactions

A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice

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Abstract

Defining the functional status of host-associated microbial ecosystems has proven challenging owing to the vast number of predicted genes within the microbiome and relatively poor understanding of community dynamics and community–host interaction. Metabolomic approaches, in which a large number of small molecule metabolites can be defined in a biological sample, offer a promising avenue to ‘fingerprint’ microbiota functional status. Here, we examined the effects of the human gut microbiota on the fecal and urinary metabolome of a humanized (HUM) mouse using an optimized ultra performance liquid chromatography–mass spectrometry-based method. Differences between HUM and conventional mouse urine and fecal metabolomic profiles support host-specific aspects of the microbiota’s metabolomic contribution, consistent with distinct microbial compositions. Comparison of microbiota composition and metabolome of mice humanized with different human donors revealed that the vast majority of metabolomic features observed in donor samples are produced in the corresponding HUM mice, and individual-specific features suggest ‘personalized’ aspects of functionality can be reconstituted in mice. Feeding the mice a defined, custom diet resulted in modification of the metabolite signatures, illustrating that host diet provides an avenue for altering gut microbiota functionality, which in turn can be monitored via metabolomics. Using a defined model microbiota consisting of one or two species, we show that simplified communities can drive major changes in the host metabolomic profile. Our results demonstrate that metabolomics constitutes a powerful avenue for functional characterization of the intestinal microbiota and its interaction with the host.

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Acknowledgements

We thank Erica Sonnenburg for providing comments on the manuscript and Tim Meyer for helpful discussions. This work was funded in part by grants from National Institutes of Health (R01-DK085025 and DP2-OD006515).

Author information

Affiliations

  1. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA

    • A Marcobal
    • , P C Kashyap
    •  & J L Sonnenburg
  2. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    • P C Kashyap
  3. Department of Chemical Engineering, Stanford University School of Medicine, Stanford, CA,USA

    • T A Nelson
    •  & A Spormann
  4. Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, USA

    • P A Aronov
  5. Department of Bioengineering and Therapeutic Sciences and California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA, USA

    • M S Donia
    •  & M A Fischbach

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to J L Sonnenburg.

Supplementary information

Supplementary Information accompanies this paper on The ISME Journal website (http://www.nature.com/ismej)