Host variables confound gut microbiota studies of human disease.

Journal: Nature
PMID: 33149306

Abstract

Low concordance between studies that examine the role of microbiota in human diseases is a pervasive challenge that limits the capacity to identify causal relationships between host-associated microorganisms and pathology. The risk of obtaining false positives is exacerbated by wide interindividual heterogeneity in microbiota composition, probably due to population-wide differences in human lifestyle and physiological variables that exert differential effects on the microbiota. Here we infer the greatest, generalized sources of heterogeneity in human gut microbiota profiles and also identify human lifestyle and physiological characteristics that, if not evenly matched between cases and controls, confound microbiota analyses to produce spurious microbial associations with human diseases. We identify alcohol consumption frequency and bowel movement quality as unexpectedly strong sources of gut microbiota variance that differ in distribution between healthy participants and participants with a disease and that can confound study designs. We demonstrate that for numerous prevalent, high-burden human diseases, matching cases and controls for confounding variables reduces observed differences in the microbiota and the incidence of spurious associations. On this basis, we present a list of host variables that we recommend should be captured in human microbiota studies for the purpose of matching comparison groups, which we anticipate will increase robustness and reproducibility in resolving the members of the gut microbiota that are truly associated with human disease.

Authors

  • Ivan Vujkovic-Cvijin
    Metaorganism Immunity Section, Laboratory of Immune Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ivc@nih.gov.
  • Jack Sklar
    Metaorganism Immunity Section, Laboratory of Immune Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Lingjing Jiang
    Division of Biostatistics, University of California San Diego, La Jolla, CA, USA.
  • Loki Natarajan
  • Rob Knight
    Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA; Center for Microbiome Innovation, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA 92093, USA.
  • Yasmine Belkaid
    Metaorganism Immunity Section, Laboratory of Immune Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ybelkaid@niaid.nih.gov.

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