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Gut microbiome structure and metabolic activity in inflammatory bowel disease


The inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial chronic conditions of the gastrointestinal tract. While IBD has been associated with dramatic changes in the gut microbiota, changes in the gut metabolome—the molecular interface between host and microbiota—are less well understood. To address this gap, we performed untargeted metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery (n = 155) and validation (n = 65) cohorts of CD, UC and non-IBD control patients. Metabolomic and metagenomic profiles were broadly correlated with faecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While > 50% of differentially abundant metabolite features were uncharacterized, many could be assigned putative roles through metabolomic ‘guilt by association’ (covariation with known metabolites). Differentially abundant species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between differentially abundant species and well-characterized differentially abundant metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome–metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.

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Data availability

Metagenomic sequences for the PRISM, LifeLines DEEP and NLIBD cohorts are available via SRA with BioProject number PRJNA400072. Metabolomics data (accession number PR000677) are available at the National Institutes of Health Common Fund’s Metabolomics Data Repository and Coordinating Center (supported by National Institutes of Health grant no. U01-DK097430): Metabolomics Workbench ( Tables of processed metabolite, microbial species and microbial enzyme abundance are available as Supplementary Datasets 2, 4 and 6.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 10 April 2019

    In the Supplementary Tables 2, 4 and 6 originally published with this Article, the authors mistakenly included sample identifiers in the form of UMCGs rather than UMCG IBDs in the validation cohort; this has now been amended.


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The authors are grateful to the members of the PRISM, LifeLines DEEP and NLIBD cohorts for participating in the study and providing sample material. We thank T. Poon for project management and coordination of data generation, T. Reimels for editorial assistance and A. Garner for providing helpful feedback on the manuscript. The Dutch research team was funded by: CVON IN-CONTROL (CVON2012–03 to A.Z. and J.F.); the Dutch Digestive Foundation (D16–14 to R.K.W. and A.Z.); the Netherlands Organization for Scientific Research (NWO-VIDI 864.13.013 to J.F., NWO-VIDI 016.Vidi.178.056 to A.Z., NWOOW-VIDI 016.136.308 to R.K.W.); a Spinoza Prize (SPI 92–266 to C.W.); and the European Research Council (ERC-Starting no. 715772 to A.Z. and ERC-Advanced 2012–322698 to C.W.). The Boston research team was funded by: the National Science Foundation (NSF CAREER DBI-1053486 and NSF EAGER MCB-1453942 to C.H.); the National Institutes of Health (R01HG00596 to C.H., U54DK102557 to C.H. and R.J.X., R01DK92405 to R.J.X., R24DK110499 to C.H.); the Crohn’s and Colitis Foundation of America to R.J.X. and C.H.; and the Center for Microbiome Informatics and Therapeutics (6933665 PO no. 5710004058 to R.J.X.). A.B.H. is a Merck Fellow of the Helen Hay Whitney Foundation.

Author information

E.A.F., A.S-M., H.V., C.H. and R.J.X. designed the research. E.A.F., A.S-M., J.A-P., N.F., T.V., H.M. and L.J.M. performed the research. H.J.H., S.R., J.S.S., R.G.W., B.W.S., F.I., A.Z., J.F., R.K.W. and C.W. contributed materials. J.A-P., J.M.S., K.P., A.A.D., K.B. and C.B.C. generated the data. E.A.F., A.S-M., J.A-P., N.F., A.B.H. and H.V. analysed the data. E.A.F., J.A.P., R.K.W., C.W., H.V., C.H. and R.J.X. provided project oversight. E.A.F., A.S-M., H.V., C.H. and R.J.X. wrote the paper.

Competing interests

F.I. received a speaker’s fee from AbbVie.

Correspondence to Curtis Huttenhower or Ramnik J. Xavier.

Supplementary information

Supplementary Information

Supplementary Figures 1–13

Reporting Summary

Supplementary Dataset 1

Metabolite feature metadata

Supplementary Dataset 2

Per-subject metabolite relative abundance profiles

Supplementary Dataset 3

IBD-metabolite associations

Supplementary Dataset 4

Per-subject microbial species relative abundance profiles

Supplementary Dataset 5

IBD-microbial species associations

Supplementary Dataset 6

Per-subject microbial enzyme relative abundance profiles

Supplementary Dataset 7

IBD-microbial enzyme associations

Supplementary Dataset 8

Genedata Expressionist configuration

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Further reading

Fig. 1: IBD is associated with broad changes in the gut multi-omic profiles of individuals.
Fig. 2: Metabolic enrichments in IBD versus control phenotypes.
Fig. 3: Clusters of chemically related, IBD-perturbed metabolites revealed by abundance covariation.
Fig. 4: Potentially mechanistic associations between IBD-linked microbes and metabolites.
Fig. 5: IBD-associated changes in microbial function and their metabolic associations.
Fig. 6: Predicting IBD status and subtype from gut microbiome multi-omic features.