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Dynamics of metatranscription in the inflammatory bowel disease gut microbiome


Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn’s disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study’s results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.

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We thank the participants from Massachusetts General Hospital, Emory University, Cedars-Sinai IBD Center and Cincinnati Children’s Hospital Medical Center, who made this study possible. Furthermore, we acknowledge B. Sayoldin for making the data available through the Sequence Read Archive and our collaborators throughout the Integrative Human Microbiome Consortium. This work was supported by the US National Institutes of Health (NIH) grants U54DK102557 (C.H. and R.J.X.), STARR Cancer Consortium (C.H.), CCFA 20144126 (R.J.X.) and R01DK92405 (R.J.X.), U01DK062413 (D.P.B.M.), P01DK046763 (D.P.B.M.), UL1TR001881 (J.B.), and The Leona M. and Harry B. Helmsley Charitable Trust (D.P.B.M.).

Author information

M.S., C.H., R.J.X. and H.V. conceived and designed the experiments. A.N.A., E.A., G.B., K.L., M.P., J.S., B.S. and R.G.W. performed the experiments. M.S., C.H. and E.A.F. analysed the data. M.S., C.H., E.A.F., J.L.-P., L.J.M., R.S., T.W.P., E.A., J.B., L.A.D., S.K. and D.P.B.M. contributed materials/analysis tools. M.S., C.H., R.J.X., J.L.-P. and H.V. wrote the paper.

Competing interests

D.P.B.M. is consulting for Cidara. The authors declare no other competing financial interests.

Correspondence to Ramnik J. Xavier or Curtis Huttenhower.

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Supplementary Information

Supplementary Figures 1–6, Supplementary Table 1.

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Supplementary Table 2

Description of pathways.

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Further reading

Fig. 1: Longitudinal metagenomes and metatranscriptomes in IBD.
Fig. 2: Metatranscriptomic activities assigned to specific microorganisms and disease phenotypes.
Fig. 3: Comparing species-specific metagenomic functional potential with metatranscriptomic functional activity.
Fig. 4: Dynamic changes in IBD-specific metatranscription over time.