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Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):E2329-38. doi: 10.1073/pnas.1319284111. Epub 2014 May 19.

Relating the metatranscriptome and metagenome of the human gut.

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Biostatistics Department andThe Broad Institute, Cambridge, MA 02142;
Biostatistics Department and.
The Broad Institute, Cambridge, MA 02142;
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114;
Department of Microbiology, The Forsyth Institute, Cambridge, MA 02142;Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115;
The Broad Institute, Cambridge, MA 02142;Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114;Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Biostatistics Department andThe Broad Institute, Cambridge, MA 02142;


Although the composition of the human microbiome is now well-studied, the microbiota's >8 million genes and their regulation remain largely uncharacterized. This knowledge gap is in part because of the difficulty of acquiring large numbers of samples amenable to functional studies of the microbiota. We conducted what is, to our knowledge, one of the first human microbiome studies in a well-phenotyped prospective cohort incorporating taxonomic, metagenomic, and metatranscriptomic profiling at multiple body sites using self-collected samples. Stool and saliva were provided by eight healthy subjects, with the former preserved by three different methods (freezing, ethanol, and RNAlater) to validate self-collection. Within-subject microbial species, gene, and transcript abundances were highly concordant across sampling methods, with only a small fraction of transcripts (<5%) displaying between-method variation. Next, we investigated relationships between the oral and gut microbial communities, identifying a subset of abundant oral microbes that routinely survive transit to the gut, but with minimal transcriptional activity there. Finally, systematic comparison of the gut metagenome and metatranscriptome revealed that a substantial fraction (41%) of microbial transcripts were not differentially regulated relative to their genomic abundances. Of the remainder, consistently underexpressed pathways included sporulation and amino acid biosynthesis, whereas up-regulated pathways included ribosome biogenesis and methanogenesis. Across subjects, metatranscriptional profiles were significantly more individualized than DNA-level functional profiles, but less variable than microbial composition, indicative of subject-specific whole-community regulation. The results thus detail relationships between community genomic potential and gene expression in the gut, and establish the feasibility of metatranscriptomic investigations in subject-collected and shipped samples.

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