A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients

Andrew Brantley Hall¹², Moran Yassour¹², Jenny Sauk³⁴, Ashley Garner¹², Xiaofang Jiang¹⁵, Timothy Arthur¹², Georgia K Lagoudas¹⁶, Tommi Vatanen¹², Nadine Fornelos¹², Robin Wilson³, Madeline Bertha⁷, Melissa Cohen³, John Garber³, Hamed Khalili³, Dirk Gevers¹²⁸, Ashwin N Ananthakrishnan³, Subra Kugathasan⁷, Eric S Lander¹⁹¹⁰, Paul Blainey¹⁶, Hera Vlamakis¹², Ramnik J Xavier^11121314, Curtis Huttenhower¹⁵¹⁶

Affiliations

¹Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
²Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
³Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁴Current address: Vatche and Tamar Manoukian Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
⁵Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁶MIT Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
⁷Emory University School of Medicine, Emory University, Atlanta, GA, 30322, USA.
⁸Current address: Janssen Human Microbiome Institute, Janssen Research & Development, Cambridge, MA, 02142, USA.
⁹MIT Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
¹⁰Department of Systems Biology, Harvard Medical School, Boston, MA, 02114, USA.
¹¹Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. xavier@molbio.mgh.harvard.edu.
¹²Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. xavier@molbio.mgh.harvard.edu.
¹³Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. xavier@molbio.mgh.harvard.edu.
¹⁴Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. xavier@molbio.mgh.harvard.edu.
¹⁵Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. chuttenh@hsph.harvard.edu.
¹⁶Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. chuttenh@hsph.harvard.edu.

PMID:29183332
PMCID:PMC5704459
DOI:10.1186/s13073-017-0490-5

Free PMC article

A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients

Andrew Brantley Hallet al. Genome Med. 2017.

Free PMC article

. 2017 Nov 28;9(1):103.

doi: 10.1186/s13073-017-0490-5.

Authors

Affiliations

¹Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
²Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
³Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁴Current address: Vatche and Tamar Manoukian Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
⁵Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁶MIT Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
⁷Emory University School of Medicine, Emory University, Atlanta, GA, 30322, USA.
⁸Current address: Janssen Human Microbiome Institute, Janssen Research & Development, Cambridge, MA, 02142, USA.
⁹MIT Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
¹⁰Department of Systems Biology, Harvard Medical School, Boston, MA, 02114, USA.
¹¹Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. xavier@molbio.mgh.harvard.edu.
¹²Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. xavier@molbio.mgh.harvard.edu.
¹³Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. xavier@molbio.mgh.harvard.edu.
¹⁴Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. xavier@molbio.mgh.harvard.edu.
¹⁵Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. chuttenh@hsph.harvard.edu.
¹⁶Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. chuttenh@hsph.harvard.edu.

PMID:29183332
PMCID:PMC5704459
DOI:10.1186/s13073-017-0490-5

Abstract

Background:Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify strain-specific functional correlates with IBD outcomes.

Methods:We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and 12 controls (266 total samples). These were taxonomically profiled with MetaPhlAn2 and functionally profiled using HUMAnN2. Differentially abundant species were identified using MaAsLin and strain-specific pangenome haplotypes were analyzed using PanPhlAn.

Results:We found a significantly higher abundance in patients of facultative anaerobes that can tolerate the increased oxidative stress of the IBD gut. We also detected dramatic, yet transient, blooms of Ruminococcus gnavus in IBD patients, often co-occurring with increased disease activity. We identified two distinct clades of R. gnavus strains, one of which is enriched in IBD patients. To study functional differences between these two clades, we augmented the R. gnavus pangenome by sequencing nine isolates from IBD patients. We identified 199 IBD-specific, strain-specific genes involved in oxidative stress responses, adhesion, iron-acquisition, and mucus utilization, potentially conferring an adaptive advantage for this R. gnavus clade in the IBD gut.

Conclusions:This study adds further evidence to the hypothesis that increased oxidative stress may be a major factor shaping the dysbiosis of the microbiome observed in IBD and suggests that R. gnavus may be an important member of the altered gut community in IBD.

Conflict of interest statement

Ethics approval and consent to participate

的设计研究是Instit批准utional Review Board of Massachusetts General Hospital (protocol number 2004P001067). Written informed consent was obtained for participation in the study, and the study design complies with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

DG is employed by the Janssen Human Microbiome Institute. CH is on the Scientific Advisory Board for Seres Therapeutics. The remaining authors declare that they have no competing interests.

Publisher’s Note

施普林格自然界e remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Dynamics of longitudinal microbial composition and facultative anaerobic microbial profiles in inflammatory bowel disease.aIndividual microbial trajectories of 20 inflammatory bowel disease (IBD) patients and 11 control individuals with sufficient longitudinal data over time, from the current study (Massachusetts General Hospital, p-identifiers) and (Emory University, S-identifiers). Each subject exhibits an individualized microbiome signature. Each phylum has an overall color while genera are represented as different shades of the overall color.bMaximal relative abundances of facultative anaerobes across all subjects in the LSS (n= 266),刘易斯et al。(n = 368) [13], and HMP (n = 80) [15] cohorts. Overall, facultative anaerobes are significantly higher in IBD patients compared to controls (nested ANOVA LSSp = 0.0478, Lewis et al.p = 0.005)

**Fig. 2**
*R. gnavus*transiently dominates the gut microbiome in IBD.aThe maximum relative abundance ofR. gnavusacross samples (time courses) is shown for all subjects in the LSS (n= 266),刘易斯et al。(n = 368), and HMP (n = 80) cohorts. While the abundance of most anaerobes are lower in IBD patients, the abundance ofR. gnavusis significantly higher in IBD patients compared to controls.bRelative abundance ofR. gnavusover time for IBD patients in the LSS cohort. The abundance ofR. gnavusis not constantly high, but rather has transient increases in the IBD gut.cA principle coordinate analysis (PCoA) of the Bray-Curtis distance of species-level microbial communities of LSS IBD patient p8808 over 9 months. The dominantR. gnavusstrain in months 4–10 and month 12 isR. gnavusclade 1, while in month 11 the dominant strain ofR. gnavusisR. gnavus进化枝2(图3)。插图显示了Harvey-BradshawIndex (HBI) score, a clinical indication of active disease and inflammation, for this patient over time. The dramatic, transient increased abundances ofR. gnavusin month 11 corresponds to an increase in HBI values (i.e., disease activity).dColony forming units ofR. gnavus,*Eubacterium elegans*, andE. coliat 0, 1, and 3 h post-transfer to atmospheric oxygen conditions (see “Methods”).Error barsrepresent standard deviation.Dotted linesignifies limit of detection. No colonies were detected for the obligate anaerobeE. elegansat the 1- and 3-h time points. As expected,*E. coli*showed growth during oxygen exposure, and interestingly, despite being classified as an obligate anaerobe,*R. gnavus*was able to tolerate atmospheric oxygen for several hours, which may partially explain its increased abundance in the increased oxidative stress of the IBD gut

**Fig. 3**
*R. gnavus*宏基因组应变phylogeny. A phylogenetic tree ofR. gnavusstrains, calculated from SNP profiles ofR. gnavusmarker genes (see “Methods”), where each tree leaf is a sample from the LSS or Lewis et al. cohorts (subject plus time point). Subject SKST012 is the only included control individual, as no other control metagenomes contained enoughR. gnavusreads for detection and strain assignment by StrainPhlAn. Bootstrap values are indicated on branches and reveal two distinct clades ofR. gnavusstrains

**Fig. 4**
Functional profiles of IBD-relatedR. gnavusstrains; 199 IBD-specific genes withinR. gnavus(*rows*) and their depth of coverage across metagenomic samples (*columns*). All samples with at least 1× coverage of theR. gnavuspangenome are shown. Cluster of genes indicate that different strain groups (clades; Fig. 3) have different subsets of IBD-specific genes. Several gene families of interest are highlighted (see text), and the fullR. gnavuspangenome can be found in Additional file 5: Figure S1

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