Gut-derived Enterococcus faecium from ulcerative colitis patients promotes colitis in a genetically susceptible mouse host

Jun Seishima,Yukako Fujinaga,Noriho Iida,Shuichi Kaneko,Eishiro Mizukoshi,Yoshio Sakai,Yukihiro Shirota,Masahiro Yutani,Akihiro Seki,Ziyu Wang,Tatsuya Yamashita,Kazuya Kitamura,Takashi Kagaya,Taro Yamashita,Masao Honda

doi:10.1186/s13059-019-1879-9

Abstract

BackgroundRecent metagenomic analyses have revealed dysbiosis of the gut microbiota of ulcerative colitis (UC) patients. However, the impacts of this dysbiosis are not fully understood, particularly at the strain level.ResultsWe perform whole-genome shotgun sequencing of fecal DNA extracts from 13 healthy donors and 16 UC and 8 Crohn’s disease (CD) patients. The microbiota of UC and CD patients is taxonomically and functionally divergent from that of healthy donors, with E. faecium being the most differentially abundant species between the two microbial communities. Transplantation of feces from UC or CD patients into Il10−/− mice promotes pathological inflammation and cytokine expression in the mouse colon, although distinct cytokine expression profiles are observed between UC and CD. Unlike isolates derived from healthy donors, E. faecium isolates from the feces of UC patients, along with E. faecium strain ATCC 19434, promotes colitis and colonic cytokine expression. Inflammatory E. faecium strains, including ATCC 19434 and a UC-derived strain, cluster separately from commercially available probiotic strains based on whole-genome shotgun sequencing analysis. The presence of E. faecium in fecal samples is associated with large disease extent and the need for multiple medications in UC patients.ConclusionsE. faecium strains derived from UC patients display an inflammatory genotype that causes colitis.

Highlights

Recent metagenomic analyses have revealed dysbiosis of the gut microbiota of ulcerative colitis (UC) patients
The gut microbiota of inflammatory bowel diseases (IBD) patients is taxonomically and functionally divergent from that of healthy donors To investigate taxonomic and functional differences in gut microbiota between patients with IBD and healthy controls, fecal samples were collected from 13 healthy donors (HD), 16 UC patients, and 8 Crohn’s disease (CD) patients
Fifteen of the 16 UC patients were being treated with medications, including mesalazine, corticosteroids, tacrolimus, azathioprine, mercaptopurine, and TNF antagonist, and both active and inactive colitis patients were represented in the UC cohort according to total Mayo scores

Summary

Introduction

Recent metagenomic analyses have revealed dysbiosis of the gut microbiota of ulcerative colitis (UC) patients. A significant amount of information on the role of the gut microbiota in IBD patients has been accumulated based on clinical studies, metagenome analyses, and animal experiments. Because of the complexity of the gut microbiota and the multifactorial nature of IBD, it is unclear exactly which bacterial species in the dysbiotic IBD microbiota are responsible for the pathogenesis of colitis. Because few reports reproduce the microbial composition of the dysbiotic microbiota in colitic mouse models, it is unclear whether decreases or increases in a single antiinflammatory or pro-inflammatory species are truly responsible for IBD pathogenesis. Metagenomic analysis of the gut microbiota, 16S ribosomal RNA (rRNA) sequencing-based approaches, cannot identify the composition of the microbiota at the strain level. It is difficult to judge based only on metagenomic analysis whether the decreased or increased prevalence of a species in the IBD microbiota has a pathogenic effect

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