title: Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.
abstract: Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases. Although numerous probiotic microorganisms have been identified, there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4(+)FOXP3(+) regulatory T (Treg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in Treg-cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing Treg cell abundance and inducing important anti-inflammatory molecules--including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)--in Treg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of Treg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.
authors.affiliation: RIKEN Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanoue
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Oshima
authors.forename: Wataru
authors.initials: W
authors.lastname: Suda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagano
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Takuro
authors.initials: T
authors.lastname: Saito
authors.forename: Seiko
authors.initials: S
authors.lastname: Narushima
authors.forename: Koji
authors.initials: K
authors.lastname: Hase
authors.forename: Sangwan
authors.initials: S
authors.lastname: Kim
authors.forename: Joëlle V
authors.initials: JV
authors.lastname: Fritz
authors.forename: Paul
authors.initials: P
authors.lastname: Wilmes
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
authors.forename: Bernat
authors.initials: B
authors.lastname: Olle
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Morita
authors.forename: Masahira
authors.initials: M
authors.lastname: Hattori
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D003013:Clostridium / Q000145:classification / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D005856:Germ-Free Life; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D054892:Metagenome / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*
chemical_list: D060889:Inducible T-Cell Co-Stimulator Protein; D012336:RNA, Ribosomal, 16S; D016753:Interleukin-10