R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease

被引：95

作者：

Hayase, Eiko ^{[1
]}

Hashimoto, Daigo ^{[1
]}

Nakamura, Kiminori ^{[2
]}

Noizat, Clara ^{[1
]}

Ogasawara, Reiki ^{[1
]}

Takahashi, Shuichiro ^{[1
]}

Ohigashi, Hiroyuki ^{[1
]}

Yokoi, Yuki ^{[3
]}

Sugimoto, Rina ^{[3
]}

Matsuoka, Satomi ^{[1
]}

Ara, Takahide ^{[1
]}

Yokoyama, Emi ^{[1
]}

Yamakawa, Tomohiro ^{[1
]}

Ebata, Ko ^{[1
]}

Kondo, Takeshi ^{[1
]}

Hiramine, Rina ^{[4
,5
]}

Aizawa, Tomoyasu ^{[4
,5
]}

Ogura, Yoshitoshi ^{[6
]}

Hayashi, Tetsuya ^{[6
]}

Mori, Hiroshi ^{[7
]}

Kurokawa, Ken ^{[7
,8
]}

Tomizuka, Kazuma ^{[9
]}

Ayabe, Tokiyoshi ^{[2
]}

Teshima, Takanori ^{[1
]}

机构：

[1] Hokkaido Univ, Grad Sch Med, Fac Med, Dept Hematol, Sapporo, Hokkaido, Japan

[2] Hokkaido Univ, Grad Sch Life Sci, Fac Adv Life Sci, Dept Cell Biol Sci, Sapporo, Hokkaido, Japan

[3] Hokkaido Univ, Grad Sch Life Sci, Innate Immun Lab, Sapporo, Hokkaido, Japan

[4] Hokkaido Univ, Grad Sch Life Sci, Dept Prot Sci Lab, Sapporo, Hokkaido, Japan

[5] Hokkaido Univ, Global Stn Soft Matter, Global Inst Collaborat Res & Educ, Sapporo, Hokkaido, Japan

[6] Kyushu Univ, Dept Bacteriol, Fac Med Sci, Fukuoka, Japan

[7] Natl Inst Genet, Ctr Informat Biol, Mishima, Shizuoka, Japan

[8] Tokyo Inst Technol, Dept Life Sci & Technol, Tokyo, Japan

[9] Kyowa Hakko Kirin, Res & Dev Div, Res Funct Unit, Innovat Technol Labs, Tokyo, Japan

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 12期

基金：

日本科学技术振兴机构; 日本学术振兴会;

关键词：

BONE-MARROW-TRANSPLANTATION; STEM-CELLS; ALPHA-DEFENSIN; GUT MICROBIOTA; LGR5; EPITHELIUM; DIVERSITY; SECRETION; MORTALITY; NICHE;

D O I：

10.1084/jem.20170418

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as alpha-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant a-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of a-defensins. Administration of R-Spo1 or recombinant a-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.

引用

页码：3507 / 3518

页数：12

共 44 条

[1] Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria [J].