title: Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins.
abstract: Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, α-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of α-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Eriguchi
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Takashima
authors.forename: Hideyo
authors.initials: H
authors.lastname: Oka
authors.forename: Sonoko
authors.initials: S
authors.lastname: Shimoji
authors.forename: Kiminori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uryu
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimono
authors.forename: Tokiyoshi
authors.initials: T
authors.lastname: Ayabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018988:Bacterial Translocation / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D004926:Escherichia coli / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000382:microbiology*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019879:Paneth Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D012720:Severity of Illness Index; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D023084:alpha-Defensins