Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins
Tóm tắt
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.
Tài liệu tham khảo
Bossaer, 2010, Incidence of vancomycin-resistant enterococci (VRE) infection in high-risk febrile neutropenic patients colonized with VRE., Support Care Cancer, 19, 231, 10.1007/s00520-009-0808-y
Winston, 1979, Infectious complications of human bone marrow transplantation., Medicine, 58, 1, 10.1097/00005792-197901000-00001
van Bekkum, 1961, Treatment of secondary disease in radiation chimaeras., Int J Radiat Biol, 3, 173
Jones, 1971, Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras., Radiation Res, 45, 577, 10.2307/3573066
van Bekkum, 1974, Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora., J Nat Cancer Inst, 52, 401, 10.1093/jnci/52.2.401
Heit, 1977, Allogeneic bone marrow transplantation in conventional mice: I. Effect of antibiotic therapy on long term survival of allogeneic chimeras., Blut, 35, 143, 10.1007/BF00996294
Takashima, 2011, The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells., J Exp Med, 208, 285, 10.1084/jem.20101559
Sato, 2011, Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts., Nature, 469, 415, 10.1038/nature09637
Selsted, 1989, Determination of the disulfide array in the human defensin HNP-2. A covalently cyclized peptide., J Biol Chem, 264, 4003, 10.1016/S0021-9258(19)84952-9
Ganz, 1990, Defensins., Eur J Haematol, 44, 1, 10.1111/j.1600-0609.1990.tb00339.x
Salzman, 2010, Enteric defensins are essential regulators of intestinal microbial ecology., Nat Immunol, 11, 76, 10.1038/ni.1825
Eckburg, 2005, Diversity of the human intestinal microbial flora., Science, 308, 1635, 10.1126/science.1110591
Qin, 2010, A human gut microbial gene catalogue established by metagenomic sequencing., Nature, 464, 59, 10.1038/nature08821
Hill, 2010, Intestinal bacteria and the regulation of immune cell homeostasis., Ann Rev Immunol, 28, 623, 10.1146/annurev-immunol-030409-101330
Zoetendal, 1998, Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria., Appl Environ Microbiol, 64, 3854, 10.1128/AEM.64.10.3854-3859.1998
Kurokawa, 2007, Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes., DNA Res, 14, 169, 10.1093/dnares/dsm018
Hooper, 2010, Immune adaptations that maintain homeostasis with the intestinal microbiota., Nature Rev Immunol, 10, 159, 10.1038/nri2710
Heimesaat, 2010, MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease., Gut, 59, 1079, 10.1136/gut.2009.197434
Ubeda, 2010, Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans., J Clin Invest, 120, 4332, 10.1172/JCI43918
Cooke, 1996, An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation. I. The roles of minor H antigens and endotoxin., Blood, 88, 3230, 10.1182/blood.V88.8.3230.bloodjournal8883230
Asakura, 2010, Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice., J Clin Invest, 120, 2370, 10.1172/JCI39165
Teshima, 2002, Acute graft-versus-host disease does not require alloantigen expression on host epithelium., Nat Med, 8, 575, 10.1038/nm0602-575
Ayabe, 2000, Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria., Nat Immunol, 1, 113, 10.1038/77783
Li, 2007, Optimization of terminal restriction fragment polymorphism (TRFLP) analysis of human gut microbiota., J Microbiol Methods, 68, 303, 10.1016/j.mimet.2006.09.006
Hayashi, 2005, Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism., J Med Microbiol, 54, 1093, 10.1099/jmm.0.45935-0
Simpson, 1949, Measurement of diversity., Nature, 163, 688, 10.1038/163688a0
Shannon, 1948, A mathematical theory of communication., Bell System Technol J, 27, 379, 10.1002/j.1538-7305.1948.tb01338.x
Ouellette, 1994, Mouse Paneth cell defensins: primary structures and antibacterial activities of numerous cryptdin isoforms., Infect Immun, 62, 5040, 10.1128/IAI.62.11.5040-5047.1994
Masuda, 2011, Bactericidal activity of mouse alpha-defensin cryptdin-4 predominantly affects noncommensal bacteria., J Innate Immun, 3, 315, 10.1159/000322037
Liu, 1997, Characterization of microbial diversity by determining terminal restriction fragment length polymorphisms of genes encoding 16S rRNA., Appl Environ Microbiol, 63, 4516, 10.1128/AEM.63.11.4516-4522.1997
Hayashi, 2002, Phylogenetic analysis of the human gut microbiota using 16S rDNA clone libraries and strictly anaerobic culture-based methods., Microbiol Immunol, 46, 535, 10.1111/j.1348-0421.2002.tb02731.x
Ivanov, 2009, Induction of intestinal Th17 cells by segmented filamentous bacteria., Cell, 139, 485, 10.1016/j.cell.2009.09.033
Shlomchik, 1999, Prevention of graft versus host disease by inactivation of host antigen-presenting cells., Science, 285, 412, 10.1126/science.285.5426.412
Vaishnava, 2008, Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface., Proc Natl Acad Sci U S A, 105, 20858, 10.1073/pnas.0808723105
Mastroianni, 2009, Alpha-defensins in enteric innate immunity: functional Paneth cell alpha-defensins in mouse colonic lumen., J Biol Chem, 284, 27848, 10.1074/jbc.M109.050773
Hooper, 2002, How host-microbial interactions shape the nutrient environment of the mammalian intestine., Annu Rev Nutr, 22, 283, 10.1146/annurev.nutr.22.011602.092259
Bäckhed, 2005, Host-bacterial mutualism in the human intestine., Science, 307, 1915, 10.1126/science.1104816
Ley, 2006, Microbial ecology: human gut microbes associated with obesity., Nature, 444, 1022, 10.1038/4441022a
Turnbaugh, 2006, An obesity-associated gut microbiome with increased capacity for energy harvest., Nature, 444, 1027, 10.1038/nature05414
Manichanh, 2006, Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach., Gut, 55, 205, 10.1136/gut.2005.073817
Bollyky, 2009, The toll-like receptor signaling molecule Myd88 contributes to pancreatic beta-cell homeostasis in response to injury., PLoS One, 4, e5063, 10.1371/journal.pone.0005063
Penders, 2007, Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study., Gut, 56, 661, 10.1136/gut.2006.100164
Hill, 2000, The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation., Blood, 95, 2754, 10.1182/blood.V95.9.2754.009k25_2754_2759
Nestel, 1992, Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease., J Exp Med, 175, 405, 10.1084/jem.175.2.405
Cooke, 2001, LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation., J Clin Invest, 107, 1581, 10.1172/JCI12156
Gerbitz, 2004, Probiotic effects on experimental graft-versus-host disease: let them eat yogurt., Blood, 103, 4365, 10.1182/blood-2003-11-3769
Bals, 1999, Mouse beta-defensin 3 is an inducible antimicrobial peptide expressed in the epithelia of multiple organs., Infect Immun, 67, 3542, 10.1128/IAI.67.7.3542-3547.1999
Sato, 2009, Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche., Nature, 459, 262, 10.1038/nature07935