Functional and phylogenetic alterations in gut microbiome are linked to graft-versus-host disease severity
Tóm tắt
Acute graft-versus-host disease (aGVHD) is the main complication of hematopoietic stem cell transplantation (HSCT). Changes in gut microbiota composition have been associated with subsequent aGVHD, and reconstitution of healthy microbiota is currently being explored as a therapeutic approach. However, the specific actors in the intestinal ecosystem involved in the pathologic process at the time of aGVHD onset are not yet fully known. We prospectively collected stool samples from patients who underwent allogeneic HSCT. Patients sampled at aGVHD onset were compared with non-GVHD patients. To identify phylogenetic and functional signatures of the disease process, we determined fecal short-chain fatty acid (SFCA) profiles and used high-throughput DNA sequencing and real-time quantitative polymerase chain reaction to assess the microbiota composition. Microbiota alterations were highly specific of gastrointestinal (GI) aGVHD severity. Bacterial biomass and α-diversity were lower in severe aGVHD. We identified several bacterial signatures associated with severe aGVHD at disease onset; a negative correlation was observed with anaerobic bacteria of the Lachnospiraceae, especially the Blautia genus, and Ruminococcaceae families. In parallel, in severe aGVHD patients, we showed a dramatic decrease in the levels of the main SFCAs: acetate (75.8%), propionate (95.8%), and butyrate (94.6%). Mild aGVHD patients were characterized by conserved levels of propionate and Blautia propionate producers. Butyrate was significantly decreased in all GI aGVHD stages, representing a potential diagnostic marker of the disease. Specific microbiota and metabolic alterations were thus associated with aGVHD severity and may be useful for diagnostic and pathophysiologic purposes.
Từ khóa
Tài liệu tham khảo
Abraham, 2014, Clinical severity scores in gastrointestinal graft-versus-host disease, Transplantation, 97, 965, 10.1097/01.TP.0000438209.50089.60
Rodriguez-Otero, 2012, Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease, Blood, 119, 5909, 10.1182/blood-2011-12-397968
Zeiser, 2017, Acute graft-versus-host disease—biologic process, prevention, and therapy, N Engl J Med, 377, 2167, 10.1056/NEJMra1609337
Sekirov, 2010, Gut microbiota in health and disease, Physiol Rev, 90, 859, 10.1152/physrev.00045.2009
Koyama, 2019, The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease, Blood, 134, 2139, 10.1182/blood.2019000823
Legoff, 2017, The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease, Nat Med, 23, 1080, 10.1038/nm.4380
Jenq, 2015, Intestinal Blautia is associated with reduced death from graft-versus-host disease, Biol Blood Marrow Transplant, 21, 1373, 10.1016/j.bbmt.2015.04.016
Peled, 2020, Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation, N Engl J Med, 382, 822, 10.1056/NEJMoa1900623
Taur, 2014, The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation, Blood, 124, 1174, 10.1182/blood-2014-02-554725
Shono, 2015, Intestinal microbiota-related effects on graft-versus-host disease, Int J Hematol, 101, 428, 10.1007/s12185-015-1781-5
Golob, 2017, Stool microbiota at neutrophil recovery is predictive for severe acute graft vs host disease after hematopoietic cell transplantation, Clin Infect Dis, 65, 1984, 10.1093/cid/cix699
Jenq, 2012, Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation, J Exp Med, 209, 903, 10.1084/jem.20112408
Michonneau, 2019, Metabolomics analysis of human acute graft-versus-host disease reveals changes in host and microbiota-derived metabolites, Nat Commun, 10, 5695, 10.1038/s41467-019-13498-3
Ríos-Covián, 2016, Intestinal short chain fatty acids and their link with diet and human health, Front Microbiol, 7, 185, 10.3389/fmicb.2016.00185
Fujiwara, 2018, Microbial metabolite sensor GPR43 controls severity of experimental GVHD, Nat Commun, 9, 3674, 10.1038/s41467-018-06048-w
Mathewson, 2016, Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease [published correction appears in Nat Immunol. 2016;17(10):1235, Nat Immunol, 17, 505, 10.1038/ni.3400
Scott, 2018, Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis, Sci Transl Med, 10, eaao4755, 10.1126/scitranslmed.aao4755
Rowlings, 1997, IBMTR severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade, Br J Haematol, 97, 855, 10.1046/j.1365-2141.1997.1112925.x
Rousseau, 2011, Clostridium difficile colonization in early infancy is accompanied by changes in intestinal microbiota composition, J Clin Microbiol, 49, 858, 10.1128/JCM.01507-10
Dore J , EhrlichSD, LevenezF, et al IHMS_SOP 07 V1: standard operating procedure for fecal samples DNA extraction. http://www.microbiome-standards.org/fileadmin/SOPs/IHMS_SOP_07_V2.pdf. Accessed 31 January 2015.
Escudié, 2018, FROGS: Find, Rapidly, OTUs with Galaxy Solution, Bioinformatics, 34, 1287, 10.1093/bioinformatics/btx791
Neau, 2016, Three novel candidate probiotic strains with prophylactic properties in a murine model of cow’s milk allergy, Appl Environ Microbiol, 82, 1722, 10.1128/AEM.03440-15
Sokol, 2008, Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients, Proc Natl Acad Sci USA, 105, 16731, 10.1073/pnas.0804812105
Djouzi, 1997, Compared effects of three oligosaccharides on metabolism of intestinal microflora in rats inoculated with a human faecal flora, Br J Nutr, 78, 313, 10.1079/BJN19970149
Lê Cao, 2011, Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems, BMC Bioinformatics, 12, 253, 10.1186/1471-2105-12-253
Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol, 15, 550, 10.1186/s13059-014-0550-8
Segata, 2011, Metagenomic biomarker discovery and explanation, Genome Biol, 12, R60, 10.1186/gb-2011-12-6-r60
Romick-Rosendale, 2018, Antibiotic exposure and reduced short chain fatty acid production after hematopoietic stem cell transplant, Biol Blood Marrow Transplant, 24, 2418, 10.1016/j.bbmt.2018.07.030
Montassier, 2014, 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation, Microb Ecol, 67, 690, 10.1007/s00248-013-0355-4
Taur, 2012, Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation, Clin Infect Dis, 55, 905, 10.1093/cid/cis580
Abubucker, 2012, Metabolic reconstruction for metagenomic data and its application to the human microbiome, PLOS Comput Biol, 8, e1002358, 10.1371/journal.pcbi.1002358
Holler, 2014, Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease, Biol Blood Marrow Transplant, 20, 640, 10.1016/j.bbmt.2014.01.030
Biagi, 2015, Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT, Bone Marrow Transplant, 50, 992, 10.1038/bmt.2015.16