Dataset Information

Intestinal Microbiota Influence Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation and Intestinal GVHD.

ABSTRACT: Under normal conditions our intestines are inhabited by trillions of diverse microorganisms composing the intestinal microbiota, which are mostly non-pathogenic anaerobic commensal bacteria vital for the maintenance of immune homeostasis. The composition and diversity of the intestinal microbiota can be disturbed by various factors including diet, antibiotics, and exposure to intestinal pathogens. Alterations of the intestinal microbiota contributes to many diseases including graft-vs.-host disease (GVHD), a life threatening complication that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) caused by an allogeneic reaction of donor T cells against recipient target tissues. Intestinal GVHD is most difficult to treat and connected to a high mortality. Due to recent advances in high-throughput sequencing technology, composition of the microbiome during allo-HCT has been characterized, and some common patterns have been identified. Metabolites produced by intestinal bacteria were shown to promote intestinal tissue homeostasis and immune tolerance post-allo-HCT. In this review, we discuss the role of the intestinal microbiota and metabolites in the context of acute GVHD. Moreover, novel therapeutic approaches that aim at protecting or regenerating intestinal cell populations will be highlighted.

SUBMITTER: Kohler N

PROVIDER: S-EPMC6344415 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Intestinal Microbiota Influence Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation and Intestinal GVHD.

Köhler Natalie N Zeiser Robert R

Frontiers in immunology 20190117

Under normal conditions our intestines are inhabited by trillions of diverse microorganisms composing the intestinal microbiota, which are mostly non-pathogenic anaerobic commensal bacteria vital for the maintenance of immune homeostasis. The composition and diversity of the intestinal microbiota can be disturbed by various factors including diet, antibiotics, and exposure to intestinal pathogens. Alterations of the intestinal microbiota contributes to many diseases including graft-vs.-host dise ...[more]

PMID: 30705680

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Project description:Pulmonary complications (PCs) cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Shifts in gut microbiota have been linked to HCT outcomes; however, their effect on PCs is unknown.To investigate whether changes in gut microbiota are associated with PCs after HCT.A single-center observational study was performed on 94 patients who underwent HCT from 2009 to 2011 and who were previously enrolled in a protocol for 16S ribosomal RNA sequencing of fecal microbiota. The primary endpoint, PC, was defined by new abnormal parenchymal findings on chest imaging in the setting of respiratory signs and/or symptoms. Outcomes were collected up to 40 months after transplant. Clinical and microbiota risk factors for PCs and mortality were evaluated using survival analysis.One hundred twelve PCs occurred in 66 (70.2%) subjects. A high comorbidity index (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.30-4.00; P?=?0.004), fluoroquinolones (HR, 2.29, 95% CI, 1.32-3.98; P?=?0.003), low baseline diversity (HR, 2.63; 95% CI, 1.22-5.32; P?=?0.015), and ?-proteobacteria domination of fecal microbiota (HR, 2.64; 95% CI, 1.10-5.65; P?=?0.031), which included common respiratory pathogens, predicted PCs. In separate analyses, low baseline diversity was associated with PCs that occurred preengraftment (HR, 6.30; 95% CI, 1.42-31.80; P?=?0.016), whereas ?-proteobacteria domination predicted PCs postengraftment (HR, 3.68; 95% CI, 1.49-8.21; P?=?0.006) and overall mortality (HR, 3.52; 95% CI, 1.28-9.21; P?=?0.016). Postengraftment PCs were also independent predictors of death (HR, 2.50; 95% CI, 1.25-5.22; P?=?0.009).This is the first study to demonstrate prospective changes in gut microbiota associated with PCs after HCT. Postengraftment PCs and ?-proteobacteria domination were predictive of mortality. This suggests an adverse relationship between the graft and lung, which is perhaps mediated by bacterial composition in the gut. Further study is warranted.

Project description:BackgroundRelationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable.MethodsThe microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death.ResultsWe profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival.ConclusionsPatterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).

Project description:BACKGROUND:There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. METHODS:Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study. The changes in serum metabolite levels were investigated using a gas chromatography-mass spectrometry-based metabolomics approach and underwent statistical analysis. RESULTS:Significant metabolic changes were observed on day 7. The stearic acid/palmitic acid (SA/PA) ratio was effective in the diagnosis of grade II-IV aGVHD. Multivariate analysis showed that patients with high SA/PA ratios on day 7 after HSCT were less likely to develop II-IV aGVHD than patients with low SA/PA ratios (odds ratio [OR] = 0.06, 95% CI 0.02-0.18, P < 0.001). After the adjustment for clinical characteristics, the SA/PA ratio had no significant effect on overall survival (hazard ratio [HR] = 1.95, 95% CI 0.92-4.14, P = 0.08), and patients in the high SA/PA ratio group were significantly more likely to relapse than those in the low ratio group (HR = 2.26, 95% CI 1.04-4.91, P = 0.04). CONCLUSION:Our findings suggest that the SA/PA ratio on day 7 after HSCT is an excellent biomarker to predict both aGVHD and relapse. The serum SA/PA ratio measured on day 7 after transplantation may improve risk stratification for aGVHD and relapse after allogeneic stem cell transplantation. FUNDING:National Natural Science Foundation of China (81470346, 81773361), Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Natural Science Foundation (BK20161204), Innovation Capability Development Project of Jiangsu Province (BM2015004), Jiangsu Medical Junior Talent Person award (QNRC2016707), and NIH (AI129582 and NS106170).

Dataset Information

Intestinal Microbiota Influence Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation and Intestinal GVHD.

Publications

Intestinal Microbiota Influence Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation and Intestinal GVHD.

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