Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation.

The microbiome is a predictor of clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT). Microbiota-derived metabolites can modulate these outcomes. How bacteria, fungi and viruses contribute to the production of intestinal metabolites is still unclear. We combined amplicon sequencing, viral metagenomics and targeted metabolomics from stool samples of patients receiving allo-SCT (n = 78) and uncovered a microbiome signature of Lachnospiraceae and Oscillospiraceae and their associated bacteriophages, correlating with the production of immunomodulatory metabolites (IMMs). Moreover, we established the IMM risk index (IMM-RI), which was associated with improved survival and reduced relapse. A high abundance of short-chain fatty acid-biosynthesis pathways, specifically butyric acid via butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT, which catalyzes EC 2.8.3.8) was detected in IMM-RI low-risk patients, and virome genome assembly identified two bacteriophages encoding BCoAT as an auxiliary metabolic gene. In conclusion, our study identifies a microbiome signature associated with protective IMMs and provides a rationale for considering metabolite-producing consortia and metabolite formulations as microbiome-based therapies.

Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant.

Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study.

We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.

Update in clinical and mouse microbiota research in allogeneic haematopoietic cell transplantation.

PURPOSE OF REVIEW: The intestinal microbiota plays a critical role in intestinal homeostasis and immune regulation and has been recognized as a predictor of clinical outcome in patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT) and specifically a determinant of the severity of graft-versus-host disease (GVHD) in mouse models. As GVHD is the most important cause of nonrelapse mortality (NRM) after allo-HCT, understanding the mechanisms by which modifying the microbiota may prevent or decrease the severity of GVHD would represent an important advance. RECENT FINDINGS: Microbiota injury was observed globally and higher diversity at peri-engraftment was associated with lower mortality. Lactose is a dietary factor that promotes post-allo-HCT Enterococcus expansion, which is itself associated with mortality from GVHD in patients and exacerbates GVHD in mice. Bacterial and fungal bloodstream infections are preceded by intestinal colonization with a corresponding organism, supporting the gut as a source for many bloodstream infections. Metabolomic profiling studies showed that GVHD is associated with changes in faecal and plasma microbiota-derived molecules. SUMMARY: In this review, we highlight some of the most recent and important findings in clinical and mouse microbiota research, as it relates to allo-HCT. Many of these are already being translated into clinical trials that have the potential to change future practice in the care of patients.

CMR imaging biosignature of cardiac involvement due to cancer-related treatment by T1 and T2 mapping.

BACKGROUND: Cancer-related treatment is associated with development of heart failure and poor outcome in cancer-survivors. T1 and T2 mapping by cardiovascular magnetic resonance (CMR) may detect myocardial injury due to cancer-related treatment. METHODS: Patients receiving cancer-related treatment regimes underwent screening of cardiac involvement with CMR, either within 3 months (early Tx) or >12 months (late Tx) post-treatment. T1 and T2 mapping, cardiac function, strain, ischaemia-testing, scar-imaging and serological cardiac biomarkers were obtained. RESULTS: Compared to age/gender matched controls (n = 57), patients (n = 115, age (yrs): median(IQR) 48(28-60), females, n = 60(52%) had reduced left ventricular ejection fraction (LV-EF) and strain, and higher native T1 and T2. The early Tx group (n = 52) had significantly higher native T1, T2 and troponin levels compared to the late Tx group, indicating myocardial inflammation and oedema (p < 0.01). On the contrary, late Tx patients showed raised native T1, increased LV-end-systolic volumes, reduced LV-EF and deformation, and elevated NT-proBNP, suggesting myocardial fibrosis and remodelling (p < 0.05). Prospective validation of these results in an independent cohort of patients with similar treatment regimens (n = 25) and longitudinal assessments revealed high concordance of CMR imaging signatures of early and late cardiac involvement. CONCLUSIONS: Native T1 and T2 mapping can be valuable in detecting and monitoring of cardiac involvement with cancer-related treatment, providing distinct biosignatures of early inflammatory involvement (raised native T1 and T2) and interstitial fibrosis and remodelling (raised native T1 but not T2), respectively. Our findings may provide an algorithm allowing to identify susceptible myocardium to potentially guide cardio-protective treatment measures.

Stenotrophomonas maltophilia colonization during allogeneic hematopoietic stem cell transplantation is associated with impaired survival.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.

Timepoints of vancomycin-resistant Enterococcus colonization predict outcomes of acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplantation.

BACKGROUND: In hematology and oncology, in particular in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT), vancomycin-resistant Enterococcus spp. (VRE) colonization rates are high due to previous hospital stays and preceding antibiotic treatment and colonized patients have a lower overall survival (OS). OBJECTIVE: We reanalyzed our previously published cohort, to unravel which colonization timepoints before and during allo-HSCT might be predictive for the subsequent outcome. PATIENTS AND METHODS: We report about 268 patients with acute myeloid leukemia receiving an allo-HSCT between 2006 and 2016. RESULTS: We identified 129 never-colonized patients, 15 previously colonized patients (positive only before admission for allo-HSCT), 41 persistently colonized patients (positive before and at admission for allo-HSCT), and 83 newly colonized patients (positive only during allo-HSCT). Persistently and newly colonized patients had a worse 60 months OS due to increased incidence of non-relapse-related mortality (NRM) than never-colonized patients (OS: never-colonized: 61.0% vs persistently colonized: 43.5%; P = 0.023 vs newly colonized: 45.6%; P = 0.046). In contrast, OS and NRM of never-colonized and previously colonized patients as well as between persistently and newly colonized patients were similar. CONCLUSION: Patients can lose their VRE colonization status and acquisition of VRE during inpatient stay for allo-HSCT decreases survival to a similar extend as persistent colonization.

Clinical impact of colonization with multidrug-resistant organisms on outcome after allogeneic stem cell transplantation in patients with acute myeloid leukemia.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for patients with acute myeloid leukemia (AML). During transplantation, patients undergo a period of severe neutropenia, which puts them at high risk for infectious complications. However, the impact of patient colonization with multidrug-resistant organisms (MDRO) on overall survival remains unclear. METHODS: In this retrospective, single-center study, the authors analyzed data from 264 patients with AML who underwent a first allo-HSCT between January 2006 and March 2016 at their institution. Primary endpoints were overall survival and nonrelapse-related mortality. RESULTS: One hundred forty-two of 264 patients (53.8%) were colonized by at least 1 MDRO, mainly with vancomycin-resistant Enterococcus faecalis/faecium (n = 122). The characteristics of colonized patients did not differ from those of MDRO-negative patients with respect to median age (53.5 vs 53 years), cytogenetic risk according to European LeukemiaNet criteria, remission status before allo-HSCT (first or second complete remission: 55.7% vs 60.7%, respectively; active disease: 44.4% vs 39.3%, respectively), donor type, or hematopoietic cell transplantation-comorbidity index (HCT-CI). Compared with noncolonized patients, MDRO-positive patients had an inferior probability of survival at 5 years (43.3% vs 65.5%; P = .002), primarily because of a higher cumulative incidence of nonrelapse-related mortality (33.9% vs 9.4%; P < .001). Death caused by infections occurred in 15.5% of colonized patients versus 4.9% of noncolonized patients. There was no difference in the cumulative incidence of relapse in MDRO-positive versus MDRO-negative patients (33.8% vs 42.1%, respectively; P = .798). CONCLUSIONS: The current data emphasize the importance of regular MDRO screenings and prompt further investigations into the impact of colonization with MDRO on the immune system after allo-HSCT. Cancer 2018;124:286-96. © 2017 American Cancer Society.