Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation

Peled, Jonathan U.; Gomes, António; Devlin, Sean M.; Littmann, Eric R.; Taur, Ying; Sung, Anthony D.; Weber, Daniela; Hashimoto, Daigo; Slingerland, Ann E.; Slingerland, John B.; Maloy, Molly; Clurman, Annelie; Stein‐Thoeringer, Christoph K.; Markey, Kate A.; Docampo, Melissa D.; Silva, Marina Burgos da; Khan, Niloufer; Gessner, André; Messina, Julia A.; Romero, Kristi; Lew, M.; Bush, Amy; Bohannon, Lauren; Brereton, Daniel G.; Fontana, Emily; Amoretti, Luigi A.; Wright, Roberta J.; Armijo, Gabriel K; Shono, Yusuke; Sanchez-Escamilla, Míriam; Flores, Nerea Castillo; Tomas, Ana Alarcón; Lin, Richard J.; Segundo, Lucrecia Yáñez San; Shah, Gunjan L.; Cho, Christina; Scordo, Michael; Politikos, Ioannis; Hayasaka, Kasumi; Hasegawa, Yuta; Gyurkocza, Boglarka; Ponce, Doris M.; Barker, Juliet N.; Perales, Miguel-Ángel; Giralt, Sergío; Jenq, Robert R.; Teshima, Takanori; Chao, Nelson J.; Holler, Ernst; Xavier, João B.; Pamer, Eric G.; Brink, Marcel R.M. van den

doi:10.1056/nejmoa1900623

Cited by 515 publications

(481 citation statements)

References 45 publications

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“…Treg-induction) 2,3 and also comprehends SCFAproducing species 46 (Figure 6). Oppositely, an increase in the abundance of oxygen-tolerant pathobionts including E. coli and E. faecium are found to be associated with promoting inflammatory exacerbation ( Figure 6) which consistent with a large body of literature demonstrating that gastrointestinal overgrowth of these species is the hallmark of gastrointestinal dysbiosis and inflammation 47,48 and often associates with adverse clinical outcome 49,50 . Taken together, our data and related computational analyses show that the changes in inflammatory gene expression that accompany treatment of TB is predicted by both the anti-microbial activity of the drugs that lead to pathogen clearance and by antibiotic induced changes in microbiome composition.…”

Section: Longitudinal Profiling In An Early Bactericidal Activity Hrzsupporting

confidence: 82%

Intestinal microbiome composition influences the peripheral inflammatory state during treatment of human tuberculosis

Wipperman¹,

Bhattarai²,

Vorkas³

et al. 2020

Preprint

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Although the composition of the intestinal microbiota influences systemic immune responses, the contribution of this relationship to infectious disease pathogenesis and to the resolution of infectious diseases by antibiotic therapy is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and salutary microbiome alteration. To address these questions in the context of Tuberculosis, we analyzed three independent human datasets from Haiti (two longitudinal treatment and one cross-sectional control), a prototypical infection remarkable for chronic inflammation, in which we had measured sputum TB bacterial load, gut microbiota composition, and peripheral blood transcriptomics. Using data from the longitudinal datasets combined with inflammatory pathway enrichment analysis, we determined that antibiotic treatment of TB, despite significantly perturbing the gut microbiota, dampens the proinflammatory signature characteristic of active TB. Contrarily, an investigational TB treatment that failed to clear TB, but that caused similar microbiota perturbations, exacerbated peripheral inflammation. To decouple the effects of antibiotic induced changes in the microbiota from Mtb sterilization as predictors of normalization of TB associated inflammation, we applied random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets. We found inflammatory renormalization is positively affected by both pathogen sterilization and by the abundance of health-associated Cluster IV and Cluster XIa Clostridia. Oppositely, increases in the abundance of commonly known pathobionts such as Bacilli and Proteobacteria clusters predict inflammatory exacerbation. We independently investigated and validated these microbiota-peripheral inflammatory signature associations by applying machine learning to the peripheral gene expression and microbiota profiling in an independent human cohort of 52 healthy control individuals. Together, our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and more broadly indicate that response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation. Our results provide support to the hypothesis that there exists clear links between microbiome composition and host peripheral gene expression in humans that can be biologically elucidated using common and well validated molecular pathway analyses.

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Section: Longitudinal Profiling In An Early Bactericidal Activity Hrzsupporting

confidence: 82%

Intestinal microbiome composition influences the peripheral inflammatory state during treatment of human tuberculosis

Wipperman¹,

Bhattarai²,

Vorkas³

et al. 2020

Preprint

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“…In the case of allogeneic stem cell transplant recipients, the increase of relative abundance of Enterococcus and Proteobacteria during peri-transplant period was found to be significantly associated to bloodstream infection (BSI) and likelihood of bacterial translocation [ 12 , 33 ]. It was also found to be associated with a loss of diversity with domination by a single taxa with the addition issue that exposure to particular anti-anaerobic antibiotics subsequently escalated the risk of graft-versus-host disease (GVHD) and mortality rate [ 15 , 16 , 34 ]. In another study, pretreatment gut microbiota was used to predict chemotherapy-related blood stream infection and machine learning was used to create a BSI risk index scoring system for non-Hodgkin lymphoma patients who underwent autologous stem cell transplantation [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota profiles of treatment-naïve adult acute myeloid leukemia patients with neutropenic fever during intensive chemotherapy

et al. 2020

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The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse. However, there are few reports of alterations of in adult acute myeloid leukemia (AML) patients. Stool samples of each treatment-naïve AML patient were collected the day before initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. No antimicrobial prophylaxis was in placed in all participants. Ten cases of AML patients (4 male and 6 female) were included with a median age of 39 years (range: 19–49) and all of patients developed febrile neutropenia. Firmicutes dominated during the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference +20.2; p < 0.0001) while Escherichia notably declined during the same period (mean difference -11.2; p = 0.0064). At the operational taxonomic unit (OTU) level, there was a significantly higher level of overall richness in the pretreatment period than in the febrile neutropenic episode (mean OTU of 203.1 vs. 131.7; p = 0.012). Both of the diversity indexes of Shannon and Simpson showed a significant decrease during the febrile neutropenic period. Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow.

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“…A number of excellent studies have associated particular groups of bacteria in the intestinal flora with relapse/progression of disease after allo-HSCT 31 and higher GM diversity at engraftment with lower mortality. 1 Data are missing in the pediatric setting, underlining the need for extensive in-depth studies with pediatric patients to confirm the association between GM composition and mortality. In this regard, a small study has shown a higher number of deaths in children with lower bacterial diversity pre-HSCT, even though the number of patients included was too low to draw any definitive conclusions.…”

Section: Gut Microbiome Trajectory Across Allogeneic Hsct and Clinicamentioning

confidence: 99%

“…There is general agreement in the adult transplant community in considering many clinical variables, namely graft-versushost diseases (GvHD), infections, mortality, and relapse, differently associated with loss of GM diversity and dominance by individual taxa. 1 This has been made possible by the revolution that nextgeneration sequencing has provided to our ability to characterize the complex microbial communities hosted by our organism. This has greatly improved our comprehension of the relationship between GM, immunity, 2 and HSCT-related complications.…”

Section: Introductionmentioning

confidence: 99%

The gut microbiome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

Masetti

Zama

Leardini

et al. 2020

Pediatric Blood & Cancer

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The gut microbiome (GM) has been associated with different clinical outcomes in the context of allogeneic hematopoietic stem cell transplantation (HSCT). Large multicenter cohort studies in adults have found significant correlations with overall survival, relapse, and incidence of complications. Moreover, GM is already a promising target for therapeutic interventions. However, few data are available in children, a population presenting unique features and challenges. During childhood, the GM evolves rapidly with large structural fluctuations, alongside with the maturation of the immune system. Furthermore, the HSCT procedure presents significant differences in children. These considerations underline the importance of a specific focus on the pediatric setting, and the role of GM and its age-dependent trajectory in influencing the immunity reconstitution and clinical outcomes. This review provides a comprehensive overview of the available evidence in the field of GM and pediatric HSCT, highlighting age-specific issues and discussing GM-based therapeutic approaches.

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Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation

Cited by 515 publications

References 45 publications

Intestinal microbiome composition influences the peripheral inflammatory state during treatment of human tuberculosis

Intestinal microbiome composition influences the peripheral inflammatory state during treatment of human tuberculosis

Gut microbiota profiles of treatment-naïve adult acute myeloid leukemia patients with neutropenic fever during intensive chemotherapy

The gut microbiome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

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