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1.
Cell ; 186(12): 2705-2718.e17, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37295406

RESUMO

Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.


Assuntos
Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas , Microbiota , Neoplasias , Humanos , Microbioma Gastrointestinal/genética , Fezes/microbiologia , Metagenoma , Antibacterianos , Neoplasias/tratamento farmacológico
2.
Nature ; 588(7837): 303-307, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33239790

RESUMO

The gut microbiota influences development1-3 and homeostasis4-7 of the mammalian immune system, and is associated with human inflammatory8 and immune diseases9,10 as well as responses to immunotherapy11-14. Nevertheless, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans, where the difficulty of direct experimentation makes inference challenging. Here we study hundreds of hospitalized-and closely monitored-patients with cancer receiving haematopoietic cell transplantation as they recover from chemotherapy and stem-cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, enabling the relationships between the two to be studied simultaneously. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota-together and over time-on systemic immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.


Assuntos
Microbioma Gastrointestinal/imunologia , Leucócitos/citologia , Leucócitos/imunologia , Fatores Etários , Teorema de Bayes , Transplante de Microbiota Fecal , Feminino , Humanos , Contagem de Leucócitos , Linfócitos/citologia , Linfócitos/imunologia , Monócitos/citologia , Monócitos/imunologia , Neutrófilos/citologia , Neutrófilos/imunologia , Reprodutibilidade dos Testes
3.
Blood ; 141(12): 1389-1401, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36399701

RESUMO

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Trato Gastrointestinal Inferior , Corticosteroides/uso terapêutico , Interleucina 22
4.
Nature ; 572(7771): 665-669, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31435014

RESUMO

Intestinal commensal bacteria can inhibit dense colonization of the gut by vancomycin-resistant Enterococcus faecium (VRE), a leading cause of hospital-acquired infections1,2. A four-strained consortium of commensal bacteria that contains Blautia producta BPSCSK can reverse antibiotic-induced susceptibility to VRE infection3. Here we show that BPSCSK reduces growth of VRE by secreting a lantibiotic that is similar to the nisin-A produced by Lactococcus lactis. Although the growth of VRE is inhibited by BPSCSK and L. lactis in vitro, only BPSCSK colonizes the colon and reduces VRE density in vivo. In comparison to nisin-A, the BPSCSK lantibiotic has reduced activity against intestinal commensal bacteria. In patients at high risk of VRE infection, high abundance of the lantibiotic gene is associated with reduced density of E. faecium. In germ-free mice transplanted with patient-derived faeces, resistance to VRE colonization correlates with abundance of the lantibiotic gene. Lantibiotic-producing commensal strains of the gastrointestinal tract reduce colonization by VRE and represent potential probiotic agents to re-establish resistance to VRE.


Assuntos
Bacteriocinas/metabolismo , Bacteriocinas/farmacologia , Enterococcus faecium/efeitos dos fármacos , Lactococcus lactis/metabolismo , Probióticos , Resistência a Vancomicina/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Animais , Antibacterianos/biossíntese , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bacteriocinas/genética , Bacteriocinas/isolamento & purificação , Enterococcus faecium/crescimento & desenvolvimento , Enterococcus faecium/isolamento & purificação , Fezes/microbiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Vida Livre de Germes , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Lactococcus lactis/química , Lactococcus lactis/crescimento & desenvolvimento , Lactococcus lactis/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Microbiota/genética , Nisina/química , Nisina/farmacologia , Simbiose/efeitos dos fármacos , Vancomicina/farmacologia , Enterococos Resistentes à Vancomicina/crescimento & desenvolvimento , Enterococos Resistentes à Vancomicina/isolamento & purificação
5.
Blood ; 140(22): 2385-2397, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-35969834

RESUMO

Following allogeneic hematopoietic cell transplantation (allo-HCT), the gastrointestinal (GI) tract is frequently affected by acute graft-versus-host disease (aGVHD), the pathophysiology of which is associated with a dysbiotic microbiome. Since microbial composition varies along the length of the GI tract, the authors hypothesized that microbiome features correlate with the pattern of organ involvement after allo-HCT. We evaluated 266 allo-HCT recipients from whom 1303 stool samples were profiled by 16S ribosomal gene sequencing. Patients were classified according to which organs were affected by aGVHD. In the 20 days prior to disease onset, GVHD patients had lower abundances of members of the class Clostridia, lower counts of butyrate producers, and lower ratios of strict-to-facultative (S/F) anaerobic bacteria compared with allograft recipients who were free of GVHD. GI GVHD patients showed significant reduction in microbial diversity preonset. Patients with lower GI aGVHD had lower S/F anaerobe ratios compared with those with isolated upper GI aGVHD. In the 20 days after disease onset, dysbiosis was observed only in GVHD patients with GI involvement, particularly those with lower-tract disease. Importantly, Clostridial and butyrate-producer abundance as well as S/F anaerobe ratio were predictors of longer overall survival; higher abundance of butyrate producers and higher S/F anaerobe ratio were associated with decreased risk of GVHD-related death. These findings suggest that the intestinal microbiome can serve as a biomarker for outcomes of allo-HCT patients with GVHD.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microbiota , Humanos , Doença Enxerto-Hospedeiro/microbiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fezes/microbiologia , Disbiose/etiologia , Bactérias , Butiratos
6.
Blood ; 139(18): 2758-2769, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35061893

RESUMO

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.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfócitos T CD4-Positivos , Humanos , Contagem de Linfócitos , RNA Ribossômico 16S , Transplante Homólogo
7.
Blood ; 139(15): 2392-2405, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-34653248

RESUMO

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Butiratos , Ácidos Graxos Voláteis/fisiologia , Camundongos , Linfócitos T
8.
N Engl J Med ; 382(9): 822-834, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101664

RESUMO

BACKGROUND: Relationships 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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: Patterns 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.).


Assuntos
Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas/mortalidade , Adulto , Biodiversidade , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Transplante Homólogo/mortalidade
9.
Blood ; 137(11): 1527-1537, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33512409

RESUMO

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.


Assuntos
Fezes/microbiologia , Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo
10.
Clin Infect Dis ; 75(11): 1912-1920, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-35435976

RESUMO

BACKGROUND: Neutropenic fever (NF) occurs in >70% of hematopoietic cell transplant (HCT) recipients, without a documented cause in most cases. Antibiotics used to prevent and treat NF disrupt the gut microbiota; these disruptions predict a higher posttransplantation mortality rate. We hypothesized that specific features in the gut microbial community may mediate the risk of NF. METHODS: We searched a large gut microbiota database in allogeneic HCT recipients (12 546 stool samples; 1278 patients) to find pairs with NF (cases) versus without NF (controls) on the same day relative to transplantation and with a stool sample on the previous day. A total of 179 such pairs were matched as to the underlying disease and graft source. Several other important clinical variables were similar between the groups. RESULTS: The gut microbiota of cases on the day before NF occurrence had a lower abundance of Blautia than their matched controls on the same day after transplantation, suggesting a protective role for Blautia. Microbiota network analysis did not find any differences in community structure between the groups, suggesting a single-taxon effect. To identify putative mechanisms, we searched a gut microbiome and serum metabolome database of patients with acute leukemia receiving chemotherapy and identified 139 serum samples collected within 24 hours after a stool sample from the same patient. Greater Blautia abundances predicted higher levels of next-day citrulline, a biomarker of total enterocyte mass. CONCLUSIONS: These findings support a model in which Blautia protects against NF by improving intestinal health. Therapeutic restoration of Blautia may help prevent NF, thus reducing antibiotic exposures and transplantation-related deaths.


Assuntos
Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microbiota , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Transplante Homólogo/efeitos adversos
11.
Cancer ; 128(21): 3850-3859, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36041227

RESUMO

BACKGROUND: Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. METHODS: We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. RESULTS: Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. CONCLUSIONS: Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. LAY SUMMARY: Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Disgeusia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Melfalan , Mieloma Múltiplo/terapia , Estudos Prospectivos , Transplante Autólogo/efeitos adversos
12.
Blood ; 136(1): 130-136, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430495

RESUMO

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.


Assuntos
Butiratos/sangue , Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro/microbiologia , Propionatos/sangue , Adulto , Aloenxertos , Bactérias/isolamento & purificação , Bactérias/metabolismo , Estudos de Casos e Controles , Doença Crônica , Disbiose/etiologia , Disbiose/microbiologia , Fezes/microbiologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Metaboloma , Ribotipagem
13.
Clin Infect Dis ; 73(11): e4627-e4635, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31976518

RESUMO

BACKGROUND: Gram-negative bloodstream infections (BSIs) represent a significant complication facing allogeneic hematopoietic cell transplant (allo-HCT) recipients, as a result of intestinal translocation during neutropenia. In this study we sought to better understand how the composition of the intestinal microbiota is connected to risk of gram-negative BSIs, expanding on our prior work in these patients. METHODS: Fecal specimens were collected from recipients of allo-HCT and analyzed using 16S ribosomal RNA gene sequencing. Samples and clinical data extending from the pretransplant conditioning period through stem cell engraftment were used in the analysis. Intestinal domination (relative abundance ≥ 30%) by gram-negative bacteria was used as predictor of gram-negative BSI using Cox proportional hazards modeling. Further analysis of microbiota composition was performed at the genus level. RESULTS: Seven hundred eight allo-HCT subjects were studied (7.5% developed gram-negative infection), with 4768 fecal samples for analysis. Gram-negative intestinal domination was associated with subsequent BSI, which was observed overall and individually at the genus level: Escherichia, Klebsiella, Enterobacter, Pseudomonas, and Stenotrophomonas. Fluoroquinolone prophylaxis was associated with decreased BSI and intestinal colonization by gram-negative microbes. In fluoroquinolone-prophylaxed patients, Escherichia coli was more frequently observed as breakthrough, both in terms of intestinal colonization and BSIs, compared with nonprophylaxed patients. Initial colonization by members of Ruminococcaceae and Bacteroidetes were associated with protection against gram-negative BSI. CONCLUSIONS: Gram-negative intestinal colonization is highly predictive of BSI in the setting of allo-HCT. Fluoroquinolones appear to reduce these infections by influencing gut colonization.


Assuntos
Bacteriemia , Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas , Sepse , Bacteriemia/microbiologia , Bactérias Gram-Negativas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Sepse/complicações
14.
Clin Infect Dis ; 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34928341

RESUMO

BACKGROUND: Enterococcus intestinal domination (EID), a state of dysbiosis wherein enterococci comprise ≥30% abundance within the microbiota, has been associated with Enterococcus bacteremia, graft-versus-host disease, and mortality in the allogeneic hematopoietic stem cell transplant (allo HCT) population. The acute leukemia (AL) chemotherapy population includes patients receiving intensive chemotherapy but do not all go on to have an allo HCT. The impact of EID on outcomes including mortality in the AL chemotherapy population is unknown. METHODS: Microbiota composition from weekly stool samples was analyzed by 16S ribosomal RNA gene sequencing. Patients were analyzed in 2 cohorts: AL chemotherapy cohort and allo HCT cohort. Alpha-diversity and richness were calculated. Kaplan Meier Analysis was used to analyze mortality. RESULTS: 929 stool samples were collected from 139 patients. Both allo HCT and AL cohorts had a decline in α-diversity and richness over the course of treatment that tends not to return to baseline months later. EID was observed in at least one sample in 36% of allo HCT patients and 49% of AL patients. Patients with observed EID had lower alpha-diversity over time. Similar to the HCT cohort, AL patients with EID had reduced overall survival. We identified 4 other genera that were commonly found in ≥30% relative abundance within the microbiota, but none were associated with mortality. In fact, in allo HCT, Bacteroides abundance ≥30% was associated with improved survival. CONCLUSIONS: EID is associated with increased all-cause mortality in HCT and AL cohorts. UnlikeEID, relative abundance ≥30% by other genera is not associated with increased all-cause mortality.

15.
Curr Opin Hematol ; 27(6): 360-367, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33003084

RESUMO

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.


Assuntos
Doença Enxerto-Hospedeiro/microbiologia , Transplante de Células-Tronco Hematopoéticas , Microbiota , Animais , Enterococcus/isolamento & purificação , Fezes/microbiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Camundongos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Transplante Homólogo/mortalidade
16.
Br J Haematol ; 189(5): 926-930, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32086815

RESUMO

We previously reported a protective association between single nucleotide polymorphisms (SNPs; rs4415345G and rs4610776A alleles) of Paneth cell α-defensin-5 against acute graft-versus-host disease (aGVHD). Because dysbiosis has been associated with aGVHD, we hypothesized that these SNPs may have a gut microbiota signature. In Lasso regression analysis of 248 healthy individuals, rs4415345G was associated with a higher abundance of Odoribacter splanchnicus, an anaerobic butyrogenic commensal. In multivariable analysis of data from 613 allogeneic haematopoietic cell transplant recipients, peri-engraftment presence of O. splanchnicus was associated with ~50% lower risk for grade II-IV aGVHD (hazard ratio 0·53, 95% confidence interval 0·28-1·00, P = 0·05). O. splanchnicus may protect rs4415345G individuals against aGVHD.


Assuntos
Bacteroidetes/isolamento & purificação , Disbiose/genética , Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro/genética , Celulas de Paneth/metabolismo , Polimorfismo de Nucleotídeo Único , alfa-Defensinas/genética , Doença Aguda , Adolescente , Adulto , Aloenxertos , Bacteroidetes/fisiologia , Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/microbiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Metagenoma , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Risco , Simbiose , Adulto Jovem
17.
Blood ; 131(26): 2978-2986, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29674425

RESUMO

Respiratory viral infections are frequent in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) and can potentially progress to lower respiratory tract infection (LRTI). The intestinal microbiota contributes to resistance against viral and bacterial pathogens in the lung. However, whether intestinal microbiota composition and associated changes in microbe-derived metabolites contribute to the risk of LRTI following upper respiratory tract viral infection remains unexplored in the setting of allo-HCT. Fecal samples from 360 allo-HCT patients were collected at the time of stem cell engraftment and subjected to deep, 16S ribosomal RNA gene sequencing to determine microbiota composition, and short-chain fatty acid levels were determined in a nested subset of fecal samples. The development of respiratory viral infections and LRTI was determined for 180 days following allo-HCT. Clinical and microbiota risk factors for LRTI were subsequently evaluated using survival analysis. Respiratory viral infection occurred in 149 (41.4%) patients. Of those, 47 (31.5%) developed LRTI. Patients with higher abundances of butyrate-producing bacteria were fivefold less likely to develop viral LRTI, independent of other factors (adjusted hazard ratio = 0.22, 95% confidence interval 0.04-0.69). Higher representation of butyrate-producing bacteria in the fecal microbiota is associated with increased resistance against respiratory viral infection with LRTI in allo-HCT patients.


Assuntos
Bactérias/metabolismo , Butiratos/metabolismo , Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções Respiratórias/etiologia , Infecções Respiratórias/microbiologia , Viroses/etiologia , Viroses/microbiologia , Adulto , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Infecções Respiratórias/metabolismo , Transplante Homólogo/efeitos adversos , Viroses/metabolismo
18.
Infect Immun ; 87(9)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31262981

RESUMO

Dramatic microbiota changes and loss of commensal anaerobic bacteria are associated with adverse outcomes in hematopoietic cell transplantation (HCT) recipients. In this study, we demonstrate these dynamic changes at high resolution through daily stool sampling and assess the impact of individual antibiotics on those changes. We collected 272 longitudinal stool samples (with mostly daily frequency) from 18 patients undergoing HCT and determined their composition by multiparallel 16S rRNA gene sequencing as well as the density of bacteria in stool by quantitative PCR (qPCR). We calculated microbiota volatility to quantify rapid shifts and developed a new dynamic systems inference method to assess the specific impact of antibiotics. The greatest shifts in microbiota composition occurred between stem cell infusion and reconstitution of healthy immune cells. Piperacillin-tazobactam caused the most severe declines among obligate anaerobes. Our approach of daily sampling, bacterial density determination, and dynamic systems modeling allowed us to infer the independent effects of specific antibiotics on the microbiota of HCT patients.


Assuntos
Antibacterianos/farmacologia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Microbiota/efeitos dos fármacos , Adulto , Idoso , Bactérias/genética , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S
19.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010813

RESUMO

Vancomycin-resistant Enterococcus faecium (VRE) is a leading cause of hospital-acquired infections. This is particularly true in immunocompromised patients, where the damage to the microbiota caused by antibiotics can lead to VRE domination of the intestine, increasing a patient's risk for bloodstream infection. In previous studies we observed that the intestinal domination by VRE of patients hospitalized to receive allogeneic bone marrow transplantation can persist for weeks, but little is known about subspecies diversification and evolution during prolonged domination. Here we combined a longitudinal analysis of patient data and in vivo experiments to reveal previously unappreciated subspecies dynamics during VRE domination that appeared to be stable from 16S rRNA microbiota analyses. Whole-genome sequencing of isolates obtained from sequential stool samples provided by VRE-dominated patients revealed an unanticipated level of VRE population complexity that evolved over time. In experiments with ampicillin-treated mice colonized with a single CFU, VRE rapidly diversified and expanded into distinct lineages that competed for dominance. Mathematical modeling shows that in vivo evolution follows mostly a parabolic fitness landscape, where each new mutation provides diminishing returns and, in the setting of continuous ampicillin treatment, reveals a fitness advantage for mutations in penicillin-binding protein 5 (pbp5) that increase resistance to ampicillin. Our results reveal the rapid diversification of host-colonizing VRE populations, with implications for epidemiologic tracking of in-hospital VRE transmission and susceptibility to antibiotic treatment.


Assuntos
DNA Bacteriano/genética , Enterococcus faecium/genética , Variação Genética , Infecções por Bactérias Gram-Positivas/microbiologia , Enterococos Resistentes à Vancomicina/genética , Animais , Evolução Biológica , Análise Mutacional de DNA , Fezes/microbiologia , Humanos , Estudos Longitudinais , RNA Ribossômico 16S/genética
20.
Clin Infect Dis ; 76(6): 1153-1154, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36370043
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