Publications by authors named "Joao B Xavier"

65 Publications

Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients.

Sci Data 2021 03 2;8(1):71. Epub 2021 Mar 2.

Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

The impact of the gut microbiota in human health is affected by several factors including its composition, drug administrations, therapeutic interventions and underlying diseases. Unfortunately, many human microbiota datasets available publicly were collected to study the impact of single variables, and typically consist of outpatients in cross-sectional studies, have small sample numbers and/or lack metadata to account for confounders. These limitations can complicate reusing the data for questions outside their original focus. Here, we provide comprehensive longitudinal patient dataset that overcomes those limitations: a collection of fecal microbiota compositions (>10,000 microbiota samples from >1,000 patients) and a rich description of the "hospitalome" experienced by the hosts, i.e., their drug exposures and other metadata from patients with cancer, hospitalized to receive allogeneic hematopoietic cell transplantation (allo-HCT) at a large cancer center in the United States. We present five examples of how to apply these data to address clinical and scientific questions on host-associated microbial communities.
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http://dx.doi.org/10.1038/s41597-021-00860-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925583PMC
March 2021

The gut microbiota is associated with immune cell dynamics in humans.

Nature 2020 12 25;588(7837):303-307. Epub 2020 Nov 25.

Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The gut microbiota influences development and homeostasis of the mammalian immune system, and is associated with human inflammatory and immune diseases as well as responses to immunotherapy. 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.
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http://dx.doi.org/10.1038/s41586-020-2971-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725892PMC
December 2020

Modeling microbial cross-feeding at intermediate scale portrays community dynamics and species coexistence.

PLoS Comput Biol 2020 08 18;16(8):e1008135. Epub 2020 Aug 18.

Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

Social interaction between microbes can be described at many levels of details: from the biochemistry of cell-cell interactions to the ecological dynamics of populations. Choosing an appropriate level to model microbial communities without losing generality remains a challenge. Here we show that modeling cross-feeding interactions at an intermediate level between genome-scale metabolic models of individual species and consumer-resource models of ecosystems is suitable to experimental data. We applied our modeling framework to three published examples of multi-strain Escherichia coli communities with increasing complexity: uni-, bi-, and multi-directional cross-feeding of either substitutable metabolic byproducts or essential nutrients. The intermediate-scale model accurately fit empirical data and quantified metabolic exchange rates that are hard to measure experimentally, even for a complex community of 14 amino acid auxotrophies. By studying the conditions of species coexistence, the ecological outcomes of cross-feeding interactions, and each community's robustness to perturbations, we extracted new quantitative insights from these three published experimental datasets. Our analysis provides a foundation to quantify cross-feeding interactions from experimental data, and highlights the importance of metabolic exchanges in the dynamics and stability of microbial communities.
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http://dx.doi.org/10.1371/journal.pcbi.1008135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480867PMC
August 2020

Compositional Lotka-Volterra describes microbial dynamics in the simplex.

PLoS Comput Biol 2020 05 29;16(5):e1007917. Epub 2020 May 29.

Department of Computer Science, Columbia University, New York, New York, United States of America.

Dynamic changes in microbial communities play an important role in human health and disease. Specifically, deciphering how microbial species in a community interact with each other and their environment can elucidate mechanisms of disease, a problem typically investigated using tools from community ecology. Yet, such methods require measurements of absolute densities, whereas typical datasets only provide estimates of relative abundances. Here, we systematically investigate models of microbial dynamics in the simplex of relative abundances. We derive a new nonlinear dynamical system for microbial dynamics, termed "compositional" Lotka-Volterra (cLV), unifying approaches using generalized Lotka-Volterra (gLV) equations from community ecology and compositional data analysis. On three real datasets, we demonstrate that cLV recapitulates interactions between relative abundances implied by gLV. Moreover, we show that cLV is as accurate as gLV in forecasting microbial trajectories in terms of relative abundances. We further compare cLV to two other models of relative abundance dynamics motivated by common assumptions in the literature-a linear model in a log-ratio transformed space, and a linear model in the space of relative abundances-and provide evidence that cLV more accurately describes community trajectories over time. Finally, we investigate when information about direct effects can be recovered from relative data that naively provide information about only indirect effects. Our results suggest that strong effects may be recoverable from relative data, but more subtle effects are challenging to identify.
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http://dx.doi.org/10.1371/journal.pcbi.1007917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325845PMC
May 2020

The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View.

Trends Cancer 2020 03 7;6(3):192-204. Epub 2020 Feb 7.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.
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http://dx.doi.org/10.1016/j.trecan.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098063PMC
March 2020

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

N Engl J Med 2020 02;382(9):822-834

From the Adult Bone Marrow Transplantation Service (J.U.P., M.M., A.G.C., K.A.M., N.K., D.G.B., M.S.-E., N.C.F., A.A.T., R.J.L., L.Y.S.S., G.L.S., C.C., M.S., I.P., B.G., D.M.P., J.N.B., M.-A.P., S.A.G., M.R.M.B.) and the Infectious Disease Service (Y.T., E.F., L.A.A., R.J.W., E.G.P.), Department of Medicine, the Department of Epidemiology and Biostatistics (S.M.D.), the Department of Immunology, Sloan Kettering Institute (A.L.C.G., E.R.L., A.E.S., J.B.S., C.K.S.-T., M.D.D., M.B.S., G.K.A., Y.S., M.R.M.B.), and the Program for Computational and Systems Biology (J.B.X.), Memorial Sloan Kettering Cancer Center, and the Department of Medicine, Weill Cornell Medical College (J.U.P., Y.T., K.A.M., M.D.D., R.J.L., G.L.S., C.C., M.S., I.P., B.G., D.M.P., J.N.B., M.-A.P., S.A.G., M.R.M.B.) - both in New York; Duchossois Family Institute of the University of Chicago, Chicago (E.R.L., E.G.P.); the Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center (A.D.S., M.V.L., A.B., L.B., N.J.C.), the Division of Infectious Diseases, Department of Medicine, Duke University (J.A.M.), and the Duke Office of Clinical Research, Duke University School of Medicine (K.R.) - all in Durham, NC; the Department of Hematology and Oncology, Internal Medicine III, University Medical Center (D.W., E.H.), the Collaborative Research Center Transregio 221 (D.W., A.G., E.H.), and Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg (A.G.) - all in Regensburg, Germany; the Department of Hematology, Hokkaido University Faculty of Medicine (D.H., Y.H., T.T.), and the Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital (K.H., T.T.) - both in Sapporo, Japan; Research Institute Marqués de Valdecilla-IDIVAL (M.S.-E.) and the Department of Hematology, Hospital Universitario Marqués de Valdecilla-IDIVAL, University of Cantabria (L.Y.S.S.), Santander, and Hospital Universitario Puerta de Hierro, Madrid (A.A.T.) - all in Spain; and the Departments of Genomic Medicine and Stem Cell Transplantation Cellular Therapy, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (R.R.J.).

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.).
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http://dx.doi.org/10.1056/NEJMoa1900623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534690PMC
February 2020

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Nat Med 2020 02 10;26(2):259-269. Epub 2020 Feb 10.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
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http://dx.doi.org/10.1038/s41591-019-0750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021003PMC
February 2020

Enhanced inference of ecological networks by parameterizing ensembles of population dynamics models constrained with prior knowledge.

BMC Ecol 2020 01 8;20(1). Epub 2020 Jan 8.

Department of Civil, Structural and Environmental Engineering, University at Buffalo, Buffalo, NY, 14260, USA.

Background: Accurate network models of species interaction could be used to predict population dynamics and be applied to manage real world ecosystems. Most relevant models are nonlinear, however, and data available from real world ecosystems are too noisy and sparsely sampled for common inference approaches. Here we improved the inference of generalized Lotka-Volterra (gLV) ecological networks by using a new optimization algorithm to constrain parameter signs with prior knowledge and a perturbation-based ensemble method.

Results: We applied the new inference to long-term species abundance data from the freshwater fish community in the Illinois River, United States. We constructed an ensemble of 668 gLV models that explained 79% of the data on average. The models indicated (at a 70% level of confidence) a strong positive interaction from emerald shiner (Notropis atherinoides) to channel catfish (Ictalurus punctatus), which we could validate using data from a nearby observation site, and predicted that the relative abundances of most fish species will continue to fluctuate temporally and concordantly in the near future. The network shows that the invasive silver carp (Hypophthalmichthys molitrix) has much stronger impacts on native predators than on prey, supporting the notion that the invader perturbs the native food chain by replacing the diets of predators.

Conclusions: Ensemble approaches constrained by prior knowledge can improve inference and produce networks from noisy and sparsely sampled time series data to fill knowledge gaps on real world ecosystems. Such network models could aid efforts to conserve ecosystems such as the Illinois River, which is threatened by the invasion of the silver carp.
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http://dx.doi.org/10.1186/s12898-019-0272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950893PMC
January 2020

Systems-level analysis of NalD mutation, a recurrent driver of rapid drug resistance in acute Pseudomonas aeruginosa infection.

PLoS Comput Biol 2019 12 20;15(12):e1007562. Epub 2019 Dec 20.

Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

Pseudomonas aeruginosa, a main cause of human infection, can gain resistance to the antibiotic aztreonam through a mutation in NalD, a transcriptional repressor of cellular efflux. Here we combine computational analysis of clinical isolates, transcriptomics, metabolic modeling and experimental validation to find a strong association between NalD mutations and resistance to aztreonam-as well as resistance to other antibiotics-across P. aeruginosa isolated from different patients. A detailed analysis of one patient's timeline shows how this mutation can emerge in vivo and drive rapid evolution of resistance while the patient received cancer treatment, a bone marrow transplantation, and antibiotics up to the point of causing the patient's death. Transcriptomics analysis confirmed the primary mechanism of NalD action-a loss-of-function mutation that caused constitutive overexpression of the MexAB-OprM efflux system-which lead to aztreonam resistance but, surprisingly, had no fitness cost in the absence of the antibiotic. We constrained a genome-scale metabolic model using the transcriptomics data to investigate changes beyond the primary mechanism of resistance, including adaptations in major metabolic pathways and membrane transport concurrent with aztreonam resistance, which may explain the lack of a fitness cost. We propose that metabolic adaptations may allow resistance mutations to endure in the absence of antibiotics and could be targeted by future therapies against antibiotic resistant pathogens.
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http://dx.doi.org/10.1371/journal.pcbi.1007562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944390PMC
December 2019

High Heterogeneity of Multidrug-Resistant Fecal Levels in Hospitalized Patients Is Partially Driven by Intravenous β-Lactams.

Antimicrob Agents Chemother 2020 01 27;64(2). Epub 2020 Jan 27.

Centro Superior de Investigación en Salud Pública-FISABIO, Valencia, Spain

Multidrug-resistant (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels. Here, we conducted one of the largest studies of MRE fecal levels by tracking longitudinally 133 acute leukemia patients and monitoring their MRE levels over time through extensive culturing. MRE were defined as species that acquired nonsusceptibility to ≥1 agent in ≥3 antimicrobial categories. In addition, due to the selective media used, the MRE had to be resistant to third-generation cephalosporins. MRE were detected in 60% of the patients, but their fecal levels varied considerably among patients and within the same patient (>6 and 4 orders of magnitude, respectively). Multivariate analysis of clinical metadata revealed an impact of intravenous beta-lactams (i.e., meropenem and piperacillin-tazobactam), which significantly diminished the fecal MRE levels in hospitalized patients. Consistent with a direct action of beta-lactams, we found an effect only when the patient was colonized with strains sensitive to the administered beta-lactam ( < 0.001) but not with nonsusceptible strains. We report previously unobserved inter- and intraindividual heterogeneity in MRE fecal levels, suggesting that quantitative surveillance is more informative than qualitative surveillance of hospitalized patients. In addition, our study highlights the relevance of incorporating antibiotic treatment and susceptibility data of gut-colonizing pathogens for future clinical studies and in clinical decision-making.
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http://dx.doi.org/10.1128/AAC.01415-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985730PMC
January 2020

Evolution at the Edge of Expanding Populations.

Am Nat 2019 09 24;194(3):291-305. Epub 2019 Jul 24.

Predicting the evolution of expanding populations is critical to controlling biological threats such as invasive species and cancer metastasis. Expansion is primarily driven by reproduction and dispersal, but nature abounds with examples of evolution where organisms pay a reproductive cost to disperse faster. When does selection favor this "survival of the fastest"? We searched for a simple rule, motivated by evolution experiments where swarming bacteria evolved into a hyperswarmer mutant that disperses ∼100% faster but pays a growth cost of ∼10% to make many copies of its flagellum. We analyzed a two-species model based on the Fisher equation to explain this observation: the population expansion rate () results from an interplay of growth () and dispersal () and is independent of the carrying capacity: . A mutant can take over the edge only if its expansion rate () exceeds the expansion rate of the established species (); this simple condition ( ) determines the maximum cost in slower growth that a faster mutant can pay and still be able to take over. Numerical simulations and time-course experiments where we tracked evolution by imaging bacteria suggest that our findings are general: less favorable conditions delay but do not entirely prevent the success of the fastest. Thus, the expansion rate defines a traveling wave fitness, which could be combined with trade-offs to predict evolution of expanding populations.
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http://dx.doi.org/10.1086/704594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206977PMC
September 2019

Antibiotic-Induced Shifts in Fecal Microbiota Density and Composition during Hematopoietic Stem Cell Transplantation.

Infect Immun 2019 09 21;87(9). Epub 2019 Aug 21.

Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering, New York, New York, USA

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.
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http://dx.doi.org/10.1128/IAI.00206-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704593PMC
September 2019

The Ultimate Guide to Bacterial Swarming: An Experimental Model to Study the Evolution of Cooperative Behavior.

Annu Rev Microbiol 2019 09 10;73:293-312. Epub 2019 Jun 10.

Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; email:

Cooperation has fascinated biologists since Darwin. How did cooperative behaviors evolve despite the fitness cost to the cooperator? Bacteria have cooperative behaviors that make excellent models to take on this age-old problem from both proximate (molecular) and ultimate (evolutionary) angles. We delve into swarming, a phenomenon where billions of bacteria move cooperatively across distances of centimeters in a matter of a few hours. Experiments with swarming have unveiled a strategy called metabolic prudence that stabilizes cooperation, have showed the importance of spatial structure, and have revealed a regulatory network that integrates environmental stimuli and direct cooperative behavior, similar to a machine learning algorithm. The study of swarming elucidates more than proximate mechanisms: It exposes ultimate mechanisms valid to all scales, from cells in cancerous tumors to animals in large communities.
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http://dx.doi.org/10.1146/annurev-micro-020518-120033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428860PMC
September 2019

Intestinal Bile Acids Induce a Morphotype Switch in Vancomycin-Resistant Enterococcus that Facilitates Intestinal Colonization.

Cell Host Microbe 2019 05 25;25(5):695-705.e5. Epub 2019 Apr 25.

Immunology Program, Infectious Diseases Service, Department of Medicine, Lucille Castori Center for Microbes Inflammation and Cancer, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Vancomycin-resistant Enterococcus (VRE) are highly antibiotic-resistant and readily transmissible pathogens that cause severe infections in hospitalized patients. We discovered that lithocholic acid (LCA), a secondary bile acid prevalent in the cecum and colon of mice and humans, impairs separation of growing VRE diplococci, causing the formation of long chains and increased biofilm formation. Divalent cations reversed this LCA-induced switch to chaining and biofilm formation. Experimental evolution in the presence of LCA yielded mutations in the essential two-component kinase yycG/walK and three-component response regulator liaR that locked VRE in diplococcal mode, impaired biofilm formation, and increased susceptibility to the antibiotic daptomycin. These mutant VRE strains were deficient in host colonization because of their inability to compete with intestinal microbiota. This morphotype switch presents a potential non-bactericidal therapeutic target that may help clear VRE from the intestines of dominated patients, as occurs frequently during hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1016/j.chom.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939634PMC
May 2019

Diversification and Evolution of Vancomycin-Resistant Enterococcus faecium during Intestinal Domination.

Infect Immun 2019 07 20;87(7). Epub 2019 Jun 20.

Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Vancomycin-resistant (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 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 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 () 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.
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http://dx.doi.org/10.1128/IAI.00102-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589067PMC
July 2019

The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes.

ISME J 2019 05 16;13(5):1280-1292. Epub 2019 Jan 16.

Department of Medicine, New York University Langone Medical Center, New York, NY, 10016, USA.

The high-fat, high-calorie diets of westernized cultures contribute to the global obesity epidemic, and early life exposure to antibiotics may potentiate those dietary effects. Previous experiments with mice had shown that sub-therapeutic antibiotic treatment (STAT)-even restricted to early life-affected the gut microbiota, altered host metabolism, and increased adiposity throughout the lifetime of the animals. Here we carried out a large-scale cohousing experiment to investigate whether cohousing STAT and untreated (Control) mice would transfer the STAT-perturbed microbiota and transmit its impact on weight. We exposed pregnant dams and their young offspring to either low-dose penicillin (STAT) or water (Control) until weaning, and then followed the offspring as they grew and endured a switch from normal to high-fat diet at week 17 of life. Cohousing, which started at week 4, rapidly approximated the microbiota within cages, lowering the weight of STAT mice relative to non-cohoused mice. The effect, however, varied between cages, and was restricted to the first 16 weeks when diet consisted of normal chow. Once mice switched to high-fat diet, the microbiota α- and β-diversity expanded and the effect of cohousing faded: STAT mice, again, were heavier than control mice independently of cohousing. Metabolomics revealed serum metabolites associated with STAT exposure, but no significant differences were detected in glucose or insulin tolerance. Our results show that cohousing can partly ameliorate the impact of STAT on the gut microbiota but not prevent increased weight with high-fat diet. These observations have implications for microbiota therapies aimed to resolve the collateral damage of antibiotics and their load on human obesity.
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http://dx.doi.org/10.1038/s41396-019-0349-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474226PMC
May 2019

Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant.

Sci Transl Med 2018 09;10(460)

Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Antibiotic treatment can deplete the commensal bacteria of a patient's gut microbiota and, paradoxically, increase their risk of subsequent infections. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), antibiotic administration is essential for optimal clinical outcomes but significantly disrupts intestinal microbiota diversity, leading to loss of many beneficial microbes. Although gut microbiota diversity loss during allo-HSCT is associated with increased mortality, approaches to reestablish depleted commensal bacteria have yet to be developed. We have initiated a randomized, controlled clinical trial of autologous fecal microbiota transplantation (auto-FMT) versus no intervention and have analyzed the intestinal microbiota profiles of 25 allo-HSCT patients (14 who received auto-FMT treatment and 11 control patients who did not). Changes in gut microbiota diversity and composition revealed that the auto-FMT intervention boosted microbial diversity and reestablished the intestinal microbiota composition that the patient had before antibiotic treatment and allo-HSCT. These results demonstrate the potential for fecal sample banking and posttreatment remediation of a patient's gut microbiota after microbiota-depleting antibiotic treatment during allo-HSCT.
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http://dx.doi.org/10.1126/scitranslmed.aap9489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468978PMC
September 2018

The type VI secretion system can modulate host intestinal mechanics to displace gut bacterial symbionts.

Proc Natl Acad Sci U S A 2018 04 2;115(16):E3779-E3787. Epub 2018 Apr 2.

Institute of Molecular Biology, Materials Science Institute and Department of Physics, The University of Oregon, Eugene, OR 97403;

Host-associated microbiota help defend against bacterial pathogens; however, the mechanisms by which pathogens overcome this defense remain largely unknown. We developed a zebrafish model and used live imaging to directly study how the human pathogen invades the intestine. The gut microbiota of fish monocolonized by symbiotic strain was displaced by expressing its type VI secretion system (T6SS), a syringe-like apparatus that deploys effector proteins into target cells. Surprisingly, displacement was independent of T6SS-mediated killing of , driven instead by T6SS-induced enhancement of zebrafish intestinal movements that led to expulsion of the resident microbiota by the host. Deleting an actin cross-linking domain from the T6SS apparatus returned intestinal motility to normal and thwarted expulsion, without weakening 's ability to kill in vitro. Our finding that bacteria can manipulate host physiology to influence intermicrobial competition has implications for both pathogenesis and microbiome engineering.
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http://dx.doi.org/10.1073/pnas.1720133115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910850PMC
April 2018

Bow-tie signaling in c-di-GMP: Machine learning in a simple biochemical network.

PLoS Comput Biol 2017 Aug 2;13(8):e1005677. Epub 2017 Aug 2.

Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.

Bacteria of many species rely on a simple molecule, the intracellular secondary messenger c-di-GMP (Bis-(3'-5')-cyclic dimeric guanosine monophosphate), to make a vital choice: whether to stay in one place and form a biofilm, or to leave it in search of better conditions. The c-di-GMP network has a bow-tie shaped architecture that integrates many signals from the outside world-the input stimuli-into intracellular c-di-GMP levels that then regulate genes for biofilm formation or for swarming motility-the output phenotypes. How does the 'uninformed' process of evolution produce a network with the right input/output association and enable bacteria to make the right choice? Inspired by new data from 28 clinical isolates of Pseudomonas aeruginosa and strains evolved in laboratory experiments we propose a mathematical model where the c-di-GMP network is analogous to a machine learning classifier. The analogy immediately suggests a mechanism for learning through evolution: adaptation though incremental changes in c-di-GMP network proteins acquires knowledge from past experiences and enables bacteria to use it to direct future behaviors. Our model clarifies the elusive function of the ubiquitous c-di-GMP network, a key regulator of bacterial social traits associated with virulence. More broadly, the link between evolution and machine learning can help explain how natural selection across fluctuating environments produces networks that enable living organisms to make sophisticated decisions.
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http://dx.doi.org/10.1371/journal.pcbi.1005677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555705PMC
August 2017

Metabolism and the Evolution of Social Behavior.

Mol Biol Evol 2017 09;34(9):2367-2379

Program in Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY.

How does metabolism influence social behavior? This fundamental question at the interface of molecular biology and social evolution is hard to address with experiments in animals, and therefore, we turned to a simple microbial system: swarming in the bacterium Pseudomonas aeruginosa. Using genetic engineering, we excised a locus encoding a key metabolic regulator and disrupted P. aeruginosa's metabolic prudence, the regulatory mechanism that controls expression of swarming public goods and protects this social behavior from exploitation by cheaters. Then, using experimental evolution, we followed the joint evolution of the genome, the metabolome and the social behavior as swarming re-evolved. New variants emerged spontaneously with mutations that reorganized the metabolome and compensated in distinct ways for the disrupted metabolic prudence. These experiments with a unicellular organism provide a detailed view of how metabolism-currency of all physiological processes-can determine the costs and benefits of a social behavior and ultimately influence how an organism behaves towards other organisms of the same species.
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http://dx.doi.org/10.1093/molbev/msx174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850603PMC
September 2017

Image-Based Measurement of HO Reaction-Diffusion in Wounded Zebrafish Larvae.

Biophys J 2017 May;112(9):2011-2018

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Epithelial injury induces rapid recruitment of antimicrobial leukocytes to the wound site. In zebrafish larvae, activation of the epithelial NADPH oxidase Duox at the wound margin is required early during this response. Before injury, leukocytes are near the vascular region, that is, ∼100-300 μm away from the injury site. How Duox establishes long-range signaling to leukocytes is unclear. We conceived that extracellular hydrogen peroxide (HO) generated by Duox diffuses through the tissue to directly regulate chemotactic signaling in these cells. But before it can oxidize cellular proteins, HO must get past the antioxidant barriers that protect the cellular proteome. To test whether, or on which length scales this occurs during physiological wound signaling, we developed a computational method based on reaction-diffusion principles that infers HO degradation rates from intravital HO-biosensor imaging data. Our results indicate that at high tissue HO levels the peroxiredoxin-thioredoxin antioxidant chain becomes overwhelmed, and HO degradation stalls or ceases. Although the wound HO gradient reaches deep into the tissue, it likely overcomes antioxidant barriers only within ∼30 μm of the wound margin. Thus, Duox-mediated long-range signaling may require other spatial relay mechanisms besides extracellular HO diffusion.
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http://dx.doi.org/10.1016/j.bpj.2017.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425381PMC
May 2017

Metabolic origins of spatial organization in the tumor microenvironment.

Proc Natl Acad Sci U S A 2017 03 28;114(11):2934-2939. Epub 2017 Feb 28.

Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;

The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity.
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http://dx.doi.org/10.1073/pnas.1700600114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358370PMC
March 2017

Microenvironment-derived factors driving metastatic plasticity in melanoma.

Nat Commun 2017 02 9;8:14343. Epub 2017 Feb 9.

Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.

Cellular plasticity is a state in which cancer cells exist along a reversible phenotypic spectrum, and underlies key traits such as drug resistance and metastasis. Melanoma plasticity is linked to phenotype switching, where the microenvironment induces switches between invasive/MITF versus proliferative/MITF states. Since MITF also induces pigmentation, we hypothesize that macrometastatic success should be favoured by microenvironments that induce a MITF/differentiated/proliferative state. Zebrafish imaging demonstrates that after extravasation, melanoma cells become pigmented and enact a gene expression program of melanocyte differentiation. We screened for microenvironmental factors leading to phenotype switching, and find that EDN3 induces a state that is both proliferative and differentiated. CRISPR-mediated inactivation of EDN3, or its synthetic enzyme ECE2, from the microenvironment abrogates phenotype switching and increases animal survival. These results demonstrate that after metastatic dissemination, the microenvironment provides signals to promote phenotype switching and provide proof that targeting tumour cell plasticity is a viable therapeutic opportunity.
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http://dx.doi.org/10.1038/ncomms14343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309794PMC
February 2017

Sociomicrobiology and Pathogenic Bacteria.

Authors:
Joao B Xavier

Microbiol Spectr 2016 06;4(3)

Program for Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

The study of microbial pathogenesis has been primarily a reductionist science since Koch's principles. Reductionist approaches are essential to identify the causal agents of infectious disease, their molecular mechanisms of action, and potential drug targets, and much of medicine's success in the treatment of infectious disease stems from that approach. But many bacteria-caused diseases cannot be explained by a single bacterium. Several aspects of bacterial pathogenesis will benefit from a more holistic approach that takes into account social interaction among bacteria of the same species and between species in consortia such as the human microbiome. The emerging discipline of sociomicrobiology provides a framework to dissect microbial interactions in single and multi-species communities without compromising mechanistic detail. The study of bacterial pathogenesis can benefit greatly from incorporating concepts from other disciplines such as social evolution theory and microbial ecology, where communities, their interactions with hosts, and with the environment play key roles.
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http://dx.doi.org/10.1128/microbiolspec.VMBF-0019-2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920084PMC
June 2016

Human symbionts inject and neutralize antibacterial toxins to persist in the gut.

Proc Natl Acad Sci U S A 2016 Mar 8;113(13):3639-44. Epub 2016 Mar 8.

Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510; Microbial Sciences Institute, Yale University School of Medicine, West Haven, CT 06516;

The human gut microbiome is a dynamic and densely populated microbial community that can provide important benefits to its host. Cooperation and competition for nutrients among its constituents only partially explain community composition and interpersonal variation. Notably, certain human-associated Bacteroidetes--one of two major phyla in the gut--also encode machinery for contact-dependent interbacterial antagonism, but its impact within gut microbial communities remains unknown. Here we report that prominent human gut symbionts persist in the gut through continuous attack on their immediate neighbors. Our analysis of just one of the hundreds of species in these communities reveals 12 candidate antibacterial effector loci that can exist in 32 combinations. Through the use of secretome studies, in vitro bacterial interaction assays and multiple mouse models, we uncover strain-specific effector/immunity repertoires that can predict interbacterial interactions in vitro and in vivo, and find that some of these strains avoid contact-dependent killing by accumulating immunity genes to effectors that they do not encode. Effector transmission rates in live animals can exceed 1 billion events per minute per gram of colonic contents, and multiphylum communities of human gut commensals can partially protect sensitive strains from these attacks. Together, these results suggest that gut microbes can determine their interactions through direct contact. An understanding of the strategies human gut symbionts have evolved to target other members of this community may provide new approaches for microbiome manipulation.
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http://dx.doi.org/10.1073/pnas.1525637113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822603PMC
March 2016

Facultative control of matrix production optimizes competitive fitness in Pseudomonas aeruginosa PA14 biofilm models.

Appl Environ Microbiol 2015 Dec 2;81(24):8414-26. Epub 2015 Oct 2.

Department of Biological Sciences, Columbia University, New York, New York, USA

As biofilms grow, resident cells inevitably face the challenge of resource limitation. In the opportunistic pathogen Pseudomonas aeruginosa PA14, electron acceptor availability affects matrix production and, as a result, biofilm morphogenesis. The secreted matrix polysaccharide Pel is required for pellicle formation and for colony wrinkling, two activities that promote access to O2. We examined the exploitability and evolvability of Pel production at the air-liquid interface (during pellicle formation) and on solid surfaces (during colony formation). Although Pel contributes to the developmental response to electron acceptor limitation in both biofilm formation regimes, we found variation in the exploitability of its production and necessity for competitive fitness between the two systems. The wild type showed a competitive advantage against a non-Pel-producing mutant in pellicles but no advantage in colonies. Adaptation to the pellicle environment selected for mutants with a competitive advantage against the wild type in pellicles but also caused a severe disadvantage in colonies, even in wrinkled colony centers. Evolution in the colony center produced divergent phenotypes, while adaptation to the colony edge produced mutants with clear competitive advantages against the wild type in this O2-replete niche. In general, the structurally heterogeneous colony environment promoted more diversification than the more homogeneous pellicle. These results suggest that the role of Pel in community structure formation in response to electron acceptor limitation is unique to specific biofilm models and that the facultative control of Pel production is required for PA14 to maintain optimum benefit in different types of communities.
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http://dx.doi.org/10.1128/AEM.02628-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644639PMC
December 2015

Cell-Size Homeostasis and the Incremental Rule in a Bacterial Pathogen.

Biophys J 2015 Aug;109(3):521-8

Program in Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, New York. Electronic address:

How populations of growing cells achieve cell-size homeostasis remains a major question in cell biology. Recent studies in rod-shaped bacteria support the "incremental rule" where each cell adds a constant length before dividing. Although this rule explains narrow cell-size distributions, its mechanism is still unknown. We show that the opportunistic pathogen Pseudomonas aeruginosa obeys the incremental rule to achieve cell-length homeostasis during exponential growth but shortens its cells when entering the stationary phase. We identify a mutant, called frik, which has increased antibiotic sensitivity, cells that are on average longer, and a fraction of filamentous cells longer than 10 μm. When growth slows due to entry in stationary phase, the distribution of frik cell sizes decreases and approaches wild-type length distribution. The rare filamentous cells have abnormally large nucleoids, suggesting that a deficiency in DNA segregation prevents cell division without slowing the exponential elongation rate.
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http://dx.doi.org/10.1016/j.bpj.2015.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572571PMC
August 2015

Integration of Metabolic and Quorum Sensing Signals Governing the Decision to Cooperate in a Bacterial Social Trait.

PLoS Comput Biol 2015 May 23;11(5):e1004279. Epub 2015 Jun 23.

Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America; Program in Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Tri-Institutional Training Program in Computational Biology and Medicine, New York, New York, United States of America.

Many unicellular organisms live in multicellular communities that rely on cooperation between cells. However, cooperative traits are vulnerable to exploitation by non-cooperators (cheaters). We expand our understanding of the molecular mechanisms that allow multicellular systems to remain robust in the face of cheating by dissecting the dynamic regulation of cooperative rhamnolipids required for swarming in Pseudomonas aeruginosa. We combine mathematical modeling and experiments to quantitatively characterize the integration of metabolic and population density signals (quorum sensing) governing expression of the rhamnolipid synthesis operon rhlAB. The combined computational/experimental analysis reveals that when nutrients are abundant, rhlAB promoter activity increases gradually in a density dependent way. When growth slows down due to nutrient limitation, rhlAB promoter activity can stop abruptly, decrease gradually or even increase depending on whether the growth-limiting nutrient is the carbon source, nitrogen source or iron. Starvation by specific nutrients drives growth on intracellular nutrient pools as well as the qualitative rhlAB promoter response, which itself is modulated by quorum sensing. Our quantitative analysis suggests a supply-driven activation that integrates metabolic prudence with quorum sensing in a non-digital manner and allows P. aeruginosa cells to invest in cooperation only when the population size is large enough (quorum sensing) and individual cells have enough metabolic resources to do so (metabolic prudence). Thus, the quantitative description of rhlAB regulatory dynamics brings a greater understating to the regulation required to make swarming cooperation stable.
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http://dx.doi.org/10.1371/journal.pcbi.1004279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477906PMC
May 2015

Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile.

Nature 2015 Jan 22;517(7533):205-8. Epub 2014 Oct 22.

1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [3] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.

The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.
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http://dx.doi.org/10.1038/nature13828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891PMC
January 2015

Turning ecology and evolution against cancer.

Nat Rev Cancer 2014 05 17;14(5):371-80. Epub 2014 Apr 17.

Massachusetts Institute of Technology, 400 Technology Square, NE46-609 Cambridge, Massachusetts, USA.

The fight against cancer has drawn researchers from a wide variety of disciplines, ranging from molecular biology to physics, but the perspective of an ecological theorist has been mostly overlooked. By thinking about the cells that make up a tumour as an endangered species, cancer vulnerabilities become more apparent. Studies in conservation biology and microbial experiments indicate that extinction is a complex phenomenon, which is often driven by the interaction of ecological and evolutionary processes. Recent advances in cancer research have shown that tumours, like species striving for survival, harbour intricate population dynamics, which suggests the possibility to exploit the ecology of tumours for treatment.
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http://dx.doi.org/10.1038/nrc3712DOI Listing
May 2014