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Diverse phage communities are maintained stably on a clonal bacterial host
Pyenson, Nora C; Leeks, Asher; Nweke, Odera; Goldford, Joshua E; Schluter, Jonas; Turner, Paul E; Foster, Kevin R; Sanchez, Alvaro
Bacteriophages are the most abundant and phylogenetically diverse biological entities on Earth, yet the ecological mechanisms that sustain this extraordinary diversity remain unclear. In this study, we discovered that phage diversity consistently outstripped the diversity of their bacterial hosts under simple experimental conditions. We assembled and passaged dozens of diverse phage communities on a single, nonevolving strain of Escherichia coli until the phage communities reached equilibrium. In all cases, we found that two or more phage species coexisted stably, despite competition for a single, clonal host population. Phage coexistence was supported through host phenotypic heterogeneity, whereby bacterial cells adopting different growth phenotypes served as niches for different phage species. Our experiments reveal that a rich community ecology of bacteriophages can emerge on a single bacterial host.
PMID: 39666794
ISSN: 1095-9203
CID: 5762972
The gut microbiota is associated with immune cell dynamics in humans
Schluter, Jonas; Peled, Jonathan U; Taylor, Bradford P; Markey, Kate A; Smith, Melody; Taur, Ying; Niehus, Rene; Staffas, Anna; Dai, Anqi; Fontana, Emily; Amoretti, Luigi A; Wright, Roberta J; Morjaria, Sejal; Fenelus, Maly; Pessin, Melissa S; Chao, Nelson J; Lew, Meagan; Bohannon, Lauren; Bush, Amy; Sung, Anthony D; Hohl, Tobias M; Perales, Miguel-Angel; van den Brink, Marcel R M; Xavier, Joao B
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.
PMID: 33239790
ISSN: 1476-4687
CID: 4680892
The ecology of the microbiome: Networks, competition, and stability
Coyte, Katharine Z; Schluter, Jonas; Foster, Kevin R
The human gut harbors a large and complex community of beneficial microbes that remain stable over long periods. This stability is considered critical for good health but is poorly understood. Here we develop a body of ecological theory to help us understand microbiome stability. Although cooperating networks of microbes can be efficient, we find that they are often unstable. Counterintuitively, this finding indicates that hosts can benefit from microbial competition when this competition dampens cooperative networks and increases stability. More generally, stability is promoted by limiting positive feedbacks and weakening ecological interactions. We have analyzed host mechanisms for maintaining stability-including immune suppression, spatial structuring, and feeding of community members-and support our key predictions with recent data.
PMID: 26542567
ISSN: 1095-9203
CID: 4298122
The TaxUMAP atlas: Efficient display of large clinical microbiome data reveals ecological competition in protection against bacteremia
Schluter, Jonas; Djukovic, Ana; Taylor, Bradford P; Yan, Jinyuan; Duan, Caichen; Hussey, Grant A; Liao, Chen; Sharma, Sneh; Fontana, Emily; Amoretti, Luigi A; Wright, Roberta J; Dai, Anqi; Peled, Jonathan U; Taur, Ying; Perales, Miguel-Angel; Siranosian, Benjamin A; Bhatt, Ami S; van den Brink, Marcel R M; Pamer, Eric G; Xavier, Joao B
Longitudinal microbiome data provide valuable insight into disease states and clinical responses, but they are challenging to mine and view collectively. To address these limitations, we present TaxUMAP, a taxonomically informed visualization for displaying microbiome states in large clinical microbiome datasets. We used TaxUMAP to chart a microbiome atlas of 1,870 patients with cancer during therapy-induced perturbations. Bacterial density and diversity were positively associated, but the trend was reversed in liquid stool. Low-diversity states (dominations) remained stable after antibiotic treatment, and diverse communities had a broader range of antimicrobial resistance genes than dominations. When examining microbiome states associated with risk for bacteremia, TaxUMAP revealed that certain Klebsiella species were associated with lower risk for bacteremia localize in a region of the atlas that is depleted in high-risk enterobacteria. This indicated a competitive interaction that was validated experimentally. Thus, TaxUMAP can chart comprehensive longitudinal microbiome datasets, enabling insights into microbiome effects on human health.
PMID: 37329880
ISSN: 1934-6069
CID: 5535112
Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy
Smith, Melody; Dai, Anqi; Ghilardi, Guido; Amelsberg, Kimberly V; Devlin, Sean M; Pajarillo, Raymone; Slingerland, John B; Beghi, Silvia; Herrera, Pamela S; Giardina, Paul; Clurman, Annelie; Dwomoh, Emmanuel; Armijo, Gabriel; Gomes, Antonio L C; Littmann, Eric R; Schluter, Jonas; Fontana, Emily; Taur, Ying; Park, Jae H; Palomba, Maria Lia; Halton, Elizabeth; Ruiz, Josel; Jain, Tania; Pennisi, Martina; Afuye, Aishat Olaide; Perales, Miguel-Angel; Freyer, Craig W; Garfall, Alfred; Gier, Shannon; Nasta, Sunita; Landsburg, Daniel; Gerson, James; Svoboda, Jakub; Cross, Justin; Chong, Elise A; Giralt, Sergio; Gill, Saar I; Riviere, Isabelle; Porter, David L; Schuster, Stephen J; Sadelain, Michel; Frey, Noelle; Brentjens, Renier J; June, Carl H; Pamer, Eric G; Peled, Jonathan U; Facciabene, Andrea; van den Brink, Marcel R M; Ruella, Marco
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.
PMID: 35288695
ISSN: 1546-170x
CID: 5183862
The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes
Schulfer, Anjelique F; Schluter, Jonas; Zhang, Yilong; Brown, Quincy; Pathmasiri, Wimal; McRitchie, Susan; Sumner, Susan; Li, Huilin; Xavier, Joao B; Blaser, Martin J
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.
PMID: 30651608
ISSN: 1751-7370
CID: 3595352
Microbe-derived short chain fatty acids butyrate and propionate are associated with protection from chronic GVHD
Markey, Kate A; Schluter, Jonas; Gomes, Antonio Lc; Littmann, Eric; Pickard, Amanda; Taylor, Bradford P; Giardina, Paul A; Weber, Daniela; Dai, Anqi; Docampo, Melissa; Armijo, Gabriel K; Slingerland, Ann; Slingerland, John; Nichols, Katherine B; Brereton, Daniel G; Clurman, Annelie; Ramos, Ruben J; Rao, Arka; Bush, Amy T; Bohannon, Lauren; Covington, Megan; Lew, Meagan V; Rizzieri, David A; Chao, Nelson J; Maloy, Molly; Cho, Christina; Politikos, Ioannis; Giralt, Sergio; Taur, Ying; Pamer, Eric; Holler, Ernst; Perales, Miguel-Angel; Ponce, Doris M; Devlin, Sean M; Xavier, Joao; Sung, Anthony; Peled, Jonathan U; Cross, Justin R; van den Brink, Marcel Rm
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 (SCFA) 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 was available - rather than plasma - and the differences in SCFA observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort, and one of two 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 short chain fatty acids.
PMID: 32430495
ISSN: 1528-0020
CID: 4444252
Review and revamp of compositional data transformation: A new framework combining proportion conversion and contrast transformation
Zhang, Yiqian; Schluter, Jonas; Zhang, Lijun; Cao, Xuan; Jenq, Robert R; Feng, Hao; Haines, Jonathan; Zhang, Liangliang
Due to the development of next-generation sequencing technology and an increased appreciation of their role in modulating host immunity and their potential as therapeutic agents, the human microbiome has emerged as a key area of interest in various biological investigations of human health and disease. However, microbiome data present a number of statistical challenges not addressed by existing methods, such as the varying sequencing depth, the compositionality, and zero inflation. Solutions like scaling and transformation methods help to mitigate heterogeneity and release constraints, but often introduce biases and yield inconsistent results on the same data. To address these issues, we conduct a systematic review of compositional data transformation, with a particular focus on the connection and distinction of existing techniques. Additionally, we create a new framework that enables the development of new transformations by combining proportion conversion with contrast transformations. This framework includes well-known methods such as Additive Log Ratio (ALR) and Centered Log Ratio (CLR) as special cases. Using this framework, we develop two novel transformations-Centered Arcsine Contrast (CAC) and Additive Arcsine Contrast (AAC)-which show enhanced performance in scenarios with high zero-inflation. Moreover, our findings suggest that ALR and CLR transformations are more effective when zero values are less prevalent. This comprehensive review and the innovative framework provide microbiome researchers with a significant direction to enhance data transformation procedures and improve analytical outcomes.
PMCID:11609487
PMID: 39624165
ISSN: 2001-0370
CID: 5804332
Author Correction: Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy
Smith, Melody; Dai, Anqi; Ghilardi, Guido; Amelsberg, Kimberly V; Devlin, Sean M; Pajarillo, Raymone; Slingerland, John B; Beghi, Silvia; Herrera, Pamela S; Giardina, Paul; Clurman, Annelie; Dwomoh, Emmanuel; Armijo, Gabriel; Gomes, Antonio L C; Littmann, Eric R; Schluter, Jonas; Fontana, Emily; Taur, Ying; Park, Jae H; Palomba, Maria Lia; Halton, Elizabeth; Ruiz, Josel; Jain, Tania; Pennisi, Martina; Afuye, Aishat Olaide; Perales, Miguel-Angel; Freyer, Craig W; Garfall, Alfred; Gier, Shannon; Nasta, Sunita; Landsburg, Daniel; Gerson, James; Svoboda, Jakub; Cross, Justin; Chong, Elise A; Giralt, Sergio; Gill, Saar I; Riviere, Isabelle; Porter, David L; Schuster, Stephen J; Sadelain, Michel; Frey, Noelle; Brentjens, Renier J; June, Carl H; Pamer, Eric G; Peled, Jonathan U; Facciabene, Andrea; van den Brink, Marcel R M; Ruella, Marco
PMID: 36253610
ISSN: 1546-170x
CID: 5360292
Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia
Bernard-Raichon, Lucie; Venzon, Mericien; Klein, Jon; Axelrad, Jordan E; Zhang, Chenzhen; Sullivan, Alexis P; Hussey, Grant A; Casanovas-Massana, Arnau; Noval, Maria G; Valero-Jimenez, Ana M; Gago, Juan; Putzel, Gregory; Pironti, Alejandro; Wilder, Evan; Thorpe, Lorna E; Littman, Dan R; Dittmann, Meike; Stapleford, Kenneth A; Shopsin, Bo; Torres, Victor J; Ko, Albert I; Iwasaki, Akiko; Cadwell, Ken; Schluter, Jonas
Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
PMID: 36319618
ISSN: 2041-1723
CID: 5358262