Publications by authors named "Eric G Pamer"

172 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

TAM mediates adaptation of carbapenem-resistant Klebsiella pneumoniae to antimicrobial stress during host colonization and infection.

PLoS Pathog 2021 Feb 8;17(2):e1009309. Epub 2021 Feb 8.

Duchossois Family Institute, The University of Chicago, Chicago, Illinois, United States of America.

Gram-negative pathogens, such as Klebsiella pneumoniae, remodel their outer membrane (OM) in response to stress to maintain its integrity as an effective barrier and thus to promote their survival in the host. The emergence of carbapenem-resistant K. pneumoniae (CR-Kp) strains that are resistant to virtually all antibiotics is an increasing clinical problem and OM impermeability has limited development of antimicrobial agents because higher molecular weight antibiotics cannot access sites of activity. Here, we demonstrate that TAM (translocation and assembly module) deletion increases CR-Kp OM permeability under stress conditions and enhances sensitivity to high-molecular weight antimicrobials. SILAC-based proteomic analyses revealed mis-localization of membrane proteins in the TAM deficient strain. Stress-induced sensitization enhances clearance of TAM-deficient CR-Kp from the gut lumen following fecal microbiota transplantation and from infection sites following pulmonary or systemic infection. Our study suggests that TAM, as a regulator of OM permeability, represents a potential target for development of agents that enhance the effectiveness of existing antibiotics.
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http://dx.doi.org/10.1371/journal.ppat.1009309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895364PMC
February 2021

Rapid transcriptional and metabolic adaptation of intestinal microbes to host immune activation.

Cell Host Microbe 2021 03 3;29(3):378-393.e5. Epub 2021 Feb 3.

Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA. Electronic address:

The gut microbiota produces metabolites that regulate host immunity, thereby impacting disease resistance and susceptibility. The extent to which commensal bacteria reciprocally respond to immune activation, however, remains largely unexplored. Herein, we colonized mice with four anaerobic symbionts and show that acute immune responses result in dramatic transcriptional reprogramming of these commensals with minimal changes in their relative abundance. Transcriptomic changes include induction of stress-response mediators and downregulation of carbohydrate-degrading factors such as polysaccharide utilization loci (PULs). Flagellin and anti-CD3 antibody, two distinct immune stimuli, induced similar transcriptional profiles, suggesting that commensal bacteria detect common effectors or activate shared pathways when facing different host responses. Immune activation altered the intestinal metabolome within 6 hours, decreasing luminal short-chain fatty acid and increasing aromatic metabolite concentrations. Thus, intestinal bacteria, prior to detectable shifts in community composition, respond to acute host immune activation by rapidly changing gene transcription and immunomodulatory metabolite production.
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http://dx.doi.org/10.1016/j.chom.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954923PMC
March 2021

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

Blood 2021 Mar;137(11):1527-1537

Adult Bone Marrow Transplantation Service, Department of Medicine.

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.
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http://dx.doi.org/10.1182/blood.2020006923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976512PMC
March 2021

Cervicovaginal bacterial communities in reproductive-aged Tanzanian women with Schistosoma mansoni, Schistosoma haematobium, or without schistosome infection.

ISME J 2021 Jan 6. Epub 2021 Jan 6.

Center for Global Health, Weill Cornell Medicine, New York, NY, USA.

Schistosome infection is recognized as a potentially modifiable risk factor for HIV in women by the World Health Organization. Alterations in cervicovaginal bacteria have been associated with HIV acquisition and have not been studied in schistosome infection. We collected cervical swabs from Tanzanian women with and without S. mansoni and S. haematobium to determine effects on cervicovaginal microbiota. Infected women were treated, and follow-up swabs were collected after 3 months. 16S rRNA sequencing was performed on DNA extracted from swabs. We compared 39 women with S. mansoni with 52 uninfected controls, and 16 with S. haematobium with 27 controls. S. mansoni-infected women had increased abundance of Peptostreptococcus (p = 0.026) and presence of Prevotella timonesis (p = 0.048) compared to controls. High-intensity S. haematobium infection was associated with more diverse cervicovaginal bacterial communities than uninfected controls (p = 0.0159). High-intensity S. mansoni infection showed a similar trend (p = 0.154). At follow-up, we observed increased alpha diversity in S. mansoni (2.53 vs. 1.72, p = 0.022) and S. haematobium (2.05 vs. 1.12, p = 0.066) infection groups compared to controls. Modifications in cervicovaginal microbiota, particularly increased diversity and abundance of taxa associated with bacterial vaginosis and HIV (Peptostreptococcus, Prevotella), were associated with schistosome infection.
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http://dx.doi.org/10.1038/s41396-020-00868-9DOI Listing
January 2021

Enhancing mucosal immunity by transient microbiota depletion.

Nat Commun 2020 09 8;11(1):4475. Epub 2020 Sep 8.

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

Tissue resident memory CD8 T cells (Trm) are poised for immediate reactivation at sites of pathogen entry and provide optimal protection of mucosal surfaces. The intestinal tract represents a portal of entry for many infectious agents; however, to date specific strategies to enhance Trm responses at this site are lacking. Here, we present TMDI (Transient Microbiota Depletion-boosted Immunization), an approach that leverages antibiotic treatment to temporarily restrain microbiota-mediated colonization resistance, and favor intestinal expansion to high densities of an orally-delivered Listeria monocytogenes strain carrying an antigen of choice. By augmenting the local chemotactic gradient as well as the antigenic load, this procedure generates a highly expanded pool of functional, antigen-specific intestinal Trm, ultimately enhancing protection against infectious re-challenge in mice. We propose that TMDI is a useful model to dissect the requirements for optimal Trm responses in the intestine, and also a potential platform to devise novel mucosal vaccination approaches.
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http://dx.doi.org/10.1038/s41467-020-18248-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479140PMC
September 2020

Functional and Genomic Variation between Human-Derived Isolates of Lachnospiraceae Reveals Inter- and Intra-Species Diversity.

Cell Host Microbe 2020 07 2;28(1):134-146.e4. Epub 2020 Jun 2.

Duchossois Family Institute, The University of Chicago, Chicago, IL 60637, USA; Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA; Department of Medicine, Section of Infectious Diseases and Global Health, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

Bacteria belonging to the Lachnospiraceae family are abundant, obligate anaerobic members of the microbiota in healthy humans. Lachnospiraceae impact their hosts by producing short-chain fatty acids, converting primary to secondary bile acids, and facilitating colonization resistance against intestinal pathogens. To increase our understanding of genomic and functional diversity between members of this family, we cultured 273 Lachnospiraceae isolates representing 11 genera and 27 species from human donors and performed whole-genome sequencing assembly and annotation. This analysis revealed substantial inter- and intra-species diversity in pathways that likely influence an isolate's ability to impact host health. These differences are likely to impact colonization resistance through lantibiotic expression or intestinal acidification, influence host mucosal immune cells and enterocytes via butyrate production, or contribute to synergism within a consortium by heterogenous polysaccharide metabolism. Identification of these specific functions could facilitate development of probiotic bacterial consortia that drive and/or restore in vivo microbiome functions.
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http://dx.doi.org/10.1016/j.chom.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351604PMC
July 2020

The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.

Blood 2020 07;136(1):130-136

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

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.
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http://dx.doi.org/10.1182/blood.2019003369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332893PMC
July 2020

Outbreaks of Typhlocolitis Caused by Hypervirulent Group ST1 in Highly Immunocompromised Strains of Mice.

Comp Med 2020 06 13;70(3):277-290. Epub 2020 May 13.

Tri-Institutional Training Program in Laboratory Animal Medicine and Science, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, New York; Center for Comparative Medicine and Pathology, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medicine, New York, New York;, Email:

is an enteric pathogen that can cause significant clinical disease in both humans and animals. However, clinical disease arises most commonly after treatment with broad-spectrum antibiotics. The organism's ability to cause naturally occurring disease in mice is rare, and little is known about its clinical significance in highly immunocompromised mice. We report on 2 outbreaks of diarrhea associated with in mice. In outbreak 1, 182 of approximately 2, 400 NOD.Cg-/SzJ (NSG) and related strains of mice became clinically ill after cessation of a 14-d course of 0.12% amoxicillin feed to control an increase in clinical signs associated with infection. Most mice had been engrafted with human tumors; the remainder were experimentally naïve. Affected animals exhibited 1 of 3 clinical syndromes: 1) peracute death; 2) severe diarrhea leading to euthanasia or death; or 3) mild to moderate diarrhea followed by recovery. A given cage could contain both affected and unaffected mice. Outbreak 2 involved a small breeding colony (approximately 50 mice) of NOD. CB17-/NCrCrl (NOD-) mice that had not received antibiotics or experimental manipulations. In both outbreaks, was isolated, and toxins A and B were detected in intestinal content or feces. Histopathologic lesions highly suggestive of enterotoxemia included fibrinonecrotizing and neutrophilic typhlocolitis with characteristic 'volcano' erosions or pseudomembrane formation. Genomic analysis of 4 isolates (3 from outbreak 1 and 1 from outbreak 2) revealed that these isolates were closely related to a pathogenic human isolate, CD 196. To our knowledge, this report is the first to describe naturally occurring outbreaks of -associated typhlocolitis with significant morbidity and mortality in highly immunocompromised strains of mice.
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http://dx.doi.org/10.30802/AALAS-CM-19-000109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287380PMC
June 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

Compositional flux within the intestinal microbiota and risk for bloodstream infection with gram-negative bacteria.

Clin Infect Dis 2020 Jan 24. Epub 2020 Jan 24.

Center for Microbes, Inflammation and Cancer, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center.

Background: Gram-negative bloodstream infections 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 bloodstream infections, expanding on our prior work in these patients.

Methods: Fecal specimens were collected from recipients of allo-HCT and analyzed using 16SrRNA gene sequencing. Samples and clinical data extending from the pre-transplant 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 bloodstream infection using Cox proportional hazards modelling. Further analysis of microbiota composition was performed at the genus level.

Results: 708 allo-HCT subjects were studied (7.5% develop gram-negative infection), with 4,768 fecal samples for analysis. Gram-negative intestinal domination was associated with subsequent bloodstream infection, which was observed overall and individually at the genus level: Escherichia, Klebsiella, Enterobacter, Pseudomonas, and Stenotrophomonas. Fluoroquinolone prophylaxis was associated with decreased bloodstream infection 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 bloodstream infections, compared with non-prophylaxed patients. Initial colonization by members of Ruminococcaceae and Bacteroidetes were associated with protection against gram-negative bloodstream infection.

Conclusion: Gram-negative intestinal colonization is highly predictive of bloodstream infection, in the setting of allo-HCT. Fluoroquinolones appear to reduce these infections by influencing gut colonization.
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http://dx.doi.org/10.1093/cid/ciaa068DOI Listing
January 2020

Antibiotic Degradation by Commensal Microbes Shields Pathogens.

Infect Immun 2020 03 23;88(4). Epub 2020 Mar 23.

Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA

The complex bacterial populations that constitute the gut microbiota can harbor antibiotic resistance genes (ARGs), including those encoding β-lactamase enzymes (BLA), which degrade commonly prescribed antibiotics such as ampicillin. The prevalence of such genes in commensal bacteria has been increased in recent years by the wide use of antibiotics in human populations and in livestock. While transfer of ARGs between bacterial species has well-established dramatic public health implications, these genes can also function in within bacterial consortia, where antibiotic-resistant bacteria can provide antibiotic-sensitive neighbors with leaky protection from drugs, as shown both and , in models of lung and subcutaneous coinfection. However, whether the expression of ARGs by harmless commensal bacterial species can destroy antibiotics in the intestinal lumen and shield antibiotic-sensitive pathogens is unknown. To address this question, we colonized germfree or wild-type mice with a model intestinal commensal strain of that produces either functional or defective BLA. Mice were subsequently infected with or , followed by treatment with oral ampicillin. The production of functional BLA by commensal markedly reduced clearance of these pathogens and enhanced systemic dissemination during ampicillin treatment. Pathogen resistance was independent of ARG acquisition via horizontal gene transfer but instead relied on antibiotic degradation in the intestinal lumen by BLA. We conclude that commensal bacteria that have acquired ARGs can mediate shielding of pathogens from the bactericidal effects of antibiotics.
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http://dx.doi.org/10.1128/IAI.00012-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093146PMC
March 2020

Impact of Antibiotic-Resistant Bacteria on Immune Activation and Clostridioides difficile Infection in the Mouse Intestine.

Infect Immun 2020 03 23;88(4). Epub 2020 Mar 23.

Immunology Program, Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Antibiotic treatment of patients undergoing complex medical treatments can deplete commensal bacterial strains from the intestinal microbiota, thereby reducing colonization resistance against a wide range of antibiotic-resistant pathogens. Loss of colonization resistance can lead to marked expansion of vancomycin-resistant (VRE), , and in the intestinal lumen, predisposing patients to bloodstream invasion and sepsis. The impact of intestinal domination by these antibiotic-resistant pathogens on mucosal immune defenses and epithelial and mucin-mediated barrier integrity is unclear. We used a mouse model to study the impact of intestinal domination by antibiotic-resistant bacterial species and strains on the colonic mucosa. Intestinal colonization with , , or promoted greater recruitment of neutrophils to the colonic mucosa. To test the hypothesis that the residual microbiota influences the severity of colitis caused by infection with , we coinfected mice that were colonized with ampicillin-resistant bacteria with a virulent strain of and monitored colonization and pathogenesis. Despite the compositional differences in the gut microbiota, the severity of infection (CDI) and mortality did not differ significantly between mice colonized with different ampicillin-resistant bacterial species. Our results suggest that the virulence mechanisms enabling CDI and epithelial destruction outweigh the relatively minor impact of less-virulent antibiotic-resistant intestinal bacteria on the outcome of CDI.
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http://dx.doi.org/10.1128/IAI.00362-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093144PMC
March 2020

Impact of TCR Diversity on the Development of Transplanted or Chemically Induced Tumors.

Cancer Immunol Res 2020 02 12;8(2):192-202. Epub 2019 Dec 12.

Institute of Immunology, Charité - Universitätsmedizin Berlin, Campus Buch, Berlin, Germany.

Burnet postulated that the diversity of T-cell receptors (TCR) allows T cells to protect against the development of cancers that display antigens with a similar, seemingly endless diversity. To test this hypothesis, we developed a strategy in which a single breeding pair of mice gives rise to four groups of sibling mice. Three of the four groups had a similar number of CD8 T cells, but TCR diversity was either broad, significantly reduced, or absent when expressing only one type of TCR. The fourth group had no T cells. All mice shared the same housing, and, therefore, their microbial environment was similar. Only slight differences in the intestinal flora were observed under these conditions. An undisturbed broad TCR repertoire was required for the rejection of inoculated cancers displaying the natural antigenic heterogeneity of primary tumors, whereas even one type of TCR was sufficient to protect against artificial cancers stably expressing cognate antigens. The three groups of mice with limited or no TCR repertoire showed an increased risk of developing primary tumors after chemical induction. However, the risk of early death or morbidity in these cohorts of mice was significantly higher than in mice with a diverse TCR repertoire, and it remains unknown whether mice with reduced TCR diversity, who died early without cancer, would have developed tumors with higher, lower, or equal probability after induction. Together, TCR diversity seems crucial to overcome the natural genetic instability of cancers and their antigenic heterogeneity, which impacts the design of cellular therapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007920PMC
February 2020

Butyrate-producing gut bacteria and viral infections in kidney transplant recipients: A pilot study.

Transpl Infect Dis 2019 Dec 8;21(6):e13180. Epub 2019 Oct 8.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Background: The gut microbiome is being associated increasingly with development of infections besides Clostridium difficile infection. A recent study found an association between butyrate-producing gut (BPG) bacteria and less frequent development of lower respiratory viral infections in allogeneic hematopoietic stem cell transplant recipients (Haak et al, Blood 131(26): 2978, 2018). In this investigation, we examine the relationship between the abundance of BPG bacteria and the development of viral infections in a cohort of kidney transplant recipients.

Methods: We recruited 168 kidney transplant recipients who provided 510 fecal specimens in the first 3 months after transplantation and profiled the gut microbiota using 16S rRNA gene sequencing of the V4-V5 hypervariable region. We classified the kidney transplant recipients into higher BPG Bacteria Group and lower BPG Bacteria Group using the same criteria of 1% relative gut abundance of BPG bacteria as the Haak et al study.

Results: Administration of antibiotics against anaerobes was associated with a significant decrease in the relative gut abundance of BPG bacteria. The higher BPG Bacteria Group was associated with less development of respiratory viral infections (Hazard Ratio [HR]: 0.28, P = .01) but not with less development of CMV viremia (HR: 0.38, P = .13) or BK viremia (HR: 1.02, P = .98) at 2 years post transplantation.

Conclusion: Our pilot investigation supports future validation of the relationship between high relative gut abundance of BPG bacteria and decreased risk for development of respiratory viral infections.
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http://dx.doi.org/10.1111/tid.13180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917841PMC
December 2019

Gastrointestinal pathogen colonization and the microbiome in asymptomatic kidney transplant recipients.

Transpl Infect Dis 2019 Dec 24;21(6):e13167. Epub 2019 Oct 24.

Division of Nephrology and Hypertension, NewYork Presbyterian Hospital - Weill Cornell Medical Center, New York, NY, USA.

Background: In kidney transplant recipients, gastrointestinal (GI) pathogens in feces are only evaluated during diarrheal episodes. Little is known about the prevalence of GI pathogens in asymptomatic individuals in this population.

Methods: We recruited 142 kidney transplant recipients who provided a non-diarrheal fecal sample within the first 10 days after transplantation. The specimens were evaluated for GI pathogens using the BioFire FilmArray GI Panel (BioFire Diagnostics, LLC), which tests for 22 pathogens. The fecal microbiome was also characterized using 16S rRNA gene sequencing of the V4-V5 hypervariable region. We evaluated whether detection of Clostridioides difficile and other GI pathogens was associated with post-transplant diarrhea within the first 3 months after transplantation.

Results: Among the 142 subjects, a potential pathogen was detected in 43 (30%) using the GI Panel. The most common organisms detected were C difficile (n = 24, 17%), enteropathogenic Escherichia coli (n = 8, 6%), and norovirus (n = 5, 4%). Detection of a pathogen on the GI panel or detection of C difficile alone was not associated with future post-transplant diarrhea (P > .05). The estimated number of gut bacterial species was significantly lower in subjects colonized with C difficile than those not colonized with a GI pathogen (P = .01).

Conclusion: Colonization with GI pathogens, particularly C difficile, is common at the time of kidney transplantation but does not predict subsequent diarrhea. Detection of C difficile carriage was associated with decreased microbial diversity and may be a biomarker of gut dysbiosis.
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http://dx.doi.org/10.1111/tid.13167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917898PMC
December 2019

Microbiota-derived lantibiotic restores resistance against vancomycin-resistant Enterococcus.

Nature 2019 08 21;572(7771):665-669. Epub 2019 Aug 21.

Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Intestinal commensal bacteria can inhibit dense colonization of the gut by vancomycin-resistant Enterococcus faecium (VRE), a leading cause of hospital-acquired infections. A four-strained consortium of commensal bacteria that contains Blautia producta BP can reverse antibiotic-induced susceptibility to VRE infection. Here we show that BP 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 BP and L. lactis in vitro, only BP colonizes the colon and reduces VRE density in vivo. In comparison to nisin-A, the BP 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.
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http://dx.doi.org/10.1038/s41586-019-1501-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717508PMC
August 2019

Minimal residual disease negativity in multiple myeloma is associated with intestinal microbiota composition.

Blood Adv 2019 07;3(13):2040-2044

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Patients with multiple myeloma (MM) who achieve minimal residual disease (MRD) negativity after upfront treatment have superior outcomes compared with those who remain MRD Recently, associations have been shown between specific commensal microbes and development of plasma cell disorders. Here, we report the association between intestinal microbiota composition and treatment outcome in MM. Microbiota composition of fecal samples collected from 34 MM patients after induction therapy and at the time of flow cytometry-based bone marrow MRD testing was determined by 16S ribosomal RNA sequencing. We observed a higher relative abundance of in the 16 MRD patients relative to the 18 MRD patients. No association was observed between microbial relative abundance and autologous stem cell transplantation history or MM paraprotein isotype. No differences in microbiota α diversity were observed between MRD and MRD patients. The potential association of microbiota composition with treatment response in MM patients is an important parameter for additional correlative and clinical investigation.
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http://dx.doi.org/10.1182/bloodadvances.2019032276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616258PMC
July 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

Genome-Wide Screening for Enteric Colonization Factors in Carbapenem-Resistant ST258 Klebsiella pneumoniae.

mBio 2019 03 12;10(2). Epub 2019 Mar 12.

Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA

A diverse, antibiotic-naive microbiota prevents highly antibiotic-resistant microbes, including carbapenem-resistant (CR), from achieving dense colonization of the intestinal lumen. Antibiotic-mediated destruction of the microbiota leads to expansion of CR in the gut, markedly increasing the risk of bacteremia in vulnerable patients. While preventing dense colonization represents a rational approach to reduce intra- and interpatient dissemination of CR, little is known about pathogen-associated factors that enable dense growth and persistence in the intestinal lumen. To identify genetic factors essential for dense colonization of the gut by CR, we constructed a highly saturated transposon mutant library with >150,000 unique mutations in an ST258 strain of CR and screened for growth and intestinal colonization in antibiotic-treated mice. Stochastic and partially reversible fluctuations in the representation of different mutations during dense colonization revealed the dynamic nature of intestinal microbial populations. We identified genes that are crucial for early and late stages of dense gut colonization and confirmed their role by testing isogenic mutants in competition assays with wild-type CR- Screening of the transposon library also identified mutations that enhanced CR growth. These newly identified colonization factors may provide novel therapeutic opportunities to reduce intestinal colonization by CR- is a common cause of bloodstream infections in immunocompromised and hospitalized patients, and over the last 2 decades, some strains have acquired resistance to nearly all available antibiotics, including broad-spectrum carbapenems. The U.S. Centers for Disease Control and Prevention has listed carbapenem-resistant (CR) as an urgent public health threat. Dense colonization of the intestine by CR and other antibiotic-resistant bacteria is associated with an increased risk of bacteremia. Reducing the density of gut colonization by CR is likely to reduce their transmission from patient to patient in health care facilities as well as systemic infections. How CR expands and persists in the gut lumen, however, is poorly understood. Herein, we generated a highly saturated mutant library in a multidrug-resistant strain and identified genetic factors that are associated with dense gut colonization by This study sheds light on host colonization by and identifies potential colonization factors that contribute to high-density persistence of in the intestine.
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http://dx.doi.org/10.1128/mBio.02663-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414703PMC
March 2019

Correction: Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them.

Mucosal Immunol 2019 05;12(3):840

Immunology Program, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.

The original version of this article contained an error in the published figures, where they appeared in black and white. These have now been corrected to display in colour.
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http://dx.doi.org/10.1038/s41385-019-0151-7DOI Listing
May 2019

Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification.

J Exp Med 2019 01 18;216(1):84-98. Epub 2018 Dec 18.

Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY

, , and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clinical isolates of , , and by acidifying the proximal colon and triggering short chain fatty acid (SCFA)-mediated intracellular acidification. High concentrations of SCFAs and the acidic environment counter the competitive edge that O and NO respiration confer upon Enterobacteriaceae during expansion. Reestablishment of a microbiota that produces SCFAs enhances clearance of , , and from the intestinal lumen and represents a potential therapeutic approach to enhance clearance of antibiotic-resistant pathogens.
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http://dx.doi.org/10.1084/jem.20181639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314524PMC
January 2019

Enlisting commensal microbes to resist antibiotic-resistant pathogens.

J Exp Med 2019 01 11;216(1):10-19. Epub 2018 Oct 11.

Immunology Program, Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY

The emergence of antibiotic-resistant bacterial pathogens is an all-too-common consequence of antibiotic use. Although antibiotic resistance among virulent bacterial pathogens is a growing concern, the highest levels of antibiotic resistance occur among less pathogenic but more common bacteria that are prevalent in healthcare settings. Patient-to-patient transmission of these antibiotic-resistant bacteria is a perpetual concern in hospitals. Many of these resistant microbes, such as vancomycin-resistant and carbapenem-resistant , emerge from the intestinal lumen and invade the bloodstream of vulnerable patients, causing disseminated infection. These infections are associated with preceding antibiotic administration, which changes the intestinal microbiota and compromises resistance to colonization by antibiotic-resistant bacteria. Recent and ongoing studies are increasingly defining commensal bacterial species and the inhibitory mechanisms they use to prevent infection. The use of next-generation probiotics derived from the intestinal microbiota represents an alternative approach to prevention of infection by enriching colonization with protective commensal species, thereby reducing the density of antibiotic-resistant bacteria and also reducing patient-to-patient transmission of infection in healthcare settings.
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http://dx.doi.org/10.1084/jem.20180399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314519PMC
January 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 effects of amine-modified single-walled carbon nanotubes on the mouse microbiota.

Int J Nanomedicine 2018 10;13:5275-5286. Epub 2018 Sep 10.

Department of Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA,

Background: Amine-modified carbon nanotubes are drug delivery platforms with great potential that have not yet been applied in human clinical trials. Although modified nanotube vectors have the ability to carry multiple effectors, targeting agents, and even wrapped RNA, reports on unmodified, insoluble carbon nanotubes have highlighted inflammation in organs, including the intestine, with disruption of its resident microbiota. Disruption of the microbiota may allow for colonization by pathogenic bacteria, such as , stimulate immunoinfiltrates into the lamina propria or alter the absorption of therapeutics. Most proposed nanotube drugs are soluble, modified structures that are administered parenterally, and the majority of these soluble macromolecules are renally excreted; however, some are released into the bile, gaining access to the gastrointestinal tract.

Methods: Using environmentally isolated BALB/C mice in oral and intraperitoneal dosing models, high dose (3.80 or 4.25 mg/week), we administered amine-modified, soluble carbon nanotubes for 7 or 8 weeks. The general health and weight of the mice were monitored weekly, and upon killing, the diversity and content of their colonic, cecal, and ileal microbiota were assessed using shotgun 16S DNA sequencing.

Results And Conclusion: We show that while oral administration at suprapharmacological doses modestly altered the α- and β-diversity of the mouse microbiome, these changes did not result in observed changes in clinical end points. Intraperitoneally-dosed mice exhibited none of the toxicities assessed.
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http://dx.doi.org/10.2147/IJN.S168554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136419PMC
October 2018

A protective Langerhans cell-keratinocyte axis that is dysfunctional in photosensitivity.

Sci Transl Med 2018 08;10(454)

Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.

Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.
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http://dx.doi.org/10.1126/scitranslmed.aap9527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365282PMC
August 2018

Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them.

Mucosal Immunol 2019 01 9;12(1):1-9. Epub 2018 Jul 9.

Immunology Program, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.

The communities of bacteria that reside in the intestinal tract are in constant competition within this dynamic and densely colonized environment. At homeostasis, the equilibrium that exists between these species and strains is shaped by their metabolism and also by pathways of active antagonism, which drive competition with related and unrelated strains. Importantly, these normal activities contribute to colonization resistance by the healthy microbiota, which includes the ability to prevent the expansion of potential pathogens. Disruption of the microbiota, resulting from, for example, inflammation or antibiotic use, can reduce colonization resistance. Pathogens that engraft following disruption of the microbiota are often adapted to expand into newly created niches and compete in an altered gut environment. In this review, we examine both the interbacterial mechanisms of colonization resistance and the strategies of pathogenic strains to exploit gaps in colonization resistance.
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http://dx.doi.org/10.1038/s41385-018-0053-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312114PMC
January 2019

Distinct behavior of myelomonocytic cells and CD8 T cells underlies the hepatic response to .

Wellcome Open Res 2018 24;3:48. Epub 2018 Apr 24.

Molecular Pathogenesis Program, The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York, NY, 10016, USA.

: The immune response to (LM) is characterized by formation of leukocyte rich foci of infection in liver and spleen.  Although much has been gained in our understanding of immune response through the study of LM, little is known about spatio-temporal regulation of immune response to Listeria in liver. We utilize a combination of molecular, genetic and intravital microscopic approaches to gain insight into the dynamics of foci and leukocyte behavior during hepatic Listeriosis.  : LM foci efficiently exclude blood flow, indicating the presence of a barrier separating the foci and healthy tissue.  Despite this barrier, sinusoidal myelomonocytic cells readily enter or transiently interact with cells at the edge of foci of infection.  Next, utilizing L9.6 transgenic CD8 T cells specific for an endogenously processed LM antigen, p60 217-225, along with LM deficient in this epitope, we define the role of TCR in T cell migratory behavior in infected liver.  Surprisingly, T cell behavior varies with micro-anatomic locale.  Near foci, non-specific adhesion mechanisms dominate lymphocyte behavior.  Antigen specific effects on motility became detectable only distal to foci.  These data suggest that LM antigens act in a paracrine manner to mediate protection from Listeriosis in the liver.
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http://dx.doi.org/10.12688/wellcomeopenres.12941.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958313PMC
April 2018

Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT.

Blood 2018 06 19;131(26):2978-2986. Epub 2018 Apr 19.

Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

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.
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http://dx.doi.org/10.1182/blood-2018-01-828996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024637PMC
June 2018