Pilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma.

PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced ≥1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts.

Germ Cell Tumor Molecular Heterogeneity Revealed Through Analysis of Primary and Metastasis Pairs.

PURPOSE: Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease. PATIENTS AND METHODS: Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients. RESULTS: The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype. CONCLUSION: Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs.

Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection.

The origin of most bacterial infections in the urinary tract is often presumed to be the gut. Herein, we investigate the relationship between the gut microbiota and future development of bacteriuria and urinary tract infection (UTI). We perform gut microbial profiling using 16S rRNA gene deep sequencing on 510 fecal specimens from 168 kidney transplant recipients and metagenomic sequencing on a subset of fecal specimens and urine supernatant specimens. We report that a 1% relative gut abundance of Escherichia is an independent risk factor for Escherichia bacteriuria and UTI and a 1% relative gut abundance of Enterococcus is an independent risk factor for Enterococcus bacteriuria. Strain analysis establishes a close strain level alignment between species found in the gut and in the urine in the same subjects. Our results support a gut microbiota-UTI axis, suggesting that modulating the gut microbiota may be a potential novel strategy to prevent UTIs.

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

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 Eubacterium hallii 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.

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

A diverse, antibiotic-naive microbiota prevents highly antibiotic-resistant microbes, including carbapenem-resistant Klebsiella pneumoniae (CR-Kp), from achieving dense colonization of the intestinal lumen. Antibiotic-mediated destruction of the microbiota leads to expansion of CR-Kp 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-Kp, 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-Kp, we constructed a highly saturated transposon mutant library with >150,000 unique mutations in an ST258 strain of CR-Kp and screened for in vitro growth and in vivo 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 in vivo competition assays with wild-type CR-Kp Screening of the transposon library also identified mutations that enhanced in vivo CR-Kp growth. These newly identified colonization factors may provide novel therapeutic opportunities to reduce intestinal colonization by CR-KpIMPORTANCEKlebsiella pneumoniae 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 K. pneumoniae (CR-Kp) as an urgent public health threat. Dense colonization of the intestine by CR-Kp and other antibiotic-resistant bacteria is associated with an increased risk of bacteremia. Reducing the density of gut colonization by CR-Kp is likely to reduce their transmission from patient to patient in health care facilities as well as systemic infections. How CR-Kp expands and persists in the gut lumen, however, is poorly understood. Herein, we generated a highly saturated mutant library in a multidrug-resistant K. pneumoniae strain and identified genetic factors that are associated with dense gut colonization by K. pneumoniae This study sheds light on host colonization by K. pneumoniae and identifies potential colonization factors that contribute to high-density persistence of K. pneumoniae in the intestine.

Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy1,2, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease3-10. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging11,12, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost13,14. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH21,2, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

Gut microbiota dysbiosis and diarrhea in kidney transplant recipients.

Posttransplant diarrhea is associated with kidney allograft failure and death, but its etiology remains unknown in the majority of cases. Because altered gut microbial ecology is a potential basis for diarrhea, we investigated whether posttransplant diarrhea is associated with gut dysbiosis. We enrolled 71 kidney allograft recipients for serial fecal specimen collections in the first 3 months of transplantation and profiled the gut microbiota using 16S ribosomal RNA (rRNA) gene V4-V5 deep sequencing. The Shannon diversity index was significantly lower in 28 diarrheal fecal specimens from 25 recipients with posttransplant diarrhea than in 112 fecal specimens from 46 recipients without posttransplant diarrhea. We found a lower relative abundance of 13 commensal genera (Benjamini-Hochberg adjusted P ≤ .15) in the diarrheal fecal specimens including the same 4 genera identified in our prior study. The 28 diarrheal fecal specimens were also evaluated by a multiplexed polymerase chain reaction (PCR) assay for 22 bacterial, viral, and protozoan gastrointestinal pathogens, and 26 specimens were negative for infectious etiologies. Using PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to predict metagenomic functions, we found that diarrheal fecal specimens had a lower abundance of metabolic genes. Our findings suggest that posttransplant diarrhea is not associated with common infectious diarrheal pathogens but with a gut dysbiosis.

The effects of amine-modified single-walled carbon nanotubes on the mouse microbiota.

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 Clostridoidies difficile, 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 ß-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.

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

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.

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

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.

Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to Clostridium difficile Virulence.

Clostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota. While some individuals are asymptomatic C. difficile carriers, symptomatic disease ranges from mild diarrhea to potentially lethal toxic megacolon. The wide disease spectrum has been attributed to the infected host's age, underlying diseases, immune status, and microbiome composition. However, strain-specific differences in C. difficile virulence have also been implicated in determining colitis severity. Because patients infected with C. difficile are unique in terms of medical history, microbiome composition, and immune competence, determining the relative contribution of C. difficile virulence to disease severity has been challenging, and conclusions regarding the virulence of specific strains have been inconsistent. To address this, we used a mouse model to test 33 clinical C. difficile strains isolated from patients with disease severities ranging from asymptomatic carriage to severe colitis, and we determined their relative in vivo virulence in genetically identical, antibiotic-pretreated mice. We found that murine infections with C. difficile clade 2 strains (including multilocus sequence type 1/ribotype 027) were associated with higher lethality and that C. difficile strains associated with greater human disease severity caused more severe disease in mice. While toxin production was not strongly correlated with in vivo colonic pathology, the ability of C. difficile strains to grow in the presence of secondary bile acids was associated with greater disease severity. Whole-genome sequencing and identification of core and accessory genes identified a subset of accessory genes that distinguish high-virulence from lower-virulence C. difficile strains.IMPORTANCEClostridium difficile is an important cause of hospital-associated intestinal infections, and recent years have seen an increase in the number and severity of cases in the United States. A patient's antibiotic history, immune status, and medical comorbidities determine, in part, the severity of C. difficile infection. The relative virulence of different clinical C. difficile strains, although postulated to determine disease severity in patients, has been more difficult to consistently associate with mild versus severe colitis. We tested 33 distinct clinical C. difficile isolates for their ability to cause disease in genetically identical mice and found that C. difficile strains belonging to clade 2 were associated with higher mortality. Differences in survival were not attributed to differences in toxin production but likely resulted from the distinct gene content in the various clinical isolates.

The oral microbiota in patients with pancreatic cancer, patients with IPMNs, and controls: a pilot study.

PURPOSE: Poor oral health appears to be a risk factor for pancreatic cancer, possibly implicating the oral microbiota. In this pilot study, we evaluated the characteristics of the oral microbiota in patients with pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasms (IPMN), and healthy controls. METHODS: Forty newly diagnosed PDAC patients, 39 IPMN patients, and 58 controls, excluding current smokers and users of antibiotics, provided saliva samples. Common oral bacterial species were comprehensively surveyed by sequencing of the 16S rRNA microbial genes. We obtained measures of diversity and the mean relative proportions of individual taxa. We explored the degree to which these measures differed according to respondent characteristics based on individual interviews. RESULTS: PDAC cases did not differ in diversity measures from either controls or IPMN cases. PDAC cases had higher mean relative proportions of Firmicutes and related taxa, while controls had higher mean relative proportions of Proteobacteria and related taxa. Results were generally similar when comparing PDAC to IPMN cases. Among IPMNs and controls combined, younger individuals had higher levels of several taxa within the Proteobacteria. The only other variable consistently related to mean relative proportions was mouthwash use, with taxa within Firmicutes more common among users. CONCLUSIONS: While there were no differences in diversity of the oral microbiota among these groups, there were differences in the mean relative proportions of some taxa. Characteristics of the oral microbiota are not associated with most measures of oral health.

Commensal microbes provide first line defense against Listeria monocytogenes infection.

Listeria monocytogenes is a foodborne pathogen that causes septicemia, meningitis and chorioamnionitis and is associated with high mortality. Immunocompetent humans and animals, however, can tolerate high doses of L. monocytogenes without developing systemic disease. The intestinal microbiota provides colonization resistance against many orally acquired pathogens, and antibiotic-mediated depletion of the microbiota reduces host resistance to infection. Here we show that a diverse microbiota markedly reduces Listeria monocytogenes colonization of the gut lumen and prevents systemic dissemination. Antibiotic administration to mice before low dose oral inoculation increases L. monocytogenes growth in the intestine. In immunodeficient or chemotherapy-treated mice, the intestinal microbiota provides nonredundant defense against lethal, disseminated infection. We have assembled a consortium of commensal bacteria belonging to the Clostridiales order, which exerts in vitro antilisterial activity and confers in vivo resistance upon transfer into germ free mice. Thus, we demonstrate a defensive role of the gut microbiota against Listeria monocytogenes infection and identify intestinal commensal species that, by enhancing resistance against this pathogen, represent potential probiotics.

Cooperating Commensals Restore Colonization Resistance to Vancomycin-Resistant Enterococcus faecium.

Antibiotic-mediated microbiota destruction and the consequent loss of colonization resistance can result in intestinal domination with vancomycin-resistant Enterococcus (VRE), leading to bloodstream infection in hospitalized patients. Clearance of VRE remains a challenging goal that, if achieved, would reduce systemic VRE infections and patient-to-patient transmission. Although obligate anaerobic commensal bacteria have been associated with colonization resistance to VRE, the specific bacterial species involved remain undefined. Herein, we demonstrate that a precisely defined consortium of commensal bacteria containing the Clostridium cluster XIVa species Blautia producta and Clostridium bolteae restores colonization resistance against VRE and clears VRE from the intestines of mice. While C. bolteae did not directly mediate VRE clearance, it enabled intestinal colonization with B. producta, which directly inhibited VRE growth. These findings suggest that therapeutic or prophylactic administration of defined bacterial consortia to individuals with compromised microbiota composition may reduce inter-patient transmission and intra-patient dissemination of highly antibiotic-resistant pathogens.

Protective Factors in the Intestinal Microbiome Against Clostridium difficile Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Clostridium difficile infection (CDI) is a frequent complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who receive intensive treatments that significantly disrupt the intestinal microbiota. In this study, we examined the microbiota composition of allo-HSCT recipients to identify bacterial colonizers that confer protection against CDI after engraftment. Methods: Feces collected from adult recipients allo-HSCT at engraftment were analyzed; 16S ribosomal RNA genes were sequenced and analyzed from each sample. Bacterial taxa with protective effects against development of CDI were identified by means of linear discriminant analysis effect size analysis and then further assessed with clinical predictors of CDI using survival analysis. Results: A total of 234 allo-HSCT recipients were studied; postengraftment CDI developed in 53 (22.6%). Within the composition of the microbiota, the presence of 3 distinct bacterial taxa was correlated with protection against CDI: Bacteroidetes, Lachnospiraceae, and Ruminococcaceae. Colonization with these groups at engraftment was associated with a 60% lower risk of CDI, independent of clinical factors. Conclusions: Colonization with these 3 bacterial groups is associated with a lower risk of CDI. These groups have been shown to be vital components of the intestinal microbiota. Targeted efforts to maintain them may help minimize the risk of CDI in this at-risk population.

Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation.

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden.

Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit antimicrobial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with those of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APC(Min/+) mice. Treatment with celecoxib also altered select luminal bacterial populations in both APC(Min/+) and wild-type mice, including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis, including glucose, amino acids, nucleotides, and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APC(Min/+) mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity. Cancer Prev Res; 9(9); 721-31. ©2016 AACR.

Complete Genome Sequence of Enterococcus faecium ATCC 700221.

We report the complete genome sequence of a vancomycin-resistant isolate of Enterococcus faecium derived from human feces. The genome comprises one chromosome of 2.9 Mb and three plasmids. The strain harbors a plasmid-borne vanA-type vancomycin resistance locus and is a member of multilocus sequencing type (MLST) cluster ST-17.

Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells.

Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17-positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17(+) γδ T cells on ischemic injury.

Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.

The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.