This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma ...patients exhibit profound response to ICT, there are fewer options for patients failing ICT—particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.
Given the lack of a complete and comprehensive library of microbial reference genomes, determining the functional profile of diverse microbial communities is challenging. The available functional ...analysis pipelines lack several key features: (i) an integrated alignment tool, (ii) operon-level analysis, and (iii) the ability to process large datasets.
Here we introduce our open-sourced, stand-alone functional analysis pipeline for analyzing whole metagenomic and metatranscriptomic sequencing data, FMAP (Functional Mapping and Analysis Pipeline). FMAP performs alignment, gene family abundance calculations, and statistical analysis (three levels of analyses are provided: differentially-abundant genes, operons and pathways). The resulting output can be easily visualized with heatmaps and functional pathway diagrams. FMAP functional predictions are consistent with currently available functional analysis pipelines.
FMAP is a comprehensive tool for providing functional analysis of metagenomic/metatranscriptomic sequencing data. With the added features of integrated alignment, operon-level analysis, and the ability to process large datasets, FMAP will be a valuable addition to the currently available functional analysis toolbox. We believe that this software will be of great value to the wider biology and bioinformatics communities.
Candida species are among the most prevalent and abundant members of the gut mycobiota, with Candida albicans (CA) being the most prominent member. CA colonizes numerous mucosal surfaces, most ...notably the gastrointestinal (GI) and genitourinary tracts. In a healthy host, CA is a pathobiont that exists as a commensal but can become pathogenic if the host’s immune system becomes suppressed. The microbial and/or host factors that dictate CA’s ability to colonize mucosal surfaces and its ability to disseminate remain of great interest. Here, we review the recent advances and insights regarding Candida colonization and dissemination of the mammalian GI tract.
Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic ...bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.
About the Authors: Andrew Y. Koh * E-mail: andrew.koh@utsouthwestern.edu Affiliations Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of ...America, Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America ORCID http://orcid.org/0000-0003-2172-5126Citation: Koh AY (2017) The microbiome in hematopoietic stem cell transplant recipients and cancer patients: ...cancer and stem cell transplant (SCT) patients often receive multiple antibiotics for long durations of time, and many patients never have a laboratory-documented infection. ...specific antibiotic therapies, particularly those that destroy specific anaerobic commensal communities, appear to be linked to the development of these complications 5, 8-10. The major host immune deficits that promote bacterial and fungal translocation from the GI tract include deficiencies in cellular immunity (particularly neutropenia); impaired intestinal barriers (an adverse consequence of cytotoxic chemotherapy, also referred to as mucositis); and GI microbiota imbalance (often driven by use of broad-spectrum antibiotics). In preclinical models emulating the development of gut-derived bacteremia and fungemia, all 3 host defense mechanisms need to be impaired to promote microbial dissemination from the gut: antibiotics to deplete gut commensal microbiota, allowing high levels of pathogenic microbial colonization (i.e., P. aeruginosa or Candida albicans) and cytotoxic chemotherapy (e.g., cyclophosphamide) to both deplete neutrophils and damage GI epithelium 11, 12. Whereas severe neutropenia and gut mucosal damage are, more or less, experienced by all cancer and SCT patients, there is emerging evidence...
The gut microbiome plays a critical role in various inflammatory conditions, and its modulation is a potential treatment option for these conditions. The role of the gut microbiome in the ...pathogenesis of thromboembolism has not been fully elucidated. In this review, we summarize the evidence linking the gut microbiome to the pathogenesis of arterial and venous thrombosis. In a human host, potentially pathogenic bacteria are normal residents of the human gut microbiome, but significantly outnumbered by commensal anaerobic bacteria. Several disease states with an increased risk of venous thromboembolism (VTE) are associated with an imbalance in the gut microbiome characterized by a decrease in commensal anaerobic bacteria and an increase in the abundance of pathogenic bacteria of which the most common is the gram-negative Enterobacteriaceae (ENTERO) family. Bacterial lipopolysaccharides (LPS), the glycolipids found on the outer membrane of gram-negative bacteria, is one of the links between the microbiome and hypercoagulability. LPS binds to toll-like receptors to activate endothelial cells and platelets, leading to activation of the coagulation cascade. Bacteria in the microbiome can also metabolite compounds in the diet to produce important metabolites like trimethylamine-N-oxide (TMAO). TMAO causes platelet hyperreactivity, promotes thrombus formation and is associated with cardiovascular disease. Modulating the gut microbiome to target LPS and TMAO levels may be an innovative approach for decreasing the risk of thrombosis.
•Several disease states with high risk of thrombosis are associated with dysbiosis.•Bacterial LPS from the gut can bind to TLRs and activates the coagulation cascade.•The microbiome can affect the innate immune system and lead to “immunothrombosis”.•Gut metabolites like TMAO can promote cardiovascular disease and thrombosis.
Gut microbiota, the collective community of microorganisms inhabiting the intestine, have been shown to provide many beneficial functions for the host. Recent advances in next-generation sequencing ...and advanced molecular biology approaches have allowed researchers to identify gut microbiota signatures associated with disease processes and, in some cases, establish causality and elucidate underlying mechanisms.
This report reviews 3 commonly used methods for studying the gut microbiota and microbiome (the collective genomes of the gut microorganisms): 16S rRNA gene sequencing, bacterial group or species-specific quantitative polymerase chain reaction (qPCR), and metagenomic shotgun sequencing (MSS). The technical approaches and resources needed for each approach are outlined, and advantages and disadvantages for each approach are summarized. The findings regarding the role of the gut microbiota in the health of patients with cancer and stem cell transplant (SCT) patients (specifically in modulating the development of gut-derived bacterial infections and a posttransplant immune-mediated complication known as graft-vs-host-disease) are reviewed. Finally, there is discussion of the potential viability of these approaches in the actual clinical treatment of cancer and SCT patients.
Advances in next-generation sequencing have revolutionized our understanding of the importance of the gut microbiome to human health. Both 16S rRNA gene sequencing and MSS are currently too labor-intensive or computationally burdensome to incorporate into real-time clinical monitoring of gut microbiomes. Yet, the lessons learned from these technologies could be adapted to currently used methods (e.g., qPCR) that could then be rigorously tested in the clinical care of these patients.
•Clostridium leptum and Bacteroidesappear reduced in psychiatric presentations.•With anhedonia, Clostridalesare reduced and Bacteroidesare higher.•Co-occurring anxiety complicates finding biomarkers ...and microbial signatures.
Characterise gut microbiota distributions of participants with co-occurring depression and anxiety, in those with only depression or with anxiety, and determine if gut bacteria differentially correlates with distinct clinical presentations.
Participants (10 healthy controls mean age: 33, 60% female and 60 psychiatric subjects; major depressive disorder (comorbid with anxiety), n = 38 mean age: 39.2, 82% female, anxiety only, n = 8 mean age: 40.0, 100% female, depression only without anxiety, n = 14 mean age: 41.9, 79% female) were characterized by psychiatric assessments. Quantitative PCR and 16S rRNA sequencing were used to characterize the gut microbiota in stool samples.
Altered microbiota correlated with pre-defined clinical presentation, with Bacteroides (p = 0.011) and the Clostridium leptum subgroup (p = 0.023) significantly different between clinical categories. Cluster analysis of the total sample using weighted UniFrac β-diversity of the gut microbiota identified two different clusters defined by differences in bacterial distribution. Cluster 2 had higher Bacteroides (p = 0.006), and much reduced presence of Clostridales (p<0.001) compared to Cluster 1. Bifidobacterium (p = 0.0173) was also reduced in Cluster 2 compared to Cluster 1. When evaluated for clinical charateristics, anhedonia scores in Cluster 2 were higher than in Cluster 1.
The sample is smaller and predominately female.
Reduced or absent Clostridia was consistently seen in those with depression, independent of the presence of anxiety. Conversely, reduced Bacteroides may be more associated with the presence of anxiety, independent of the presence of depression. These differences suggest that gut microbiota distribution could help clarify the underlying pathology of comorbid clinical presentation.
Bacterial-fungal interactions have important physiologic and medical ramifications, but the mechanisms of these interactions are poorly understood. The gut is host to trillions of microorganisms, and ...bacterial-fungal interactions are likely to be important. Using a neutropenic mouse model of microbial gastrointestinal colonization and dissemination, we show that the fungus Candida albicans inhibits the virulence of the bacterium Pseudomonas aeruginosa by inhibiting P. aeruginosa pyochelin and pyoverdine gene expression, which plays a critical role in iron acquisition and virulence. Accordingly, deletion of both P. aeruginosa pyochelin and pyoverdine genes attenuates P. aeruginosa virulence. Heat-killed C. albicans has no effect on P. aeruginosa, whereas C. albicans secreted proteins directly suppress P. aeruginosa pyoverdine and pyochelin expression and inhibit P. aeruginosa virulence in mice. Interestingly, suppression or deletion of pyochelin and pyoverdine genes has no effect on P. aeruginosa's ability to colonize the GI tract but does decrease P. aeruginosa's cytotoxic effect on cultured colonocytes. Finally, oral iron supplementation restores P. aeruginosa virulence in P. aeruginosa and C. albicans colonized mice. Together, our findings provide insight into how a bacterial-fungal interaction can modulate bacterial virulence in the intestine. Previously described bacterial-fungal antagonistic interactions have focused on growth inhibition or colonization inhibition/modulation, yet here we describe a novel observation of fungal-inhibition of bacterial effectors critical for virulence but not important for colonization. These findings validate the use of a mammalian model system to explore the complexities of polymicrobial, polykingdom infections in order to identify new therapeutic targets for preventing microbial disease.
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