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Neoplasia (New York, N.Y.) Oct 2017This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients....
Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients.
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.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Chromatography, High Pressure Liquid; Cluster Analysis; Female; Gastrointestinal Microbiome; High-Throughput Nucleotide Sequencing; Humans; Male; Melanoma; Metabolomics; Metagenome; Metagenomics; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Tandem Mass Spectrometry; Treatment Outcome
PubMed: 28923537
DOI: 10.1016/j.neo.2017.08.004 -
American Heart Journal Sep 2021Hypertension (HTN) is frequently linked with depression (DEP) in adults with cardiovascular disease (CVD), yet the underlying mechanism and successful management remain...
BACKGROUND
Hypertension (HTN) is frequently linked with depression (DEP) in adults with cardiovascular disease (CVD), yet the underlying mechanism and successful management remain elusive. We approached this knowledge gap through the lens that humans are eukaryote-prokaryote "meta-organisms," such that cardiovascular disease dysregulation is a mosaic disorder involving dysbiosis of the gut. We hypothesized that patients diagnosed with hypertension plus depression harbor a unique gut microbial ecology with attending functional genomics engaged with their hosts' gut/brain axis physiology.
METHODS
Stool microbiome DNA was analyzed by whole metagenome shotgun sequencing in 54 subjects parsed into cohorts diagnosed with HTN only (N = 18), DEP only (N = 7), DEP plus HTN (DEP-HTN) (N = 8), or reference subjects with neither HTN nor DEP (N = 21). A novel battery of machine-learning multivariate analyses of de-noised data yielded effect sizes and permutational covariance-based dissimilarities that significantly differentiated the cohorts (false discovery rate (FDR)-adjusted P ≤ .05); data clustering within 95% confidence interval).
RESULTS
Metagenomic significant differences extricated the four cohorts. Data of the cohort exhibiting DEP-HTN were germane to the interplay of central control of blood pressure concomitant with the neuropathology of depressive disorders. DEP-HTN gut bacterial community ecology was defined by co-occurrence of Eubacterium siraeum, Alistipes obesi, Holdemania filiformis, and Lachnospiraceae bacterium 1.1.57FAA with Streptococcus salivariu. The corresponding microbial functional genomics of DEP-HTN engaged pathways degrading GABA and beneficial short chain fatty acids (SCFA), and are associated with enhanced sodium absorption and inflammasome induction.
CONCLUSIONS
These data suggest a new putative endotype of hypertension, which we denote "depressive-hypertension" (DEP-HTN), for which we posit a model that is distinctive from either HTN alone or DEP alone. An "endotype" is a subtype of a heterogeneous pathophysiological mechanism. The DEP-HTN model incorporates a unique signature of microbial taxa and functional genomics with crosstalk that putatively intertwines host pathophysiology involving the gastrointestinal tract with disruptions in central control of blood pressure and mood. The DEP-HTN endotype model engages cardiology with gastroenterology and psychiatry, providing a proof-of-concept foundation to explore future treatments, diagnosis, and prevention of HTN-coupled mood disorders.
Topics: Adult; Affect; Biobehavioral Sciences; Biota; Depression; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Hypertension; Machine Learning; Male; Metabolic Networks and Pathways; Metagenome
PubMed: 33984318
DOI: 10.1016/j.ahj.2021.05.002 -
Scientific Reports Apr 2024Vulvar lichen sclerosus (VLS) is a chronic and progressive dermatologic condition that can cause physical dysfunction, disfigurement, and impaired quality of life....
Vulvar lichen sclerosus (VLS) is a chronic and progressive dermatologic condition that can cause physical dysfunction, disfigurement, and impaired quality of life. However, the etiology of VLS remains unknown. The vulvar skin, intestinal and vaginal microbiomes have been postulated to play important roles in the pathogenesis of this disease. The aim of this study was to compare the compositional characteristics of the vulvar skin, vagina, and gut microbiota between perimenopausal or postmenopausal VLS patients and healthy controls. The study involved six perimenopausal or postmenopausal VLS patients which were based on characteristic clinical manifestations and histologic confirmation and five healthy controls. The pruritus severity of each patient was evaluated using the NRS scale, and the dermatology-specific health-related quality of life was assessed using the Skindex-16. Metagenomic sequencing was performed, and the results were analyzed for alpha and beta diversity. LEfSe analysis were used to investigate the microbial alterations in vulvar skin, gut and vagina. KEGG databases were used to analyze differences in functional abundance. The study found significant differences in alpha diversity between the two groups in stool and vaginal samples (P < 0.05). Patients with VLS had a higher abundance of Enterobacter cloacae, Flavobacterium_branchiophilum, Mediterranea_sp._An20, Parabacteroides_johnsoniiand Streptococcus_bovimastitidis on the vulvar skin, while Corynebacterium_sp._zg-913 was less abundant compared to the control group. The relative abundance of Sphingomonas_sp._SCN_67_18, Sphingobium_sp._Ant17, and Pontibacter_sp_BT213 was significantly higher in the gut samples of patients with VLS.Paenibacillus_popilliae,Gemella_asaccharolytica, and Coriobacteriales_bacterium_DNF00809 compared to the control group. Additionally, the vaginal samples of patients with VLS exhibited a significantly lower relative abundance of Bacteroidales_bacterium_43_8, Bacteroides_sp._CAG:20, Blautia_sp._AM28-10, Fibrobacter_sp._UWB16, Lachnospiraceae_bacterium_AM25-39, Holdemania_filiformis, Lachnospiraceae_bacterium_GAM79, and Tolumonas_sp. Additionally, the butyrate-producing bacterium SS3/4 showed a significant difference compared to the controls. The study found a negative relationship between Sphingobium_sp._Ant17 in stool and Skindex-16 (P < 0.05), while Mediterranea_sp._An20 had a positive correlation with Skindex-16 (P < 0.05) in the skin. Additionally, our functional analysis revealed alterations in Aminoacyl_tRNA_biosynthesis, Glutathione_metabolism, the pentose phosphate pathway, and Alanine__aspartate_and_glutamate_metabolism in the VLS patient group. The study suggests that perimenopausal or postmenopausal patients with VLS have a modified microbiome in the vulvar skin, gut, and vagina. This modification is linked to abnormal energy metabolism, increased oxidative stress, and abnormal amino acid metabolism.
Topics: Female; Humans; Vulvar Lichen Sclerosus; Postmenopause; Perimenopause; Quality of Life; Microbiota; Arrhythmias, Cardiac; Vagina
PubMed: 38600101
DOI: 10.1038/s41598-024-58983-y -
World Journal of Gastroenterology Apr 2017To evaluate the ability of HN001 and BB536 to colonize the intestinal environment of healthy subjects and modify the gut microbiota composition. (Clinical Trial)
Clinical Trial
AIM
To evaluate the ability of HN001 and BB536 to colonize the intestinal environment of healthy subjects and modify the gut microbiota composition.
METHODS
Twenty healthy Italian volunteers, eight males and twelve females, participated in the study. Ten subjects took a sachet containing 4 × 10 colony-forming units (CFU) of BB536 and 10 CFU of HN001, 30 min before breakfast (pre-prandial administration), while ten subjects took a sachet of probiotic product 30 min after breakfast (post-prandial administration). The ability of HN001 and BB536 to colonize human gut microbiota was assessed by means of quantitative real-time PCR, while changes in gut microbiota composition were detected by using Ion Torrent Personal Genome Machine.
RESULTS
Immediately after 1-mo of probiotic administration, BB536 and HN001 load was increased in the majority of subjects in both pre-prandial and post-prandial groups. This increase was found also 1 mo after the end of probiotic oral intake in both groups, if compared to samples collected before probiotic consumption. At phyla level a significant decrease in abundance was detected immediately after 1-mo of BB536 and HN001 oral intake. This reduction persisted up to 1 mo after the end of probiotic oral intake together with a significant decrease of abundance if compared to samples collected before probiotic administration. Whereas, at species level, a higher abundance of , and was observed, together with a reduction of , , and abundance. In addition, during follow-up period we observed a further reduction in and , together with a decrease in and abundance. Conversely, the abundance of was increased if compared to samples collected at the beginning of the experimental time course.
CONCLUSION
BB536 and HN001 showed the ability to modulate the gut microbiota composition, leading to a significant reduction of potentially harmful bacteria and an increase of beneficial ones. Further studies are needed to better understand the specific mechanisms involved in gut microbiota modulation.
Topics: Adult; Bifidobacterium longum; Female; Gastrointestinal Microbiome; Healthy Volunteers; Humans; Lacticaseibacillus rhamnosus; Male; Middle Aged; Probiotics
PubMed: 28487606
DOI: 10.3748/wjg.v23.i15.2696 -
Alimentary Pharmacology & Therapeutics May 2016Proton pump inhibitor (PPI) use is associated with an increased risk of Clostridium difficile infection (CDI), though the mechanism is unclear. PPI induced alterations...
BACKGROUND
Proton pump inhibitor (PPI) use is associated with an increased risk of Clostridium difficile infection (CDI), though the mechanism is unclear. PPI induced alterations to the gut microbiome may facilitate the emergence of CDI, though the effects of PPIs on gut microbiota are not well characterised. [Correction added on 10 March 2016, after first online publication: microflora has been changed to microbiota throughout the article.]
AIM
To compare the faecal microbiomes of long-term PPI users to those with no history of PPI use.
METHODS
We used a population-based database to identify individuals with ≥5 years of continuous PPI use along with non-PPI using controls. Stool samples were subjected to microbiological analysis, with hierarchical clustering at genus level, along with alpha and beta diversity measures comparing the two groups. Metadata was accounted for using quantile regression to eliminate potential confounding variables in taxonomic abundance comparisons.
RESULTS
Sixty-one subjects (32 PPI, 29 controls) were analysed. While no significant differences in alpha diversity were found between the PPI users and controls, a moderate shift of the PPI users away from the non-PPI user cluster in the beta diversity was observed. After controlling for pertinent confounders, we discovered a decrease in Bacteroidetes and an increase in Firmicutes at the phylum level. We also performed species classifications and found Holdemania filiformis and Pseudoflavonifractor capillosus to be increased and decreased in the PPI cohort, respectively.
CONCLUSIONS
Long-term PPIs use has an effect on the gut microbiome. The alteration in the ratio of Firmicutes to Bacteroidetes may pre-dispose to the development of CDI.
Topics: Aged; Bacteroidetes; Clostridium Infections; Feces; Female; Firmicutes; Gastrointestinal Microbiome; Humans; Male; Middle Aged; Proton Pump Inhibitors; Risk Factors
PubMed: 26923470
DOI: 10.1111/apt.13568 -
Microbiology and Immunology 2000Three isolated strains from human feces were characterized by biochemical tests and 16S rDNA analysis. Phylogenetic analysis revealed that these isolated strains were...
Three isolated strains from human feces were characterized by biochemical tests and 16S rDNA analysis. Phylogenetic analysis revealed that these isolated strains were members of the Clostridium subphylum of gram-positive bacteria. The phenotypic characters resembled those of the genus Eubacterium, but these strains were shown to be phylogenetically distant from the type species of the genus, Eubacterium limosum. The strains showed a specific phylogenetic association with Holdemania filiformis and Erysipelothrix rhusiopathiae. Based on a 16S rDNA sequence divergence of greater than 12% with H. filiformis and E. rhusiopathiae, a new genus, Solobacterium, is proposed for three strains, with one species, Solobacterium moorei. The type strain of Solobacterium moorei is JCM 10645T.
Topics: Bacteria, Anaerobic; DNA, Bacterial; DNA, Ribosomal; Eubacterium; Feces; Genes, rRNA; Gram-Positive Asporogenous Rods; Humans; Molecular Sequence Data; Phenotype; Phylogeny; RNA, Ribosomal, 16S; Sequence Analysis, DNA
PubMed: 10832964
DOI: 10.1111/j.1348-0421.2000.tb02487.x -
Cancer Medicine Feb 2023Colorectal cancer (CRC) incidence is increasing in young patients without a clear etiology. Emerging data have implicated the fecal microbiome in CRC carcinogenesis.... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Colorectal cancer (CRC) incidence is increasing in young patients without a clear etiology. Emerging data have implicated the fecal microbiome in CRC carcinogenesis. However, its impact on young onset CRC is poorly defined.
METHODS
We performed a meta-analysis of fecal metagenomics sequencing data from n = 692 patients with CRC and n = 602 healthy controls from eleven studies to evaluate features of the fecal metagenome associated with CRC. We hypothesized that known carcinogenic virulence factors (colibactin, fadA) and species abundance may be differentially enriched in young CRC patients relative to older CRC patients and controls.
RESULTS
Summary odds ratios (OR) for CRC were increased with the presence of colibactin (OR 1.92 95% CI 1.08-3.38), fadA (OR 4.57 95% CI 1.63-12.85), and F. nucleatum (OR 6.93 95% CI 3.01-15.96) in meta-analysis models adjusted for age, gender, and body mass index. The OR for CRC for the presence of E.coli was 2.02 (0.92-4.45). An increase in the prevalence of Fusobacterium nucleatum (OR = 1.40 [1.18; 1.65]) and Escherichia coli (OR = 1.14 [1.02; 1.28]) per 10-year increase in age was observed in models including samples from both CRC and healthy controls. Species relative abundance was differentially enriched in young CRC patients for five species-Intestinimonas butyriciproducens, Holdemania filiformis, Firimicutues bacterium CAG 83, Bilophilia wadsworthia, and Alistipes putredinis.
CONCLUSION
In this study, we observed strong associations with CRC status for colibactin, fadA, and Fusobacterium nucleatum with CRC relative to controls. In addition, we identified several microbial species differentially enriched in young colorectal cancer patients. Studies targeting the young CRC patients are warranted to elucidate underlying preclinical mechanisms.
Topics: Humans; Colorectal Neoplasms; Metagenome; Metagenomics; Fusobacterium nucleatum; Carcinogenesis; Microbiota
PubMed: 36056757
DOI: 10.1002/cam4.5197