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Gastroenterology Dec 2023Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect...
BACKGROUND & AIMS
Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota.
METHODS
CRC mouse models were established by azoxymethane plus dextran sulfate sodium treatment or in Apc mice treated with or without PZH (270 mg/kg and 540 mg/kg). Gut barrier function was determined by means of intestinal permeability assays and transmission electron microscopy. Fecal microbiota and metabolites were analyzed by means of metagenomic sequencing and liquid chromatography mass spectrometry, respectively. Germ-free mice or antibiotic-treated mice were used as models of microbiota depletion.
RESULTS
PZH inhibited colorectal tumorigenesis in azoxymethane plus dextran sulfate sodium-treated mice and in Apc mice in a dose-dependent manner. PZH treatment altered the gut microbiota profile, with an increased abundance of probiotics Pseudobutyrivibrio xylanivorans and Eubacterium limosum, while pathogenic bacteria Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, and Peptoniphilus harei were depleted. In addition, PZH increased beneficial metabolites taurine and hypotaurine, bile acids, and unsaturated fatty acids, and significantly restored gut barrier function. Transcriptomic profiling revealed that PZH inhibited PI3K-Akt, interleukin-17, tumor necrosis factor, and cytokine-chemokine signaling. Notably, the chemopreventive effect of PZH involved both microbiota-dependent and -independent mechanisms. Fecal microbiota transplantation from PZH-treated mice to germ-free mice partly recapitulated the chemopreventive effects of PZH. PZH components ginsenoside-F2 and ginsenoside-Re demonstrated inhibitory effects on CRC cells and primary organoids, and PZH also inhibited tumorigenesis in azoxymethane plus dextran sulfate sodium-treated germ-free mice.
CONCLUSIONS
PZH manipulated gut microbiota and metabolites toward a more favorable profile, improved gut barrier function, and suppressed oncogenic and pro-inflammatory pathways, thereby suppressing colorectal carcinogenesis.
Topics: Mice; Animals; Signal Transduction; Gastrointestinal Microbiome; Dextran Sulfate; Phosphatidylinositol 3-Kinases; Apoptosis; Medicine, Traditional; Colorectal Neoplasms; Carcinogenesis; Azoxymethane
PubMed: 37704113
DOI: 10.1053/j.gastro.2023.08.052 -
Science (New York, N.Y.) Jan 2018Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to...
Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16 ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included , , and Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.
Topics: Animals; Antibodies, Monoclonal; Bifidobacterium longum; Enterococcus faecium; Feces; Gastrointestinal Microbiome; Humans; Immunotherapy; Melanoma; Mice; Programmed Cell Death 1 Receptor; RNA, Ribosomal, 16S; Skin Neoplasms; T-Lymphocytes
PubMed: 29302014
DOI: 10.1126/science.aao3290 -
Nutrients Dec 2022Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included and . To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. and were positively correlated with unconjugated bile acids. , , and were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.
Topics: Humans; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Feces; Bacteria; Bile Acids and Salts
PubMed: 36558359
DOI: 10.3390/nu14245200 -
Nature Jan 2024Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established, little is known about how host genetics regulates... (Meta-Analysis)
Meta-Analysis
Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.
Topics: Humans; Acetylgalactosamine; Bacteria; Cohort Studies; Computer Simulation; Faecalibacterium prausnitzii; Gastrointestinal Microbiome; Genome, Human; Genotype; Host Microbial Interactions; In Vitro Techniques; Metagenome; Multigene Family; Netherlands; Tanzania
PubMed: 38172637
DOI: 10.1038/s41586-023-06893-w -
Gut May 2011A general dysbiosis of the intestinal microbiota has been established in patients with Crohn's disease (CD), but a systematic characterisation of this dysbiosis is...
BACKGROUND AND AIMS
A general dysbiosis of the intestinal microbiota has been established in patients with Crohn's disease (CD), but a systematic characterisation of this dysbiosis is lacking. Therefore the composition of the predominant faecal microbiota of patients with CD was studied in comparison with the predominant composition in unaffected controls. Whether dysbiosis is present in relatives of patients CD was also examined.
METHODS
Focusing on families with at least three members affected with CD, faecal samples of 68 patients with CD, 84 of their unaffected relatives and 55 matched controls were subjected to community fingerprinting of the predominant microbiota using denaturing gradient gel electrophoresis (DGGE). To analyse the DGGE profiles, BioNumerics software and non-parametric statistical analyses (SPSS V.17.0) were used. Observed differences in the predominant microbiota were subsequently confirmed and quantified with real-time PCR.
RESULTS
Five bacterial species characterised dysbiosis in CD, namely a decrease in Dialister invisus (p=0.04), an uncharacterised species of Clostridium cluster XIVa (p = 0.03), Faecalibacterium prausnitzii (p < 1.3 × 10⁻⁵) and Bifidobacterium adolescentis (p = 5.4 × 10⁻⁶), and an increase in Ruminococcus gnavus (p = 2.1 × 10⁻⁷). Unaffected relatives of patients with CD had less Collinsella aerofaciens (p = 0.004) and a member of the Escherichia coli-Shigella group (p = 0.01) and more Ruminococcus torques (p = 0.02) in their predominant microbiota as compared with healthy subjects.
CONCLUSION
Unaffected relatives of patients with CD have a different composition of their microbiota compared with healthy controls. This dysbiosis is not characterised by lack of butyrate producing-bacteria as observed in CD but suggests a role for microorganisms with mucin degradation capacity.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bacteria; Case-Control Studies; Crohn Disease; DNA, Bacterial; Denaturing Gradient Gel Electrophoresis; Feces; Female; Humans; Male; Metagenome; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Symbiosis; Young Adult
PubMed: 21209126
DOI: 10.1136/gut.2010.223263 -
Journal of the American Chemical Society Apr 2023Some members of the human gut microbiota profoundly influence their host's physiology, health, and therapeutic responses, but the responsible molecules and mechanisms...
Some members of the human gut microbiota profoundly influence their host's physiology, health, and therapeutic responses, but the responsible molecules and mechanisms are largely unknown. As part of a project to identify immunomodulators produced by gut microbes, we analyzed the metabolome of , an actinomycete that figures prominently in numerous association studies. The associations are typically positive correlations of with pro-inflammatory responses and undesirable outcomes, but an association with favorable responses to PD-1/PD-L1 cancer immunotherapy is a notable exception. A phenotypic assay-guided screen using dendritic cells (mBMDCs) and cytokine readouts identified the active compound, which was structurally characterized as a lysoglycoglycerolipid with an acetal-bearing β-galactofuranose head group (CaLGL-1, ). The structural assignment was confirmed through total synthesis. Assays with , , and wt mBMDCs revealed TLR2-dependent signaling. CaLGL-1 is produced by a conversion of a bacterially biosynthesized plasmalogen (CaPlsM, ) to CaLGL-1 () in a low-pH environment.
Topics: Humans; Actinobacteria; Hydrogen-Ion Concentration; Lipids; Microbiota; Toll-Like Receptor 2; Dendritic Cells
PubMed: 36952265
DOI: 10.1021/jacs.3c00250 -
The Journal of Nutrition Jan 2023Animal and small-cohort human studies have shown that tea consumption affects the gut microbiome, but evidence from large cohort studies is lacking.
BACKGROUND
Animal and small-cohort human studies have shown that tea consumption affects the gut microbiome, but evidence from large cohort studies is lacking.
OBJECTIVES
We examined associations between tea consumption and gut microbiome composition among older Chinese adults.
METHODS
The study included 1179 men and 1078 women from the Shanghai Men's and Women's Health Studies, who reported tea drinking status, type, amount, and duration at baseline and follow-up surveys (1996-2017) and were free of cancer, cardiovascular disease, and diabetes at stool collection (2015-2018). Fecal microbiome was profiled using 16S rRNA sequencing. Associations of tea variables with microbiome diversity and taxa abundance were evaluated using linear or negative binomial hurdle models after adjusting for sociodemographics, lifestyle, and hypertension status.
RESULTS
Mean age at stool collection was 67.2 ± 9.0 y in men and 69.6 ± 8.5 y in women. Tea drinking was not associated with microbiome ɑ-diversity in men or women; however, all tea variables were associated with β-diversity in men (P < 0.001). Significant associations with taxa abundance were also observed mostly in men. Current tea drinking, mainly green tea drinking, was associated with increase in orders Synergistales and RF39 in men (β = 0.30 to 0.42, all P ≤ 0.10) but not in women (P = 0.01). Also, increase in families Coriobacteriaceae, Odoribacteraceae, genera Collinsella, Odoribacter, and species Collinsella aerofaciens, Coprococcus catus, and Dorea formicigenerans were observed among men who drank >3.3 cups (781 mL)/d compared to that of nondrinkers (all P <0.10). The increased Coprococcus catus related to tea drinking was more evident among men without hypertension and inversely associated with the prevalence of hypertension (OR: 0.90; 95% CI: 0.84, 0.97; P = 0.03).
CONCLUSIONS
Tea consumption may affect gut microbiome β-diversity and abundance of some bacteria, which may contribute to reduced hypertension risk in Chinese men. Future studies should examine the sex-specific tea-gut microbiome associations and how certain bacteria may mediate the health benefits of tea.
Topics: Male; Humans; Adult; Female; Middle Aged; Aged; Gastrointestinal Microbiome; East Asian People; RNA, Ribosomal, 16S; Prospective Studies; China; Tea; Hypertension
PubMed: 36913464
DOI: 10.1016/j.tjnut.2022.12.002 -
Frontiers in Cellular and Infection... 2022In this study, we examined the changes to the composition and function of the gut microbiota from patients with metabolic dysfunction-associated fatty liver disease...
PURPOSE
In this study, we examined the changes to the composition and function of the gut microbiota from patients with metabolic dysfunction-associated fatty liver disease (MAFLD).We compared patients in a case group (liver stiffness (LSM) ≥ 7.4 kPa) with a matched control group (LSM < 7.4 kPa) and investigated the correlation between characteristics of the microbiota and other biochemical indicators.
METHODS
The study looked at a total of 85 men with MAFLD, 17 of whom were in the case group and 68 of whom were in the control group. We measured waist circumference, blood pressure, and body mass index, as well as clinical parameters including liver stiffness, enzyme levels, cholesterol levels, and fat attenuation. Whole-genome shotgun sequencing technology and the MetaCyc database were then used to detect the composition and major pathways of the gut microbiota for each patient. Statistical analyses were performed, including the chi-square test, the student's t-test, the Wilcoxon rank-sum test, and the Mann-Whitney test.
RESULTS
Whole-genome sequencing showed that the composition of the gut microbiota in patients with an LSM of above 7.4 kPa was significantly different to that of the control group. There were seven bacterial species that were different between the two groups. Prevotella copri, Phascolarctobacterium succinatutens, Eubacterium biforme, and Collinsella aerofaciens were enriched in the case group (P < 0.05). Conversely, Bacteroides coprocola, Bacteroides stercoris and Clostridiales bacterium 1_7_47FAA were decreased in the case group (P < 0.05). Furthermore, after removing low abundance pathways, a total of 32 microbial pathways were found to be significantly different between the two groups. Most pathways enriched in the case group over the control were related to biosynthesis of metabolites including amino acids, vitamins, nucleosides, and nucleotides. Conclusion. The composition and function of the gut microbiota in patients with increased liver stiffness are significantly altered. This observation may provide new avenues to better understand the mechanism of liver fibrosis.
Topics: Bacteria; Clostridiales; Eubacterium; Gastrointestinal Microbiome; Humans; Liver; Male
PubMed: 35992168
DOI: 10.3389/fcimb.2022.873048 -
Gut Microbes 2024Probiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We... (Randomized Controlled Trial)
Randomized Controlled Trial
Probiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We aimed to identify markers for recognizing non-constipated (NC) IBS patients that may show significant clinical improvements upon treatment with the probiotic strain DG (LDG). To this purpose, we performed a post-hoc analysis of samples collected during a multicenter, double-blind, parallel-group, placebo-controlled trial in which NC-IBS patients were randomized to receive at least 24 billion CFU LDG or placebo capsules . for 12 weeks. The primary clinical endpoint was the composite response based on improved abdominal pain and fecal type. The fecal microbiome and serum markers of intestinal (PV1 and zonulin), liver, and kidney functions were investigated. We found that responders (R) in the probiotic arm (25%) differed from non-responders (NR) based on the abundance of 18 bacterial taxa, including the families , spp. and , which were overrepresented in R patients. These taxa also distinguished R (but not NR) patients from healthy controls. Probiotic intervention significantly reduced the abundance of these bacteria in R, but not in NR. Analogous results emerged for from the analysis of data from a previous trial on IBS with the same probiotic. Finally, was positively correlated with the plasmalemmal vesicle associated protein-1 (PV-1) and the markers of liver function. In conclusion, LDG is effective on NC-IBS patients with NC-IBS with a greater abundance of potential pathobionts. Among these, has emerged as a potential predictor of probiotic efficacy.
Topics: Humans; Irritable Bowel Syndrome; Treatment Outcome; Gastrointestinal Microbiome; Constipation; Probiotics; Eubacterium; Double-Blind Method; Diarrhea
PubMed: 38178601
DOI: 10.1080/19490976.2023.2298246 -
Gut Microbes 2022The age-associated alterations in microbiomes vary across populations due to the influence of genetics and lifestyles. To the best of our knowledge, the microbial...
The age-associated alterations in microbiomes vary across populations due to the influence of genetics and lifestyles. To the best of our knowledge, the microbial changes associated with aging have not yet been investigated in Singapore adults. We conducted shotgun metagenomic sequencing of fecal and saliva samples, as well as fecal metabolomics to characterize the gut and oral microbial communities of 62 healthy adult male Singaporeans, including 32 young subjects (age, 23.1 ± 1.4 years) and 30 elderly subjects (age, 69.0 ± 3.5 years). We identified 8 gut and 13 oral species that were differentially abundant in elderly compared to young subjects. By combining the gut and oral microbiomes, 25 age-associated oral-gut species connections were identified. Moreover, oral bacteria and were less prevalent/abundant in elderly gut samples than in young gut samples, whereas and showed the opposite trends. These results indicate the varied gut-oral communications with aging. Subsequently, we expanded the association studies on microbiome, metabolome and host phenotypic parameters. In particular, increased in elderly compared to young subjects, and was positively correlated with triglycerides, which implies that the potential role of in lipid metabolism is altered during the aging process. Our results demonstrated aging-associated changes in the gut and oral microbiomes, as well as the connections between metabolites and host-microbe interactions, thereby deepening the understanding of alterations in the human microbiome during the aging process in a Singapore population.
Topics: Adult; Aged; Aging; Feces; Gastrointestinal Microbiome; Humans; Male; Metabolome; Metagenomics; Singapore; Young Adult
PubMed: 35549618
DOI: 10.1080/19490976.2022.2070392