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Cancer Cell Jan 2023Gut microorganisms can modulate response to cancer therapies. In this issue of Cancer Cell, Teng et al. trace the gut bacteria and metabolites in rectal cancer patients...
Gut microorganisms can modulate response to cancer therapies. In this issue of Cancer Cell, Teng et al. trace the gut bacteria and metabolites in rectal cancer patients over the course of neoadjuvant chemoradiotherapy and identify Bacteroides vulgatus as a driver bacterium of therapeutic resistance by supplying tumors with nucleotides.
Topics: Humans; Gastrointestinal Microbiome; Rectal Neoplasms; Chemoradiotherapy; Neoadjuvant Therapy
PubMed: 36563683
DOI: 10.1016/j.ccell.2022.11.017 -
Cellular & Molecular Immunology Feb 2023CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells; however, information on the NLRP3 inflammasome is limited. Herein, we...
CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells; however, information on the NLRP3 inflammasome is limited. Herein, we show that although CD82 suppressed the activation of the NLRP3 inflammasome in vivo and in vitro, CD82 deficiency decreased the severity of colitis in mice. Furthermore, two binding partners of CD82, NLRP3 and BRCC3, were identified. CD82 binding to these partners increased the degradation of NLRP3 by blocking BRCC3-dependent K63-specific deubiquitination. Previous studies have shown that CD82-specific bacteria in the colon microbiota called Bacteroides vulgatus (B. vulgatus) regulated the expression of CD82 and promoted the activation of the NLRP3 inflammasome. Accordingly, we observed that B. vulgatus administration increased mouse survival by mediating CD82 expression and activating NLRP3 in mice with colitis. Overall, this study showed that CD82 suppression reduced the pathogenesis of colitis by elevating the activation of the NLRP3 inflammasome through BRCC3-dependent K63 deubiquitination. Based on our findings, we propose that B. vulgatus is a novel therapeutic candidate for colitis.
Topics: Animals; Mice; Colitis; Dextran Sulfate; Inflammasomes; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 36600050
DOI: 10.1038/s41423-022-00971-1 -
EBioMedicine Jul 2023Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown.
BACKGROUND
Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown.
METHODS
Azoxymethane (AOM)-treated, Apc and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated.
FINDINGS
Conventional AOM-treated and Apc mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth.
INTERPRETATION
Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC.
FUNDING
This work was funded by National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065-18GF), RGC-GRF Hong Kong (14110819, 14111621), and NTU Start-Up Grant (021337-00001).
Topics: Humans; Mice; Animals; Gastrointestinal Microbiome; Colonic Neoplasms; Carcinogenesis; Obesity; Azoxymethane; Colorectal Neoplasms; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37343363
DOI: 10.1016/j.ebiom.2023.104670 -
Microbiome Aug 2023A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are acknowledged as a viable and achievable strategy for preventing disorders and improving human health. However, due to the significant inter-individual diversity of the gut microbiota between subjects, lifestyle recommendations are expected to have distinct and highly variable impacts to the microbiome structure.
RESULTS
Here, through a large-scale meta-analysis including 1448 shotgun metagenomics samples obtained longitudinally from 396 individuals during lifestyle studies, we revealed Bacteroides stercoris, Prevotella copri, and Bacteroides vulgatus as biomarkers of microbiota's resistance to structural changes, and aromatic and non-aromatic amino acid biosynthesis as important regulator of microbiome dynamics. We established criteria for distinguishing between significant compositional changes from normal microbiota fluctuation and classified individuals based on their level of response. We further developed a machine learning model for predicting "responders" and "non-responders" independently of the type of intervention with an area under the curve of up to 0.86 in external validation cohorts of different ethnicities.
CONCLUSIONS
We propose here that microbiome-based stratification is possible for identifying individuals with highly plastic or highly resistant microbial structures. Identifying subjects that will not respond to generalized lifestyle therapeutic interventions targeting the restructuring of gut microbiota is important to ensure that primary end-points of clinical studies are reached. Video Abstract.
Topics: Humans; Microbiota; Gastrointestinal Microbiome; Biomarkers; Diet; Life Style
PubMed: 37553697
DOI: 10.1186/s40168-023-01604-z -
Pediatric Research Apr 2024We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease...
BACKGROUND AND AIMS
We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions.
METHODS
We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS).
RESULTS
Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS.
CONCLUSIONS
We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming.
IMPACT
Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.
PubMed: 38177249
DOI: 10.1038/s41390-023-02960-0 -
Cancer Medicine Sep 2023Aging is one of the factors leading to cancer. Gut microbiota is related to aging and colorectal cancer (CRC).
BACKGROUND
Aging is one of the factors leading to cancer. Gut microbiota is related to aging and colorectal cancer (CRC).
METHODS
A total of 11 metagenomic data sets related to CRC were collected from the R package curated Metagenomic Data. After batch effect correction, healthy individuals and CRC samples were divided into three age groups. Ggplot2 and Microbiota Process packages were used for visual description of species composition and PCA in healthy individuals and CRC samples. LEfSe analysis was performed for species relative abundance data in healthy/CRC groups according to age. Spearman correlation coefficient of age-differentiated bacteria in healthy individuals and CRC samples was calculated separately. Finally, the age prediction model and CRC risk prediction model were constructed based on the age-differentiated bacteria.
RESULTS
The structure and composition of the gut microbiota were significantly different among the three groups. For example, the abundance of Bacteroides vulgatus in the old group was lower than that in the other two groups, the abundance of Bacteroides fragilis increased with aging. In addition, seven species of bacteria whose abundance increases with aging were screened out. Furthermore, the abundance of pathogenic bacteria (Escherichia_coli, Butyricimonas_virosa, Ruminococcus_bicirculans, Bacteroides_fragilis and Streptococcus_vestibularis) increased with aging in CRCs. The abundance of probiotics (Eubacterium_eligens) decreased with aging in CRCs. The age prediction model for healthy individuals based on the 80 age-related differential bacteria and model of CRC patients based on the 58 age-related differential bacteria performed well, with AUC of 0.79 and 0.71, respectively. The AUC of CRC risk prediction model based on 45 disease differential bacteria was 0.83. After removing the intersection between the disease-differentiated bacteria and the age-differentiated bacteria from the healthy samples, the AUC of CRC risk prediction model based on remaining 31 bacteria was 0.8. CRC risk prediction models for each of the three age groups showed no significant difference in accuracy (young: AUC=0.82, middle: AUC=0.83, old: AUC=0.85).
CONCLUSION
Age as a factor affecting microbial composition should be considered in the application of gut microbiota to predict the risk of CRC.
Topics: Humans; Gastrointestinal Microbiome; Colorectal Neoplasms; Bacteria; Microbiota; Aging
PubMed: 37548332
DOI: 10.1002/cam4.6414 -
Frontiers in Immunology 2017Intestinal dysbiosis and metabolic endotoxemia have been associated with metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes (T2D). The main...
Intestinal dysbiosis and metabolic endotoxemia have been associated with metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes (T2D). The main goal of the present study was to evaluate the intestinal dysbiosis in Brazilian T2D patients and correlate these data with inflammatory cytokines and lipopolysaccharides (LPS) plasma concentrations. This study was approved by the Ethics Committees from Barretos Cancer Hospital and all individuals signed the informed consent form. Stool samples were required for DNA extraction, and the V3/V4 regions of bacterial 16S were sequenced using an Illumina platform. Peripheral blood was used to quantify inflammatory cytokines and plasma LPS concentrations, by CBA flex and ELISA, respectively. Statistical analyses were performed using Mann-Whitney and Spearman's tests. Analysis of variance, diversity indexes, and analysis of alpha- and beta-diversity were conducted using an annotated Operational Taxonomic Unit table. This study included 20 patients and 22 controls. We observed significant differences ( < 0.01) in the microbiota composition (beta-diversity) between patients and controls, suggesting intestinal dysbiosis in Brazilian T2D patients. The prevalent species found in patients' feces were the Gram-negatives , and . The proinflammatory interleukin-6 (IL-6) was significantly increased ( < 0.05) in patients' plasma and LPS levels were decreased. We find correlations between the proinflammatory interferon-gamma with Gram-negatives and species, and a positive correlation between the LPS levels and reads. The and species were associated with insulin resistance in previous studies. In this study, we suggested that the prevalence of Gram-negative species in the gut and the increased plasma IL-6 in patients could be linked to low-grade inflammation and insulin resistance. In conclusion, the and species could represent an intestinal microbiota signature, associated with T2D development. Furthermore, the identification of these Gram-negative bacteria, and the detection of inflammatory markers, such as increased IL-6, could be used as diabetes predictive markers in overweight, obese and in genetically predisposed individuals to develop T2D.
PubMed: 28966614
DOI: 10.3389/fimmu.2017.01107 -
BMC Microbiology Dec 2023The promising yet barely investigated anaerobic species Phocaeicola vulgatus (formerly Bacteroides vulgatus) plays a vital role for human gut health and effectively...
BACKGROUND
The promising yet barely investigated anaerobic species Phocaeicola vulgatus (formerly Bacteroides vulgatus) plays a vital role for human gut health and effectively produces organic acids. Among them is succinate, a building block for high-value-added chemicals. Cultivating anaerobic bacteria is challenging, and a detailed understanding of P. vulgatus growth and metabolism is required to improve succinate production. One significant aspect is the influence of different gas concentrations. CO is required for the growth of P. vulgatus. However, it is a greenhouse gas that should not be wasted. Another highly interesting aspect is the sensitivity of P. vulgatus towards O. In this work, the effects of varying concentrations of both gases were studied in the in-house developed Respiratory Activity MOnitoring System (RAMOS), which provides online monitoring of CO, O and pressure under gassed conditions. The RAMOS was combined with a gas mixing system to test CO and O concentrations in a range of 0.25-15.0 vol% and 0.0-2.5 vol%, respectively.
RESULTS
Changing the CO concentration in the gas supply revealed a CO optimum of 3.0 vol% for total organic acid production and 15.0 vol% for succinate production. It was demonstrated that the organic acid composition changed depending on the CO concentration. Furthermore, unrestricted growth of P. vulgatus up to an O concentration of 0.7 vol% in the gas supply was proven. The viability decreased rapidly at concentrations larger than or equal to 1.3 vol% O.
CONCLUSIONS
The study showed that P. vulgatus requires little CO, has a distinct O tolerance and is therefore well suited for industrial applications.
Topics: Humans; Carbon Dioxide; Bacteroides; Succinates; Succinic Acid; Oxygen
PubMed: 38062358
DOI: 10.1186/s12866-023-03127-x -
Gut Microbes Dec 2023Morphine addiction is closely associated with dysbiosis of the gut microbiota. miRNAs play a crucial role in regulating intestinal bacterial growth and are involved in...
Morphine addiction is closely associated with dysbiosis of the gut microbiota. miRNAs play a crucial role in regulating intestinal bacterial growth and are involved in the development of disease. Ginsenoside Rg1 exhibits an anti-addiction effect and significantly improves intestinal microbiota disorders. In pseudo-germfree mice, supplementation with () synergistically enhanced Rg1 to alleviate morphine addiction. However, it is currently unknown the relationship between fecal miRNAs in morphine-exposed mice and their potential modulation of gut microbiome, as well as their role in mediating the resistance of ginsenoside Rg1 to drug addiction. Here, we studied the fecal miRNA abundance in mice treated with morphine to explore the different miRNAs expressed, their association with and their role in the amelioration of morphine reward by ginsenoside Rg1. Our results indicated ginsenoside Rg1 attenuated the significant increase in miR-129-5p expression observed in the feces of morphine-treated mice. The miR-129-5p, specifically, inhibited the growth of by modulating the transcript of the site-tag BVU_RS11835 and increased the levels of 5-hydroxytryptophan and indole-3-carboxaldehyde in vitro. Subsequently, we noticed that oral administration of synthetic miR-129-5p increased 5-HT levels in the hippocampus and inhibited the reversal effect of ginsenoside Rg1 both on the relative abundance of in the feces and CPP effect induced by morphine exposure. In short, Ginsenoside Rg1 might play an indirect role in remodeling the against morphine reward by suppressing miR-129-5p expression. These results highlight the role of miR-129-5p and in morphine reward and the anti-morphine addiction of ginsenoside Rg1.
Topics: Animals; Mice; Gastrointestinal Microbiome; Hippocampus; MicroRNAs; Morphine; Reward; Serotonin
PubMed: 37698853
DOI: 10.1080/19490976.2023.2254946 -
Genome Biology and Evolution Apr 2016Like many other Bacteroides species, Bacteroides vulgatus strain mpk, a mouse fecal isolate which was shown to promote intestinal homeostasis, utilizes a variety of...
Like many other Bacteroides species, Bacteroides vulgatus strain mpk, a mouse fecal isolate which was shown to promote intestinal homeostasis, utilizes a variety of mobile elements for genome evolution. Based on sequences collected by Pacific Biosciences SMRT sequencing technology, we discuss the challenges of assembling and studying a bacterial genome of high plasticity. Additionally, we conducted comparative genomics comparing this commensal strain with the B. vulgatus type strain ATCC 8482 as well as multiple other Bacteroides and Parabacteroides strains to reveal the most important differences and identify the unique features of B. vulgatus mpk. The genome of B. vulgatus mpk harbors a large and diverse set of mobile element proteins compared with other sequenced Bacteroides strains. We found evidence of a number of different horizontal gene transfer events and a genome landscape that has been extensively altered by different mobilization events. A CRISPR/Cas system could be identified that provides a possible mechanism for preventing the integration of invading external DNA. We propose that the high genome plasticity and the introduced genome instabilities of B. vulgatus mpk arising from the various mobilization events might play an important role not only in its adaptation to the challenging intestinal environment in general, but also in its ability to interact with the gut microbiota.
Topics: Animals; Bacteroides; Base Sequence; CRISPR-Cas Systems; DNA, Bacterial; Evolution, Molecular; Gene Transfer, Horizontal; Genome, Bacterial; Intestines; Mice; Phylogeny
PubMed: 27071651
DOI: 10.1093/gbe/evw070