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2.
Front Immunol ; 13: 1030745, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36426359

RESUMO

Accumulating evidence suggests that gut microbial dysbiosis is implicated in colorectal cancer (CRC) initiation and progression through interaction with host immune system. Given the intimate relationship between the gut microbiota and the antitumor immune responses, the microbiota has proven to be effective targets in modulating immunotherapy responses of preclinical CRC models. However, the proposed putative mechanisms of how these bacteria affect immune responses and immunotherapy efficacy remains obscure. In this review, we summarize recent findings of clinical gut microbial dysbiosis in CRC patients, the reciprocal interactions between gut microbiota and the innate and/or the adaptive immune system, as well as the effect of gut microbiota on immunotherapy response in CRC. Increased understanding of the gut microbiota-immune system interactions will benefit the rational application of microbiota to the clinical promising biomarker or therapeutic strategy as a cancer immunotherapy adjuvant.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Humanos , Disbiose/microbiologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/microbiologia , Imunidade , Imunoterapia
3.
PLoS One ; 17(11): e0262662, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36367873

RESUMO

Colorectal cancer (CRC) is the third most prevalent cause of tumorigenesis and several pathogenic bacteria have been correlated with aggressive cases of cancer i.e., genotoxin (colibactin) producing Escherichia coli (E. coli). This study was designed to investigate the genetic diversity of clb+clb+ E. coli strains and their association with CRC. Pathogenic E. coli isolates from colorectal biopsies were characterized based on phylotypes, antibiotic resistance pattern, and (Enterobacterial Repetitive Intergenic Consensus Sequence-based Polymerase Chain Reaction) ERIC-PCR. Furthermore, isolates were screened for the presence of the Pks (polyketide synthase) Island specifically targeting colibactin genes A and Q. The selective clb+clb+ isolates were subjected to cytotoxicity assay using Human embryonic kidney (HEK) cell lines. We revealed that 43.47% of the cancer-associated E. coli isolates were from phylogroup B2 comparatively more pathogenic than rest while in the case of healthy controls no isolate was found from B2. Moreover, 90% were found positive for colibactin and pks (polyketide synthase) island, while none of the healthy controls were found positive for colibactin genes. All healthy and cancer-associated isolates were tested against 15 antibiotic agents, we observed that cancer-associated isolates showed a wide range of resistance from 96% against Nalidixic acid to 48% against Doxycycline. Moreover, E. coli isolates were further genotyped using ERIC-PCR, and selected clb+clb+ E. coli isolates were subjected to cytotoxicity assay. We recorded the significant cytotoxic activity of clb+clb+ E. coli phylogroup B2 isolates that might have contributed towards the progression of CRC or dysbiosis of healthy gut microbiota protecting against CRC pathogenesis. Our results revealed a significant p<0.023 association of dietary habits and hygiene p<0.001with CRC. This is the first study to report the prevalence of E. coli phylogroups and the role of colibactin most virulent phylogroup B2 among Pakistani individuals from low socioeconomic setup.


Assuntos
Neoplasias Colorretais , Infecções por Escherichia coli , Policetídeos , Humanos , Escherichia coli/metabolismo , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Paquistão/epidemiologia , Policetídeos/metabolismo , Infecções por Escherichia coli/microbiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Variação Genética
4.
Front Cell Infect Microbiol ; 12: 925444, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189350

RESUMO

Colorectal cancer (CRC) is one of the most common malignant diseases. Generally, stoma construction is performed following surgery for the resection of the primary tumor in patients with CRC. The association of CRC with the gut microbiota has been widely reported, and the gut microbiota is known to play an important role in the carcinogenesis, progression, and treatment of CRC. In this study, we compared the microbiota of patients with CRC between with and without a stoma using fecal metagenomic sequencing data from SCRUM-Japan MONSTAR-SCREEN, a joint industry-academia cancer research project in Japan. We found that the composition of anaerobes was reduced in patients with a stoma. In particular, the abundance of Alistipes, Akkermansia, Intestinimonas, and methane-producing archaea decreased. We also compared gene function (e.g., KEGG Orthology and KEGG pathway) and found that gene function for methane and short-chain fatty acids (SCFAs) production was underrepresented in patients with a stoma. Furthermore, a stoma decreased Shannon diversity based on taxonomic composition but increased that of the KEGG pathway. These results suggest that the feces of patients with a stoma have a reduced abundance of favorable microbes for cancer immunotherapy. In conclusion, we showed that a stoma alters the taxonomic and functional profiles in feces and may be a confounding factor in fecal microbiota analysis.


Assuntos
Neoplasias Colorretais , Microbiota , Bactérias Anaeróbias/genética , Bactérias Anaeróbias/metabolismo , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/cirurgia , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Humanos , Metano , RNA Ribossômico 16S/genética
5.
Science ; 378(6618): 358-359, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36302018
6.
PLoS Pathog ; 18(10): e1010894, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36191045

RESUMO

Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. Previous work showed that this organism stimulates CRC cells proliferation and tumor growth. However, the molecular mechanisms underlying these activities are not well understood. Here, we found that Sgg upregulates the expression of several type of collagens in HT29 and HCT116 cells, with type VI collagen (ColVI) being the highest upregulated type. Knockdown of ColVI abolished the ability of Sgg to induce cell proliferation and reduced the adherence of Sgg to CRC cells. The extracellular matrix (ECM) is an important regulator of cell proliferation. Therefore, we further examined the role of decellularized matrix (dc-matrix), which is free of live bacteria or cells, in Sgg-induced cell proliferation. Dc-matrix prepared from Sgg-treated cells showed a significantly higher pro-proliferative activity than that from untreated cells or cells treated with control bacteria. On the other hand, dc-matrix from Sgg-treated ColVI knockdown cells showed no difference in the capacity to support cell proliferation compared to that from untreated ColVI knockdown cells, suggesting that the ECM by itself is a mediator of Sgg-induced cell proliferation. Furthermore, Sgg treatment of CRC cells but not ColVI knockdown CRC cells resulted in significantly larger tumors in vivo, suggesting that ColVI is important for Sgg to promote tumor growth in vivo. These results highlight a dynamic bidirectional interplay between Sgg and the ECM, where Sgg upregulates collagen expression. The Sgg-modified ECM in turn affects the ability of Sgg to adhere to host cells and more importantly, acts as a mediator for Sgg-induced CRC cell proliferation. Taken together, our results reveal a novel mechanism in which Sgg stimulates CRC proliferation through modulation of the ECM.


Assuntos
Neoplasias Colorretais , Streptococcus gallolyticus subspecies gallolyticus , Proliferação de Células , Colágeno Tipo VI , Neoplasias Colorretais/microbiologia , Matriz Extracelular/patologia , Humanos , Streptococcus gallolyticus subspecies gallolyticus/fisiologia
7.
Science ; 378(6618): eabm3233, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36302024

RESUMO

Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of an extensive collection of gut commensals from inflammatory bowel disease patients. We identified isolates from divergent phylogenies whose metabolites caused DNA damage and discovered a distinctive family of genotoxins-termed the indolimines-produced by the CRC-associated species Morganella morganii. A non-indolimine-producing M. morganii mutant lacked genotoxicity and failed to exacerbate colon tumorigenesis in mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease.


Assuntos
Neoplasias Colorretais , Dano ao DNA , Microbioma Gastrointestinal , Indóis , Doenças Inflamatórias Intestinais , Morganella morganii , Mutagênicos , Animais , Camundongos , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Morganella morganii/genética , Morganella morganii/isolamento & purificação , Morganella morganii/metabolismo , Indóis/metabolismo , Carcinogênese/genética , Humanos , Mutagênicos/metabolismo , Células HeLa
8.
NPJ Biofilms Microbiomes ; 8(1): 87, 2022 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-36307484

RESUMO

Perturbations in the gut microbiome have been associated with colorectal cancer (CRC), with the colonic overabundance of Fusobacterium nucleatum shown as the most consistent marker. Despite its significance in the promotion of CRC, genomic studies of Fusobacterium is limited. We enrolled 43 Vietnamese CRC patients and 25 participants with non-cancerous colorectal polyps to study the colonic microbiomes and genomic diversity of Fusobacterium in this population, using a combination of 16S rRNA gene profiling, anaerobic microbiology, and whole genome analysis. Oral bacteria, including F. nucleatum and Leptotrichia, were significantly more abundant in the tumour microbiomes. We obtained 53 Fusobacterium genomes, representing 26 strains, from the saliva, tumour and non-tumour tissues of six CRC patients. Isolates from the gut belonged to diverse F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and a potential new subspecies of Fusobacterium periodonticum. The Fusobacterium population within each individual was distinct and in some cases diverse, with minimal intra-clonal variation. Phylogenetic analyses showed that within four individuals, tumour-associated Fusobacterium were clonal to those isolated from non-tumour tissues. Genes encoding major virulence factors (Fap2 and RadD) showed evidence of horizontal gene transfer. Our work provides a framework to understand the genomic diversity of Fusobacterium within the CRC patients, which can be exploited for the development of CRC diagnostic and therapeutic options targeting this oncobacterium.


Assuntos
Neoplasias Colorretais , Microbiota , Humanos , RNA Ribossômico 16S/genética , Filogenia , Fusobacterium/genética , Genômica , Neoplasias Colorretais/microbiologia , Asiáticos
9.
World J Gastroenterol ; 28(30): 4053-4060, 2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36157114

RESUMO

The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn's disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of Firmicute sand Bacteroidetes. Specific bacteria are also associated with the onset and progression of CRC, such as Fusobacterium nucleatum, E. coli, Enterococcus faecalis, Streptococcus gallolyticus, and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Bactérias , Bacteroides fragilis , Neoplasias Colorretais/microbiologia , Disbiose/complicações , Disbiose/microbiologia , Escherichia coli , Humanos , Inflamação/complicações , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/microbiologia , Qualidade de Vida , Areia
10.
World J Gastroenterol ; 28(27): 3370-3382, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-36158273

RESUMO

Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative "drug-free" cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive in vitro, animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions via the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.


Assuntos
Produtos Biológicos , Neoplasias Colorretais , Terapias Complementares , Probióticos , Animais , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/prevenção & controle , Disbiose/microbiologia , Humanos , Prebióticos , Probióticos/uso terapêutico
11.
Gut Microbes ; 14(1): 2100203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35877697

RESUMO

The gut microbiome is a vast reservoir of microbes, some of which produce antimicrobial peptides called bacteriocins that may inhibit specific bacteria associated with disease. Fusobacterium nucleatum is an emerging human bacterial pathogen associated with gastrointestinal diseases including colorectal cancer (CRC). In this study, fecal samples of healthy donors were screened for potential bacteriocin-producing probiotics with antimicrobial activity against F. nucleatum. A novel isolate, designated as Streptococcus salivarius DPC6993 demonstrated a narrow-spectrum of antimicrobial activity against F. nucleatum in vitro. In silico analysis of the S. salivarius DPC6993 genome revealed the presence of genes involved in the production of the bacteriocins salivaricin A5 and salivaricin B. After 6 h in a colon fermentation model, there was a significant drop in the number of F. nucleatum in samples that had been simultaneously inoculated with S. salivarius DPC6993 + F. nucleatum DSM15643 compared to those inoculated with F. nucleatum DSM15643 alone (mean ± SD: 9243.3 ± 3408.4 vs 29688.9 ± 4993.9 copies/µl). Furthermore, 16S rRNA amplicon analysis revealed a significant difference in the mean relative abundances of Fusobacterium between samples inoculated with both S. salivarius DPC6993 and F. nucleatum DSM15643 (0.05%) and F. nucleatum DSM15643 only (0.32%). Diversity analysis indicated minimal impact exerted by S. salivarius DPC6993 on the surrounding microbiota. Overall, this study highlights the ability of a natural gut bacterium to target a bacterial pathogen associated with CRC. The specific targeting of CRC-associated pathogens by biotherapeutics may ultimately reduce the risk of CRC development and positively impact CRC outcomes.


Assuntos
Anti-Infecciosos , Bacteriocinas , Neoplasias Colorretais , Microbioma Gastrointestinal , Streptococcus salivarius , Colo , Neoplasias Colorretais/microbiologia , Fusobacterium nucleatum/genética , Humanos , RNA Ribossômico 16S
12.
Ann Clin Biochem ; 59(6): 396-403, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821582

RESUMO

BACKGROUND: Although faecal DNA testing of Fusobacterium nucleatum (Fn) is expected to be useful for colorectal neoplasia detection, there is no standardized quantification method of Fn. We performed this study to establish a possible standardized method. METHODS: In this study, 322 participants including 71 subjects without colorectal neoplasia (control group), 31 patients with non-advanced colorectal adenoma, 93 patients with advanced colorectal adenoma, and 127 patients with colorectal cancer were enrolled. Faecal Fn were quantified by droplet digital PCR (ddPCR) using two PCR primer-probe sets reported previously that are tentatively named Fn1 and Fn2. Fn1 has been used in ddPCR by us and Fn2 has been widely used in quantitative real-time PCR. RESULTS: The Fn copy number using Fn1 was five times higher than that using Fn2, with a linear relationship shown between them. Receiver operating characteristic curve analysis showed the area under the curve (AUC) to be almost the same between Fn1 and Fn2 in discriminating between the control group and the colorectal cancer group (AUC = 0.81 and 0.81, respectively), and between the control/non-advanced colorectal adenoma group and the advanced colorectal adenoma/colorectal cancer group (AUC = 0.74 and 0.74, respectively). CONCLUSIONS: As the diagnostic performance was quite similar between Fn1 and Fn2, ddPCR-based Fn testing using Fn1 and Fn2 could be a possible standardized method for a colorectal neoplasia screening test, considering that Fn levels quantified by Fn1 are about five times higher than those by Fn2.


Assuntos
Adenoma , Neoplasias Colorretais , Humanos , Fusobacterium nucleatum/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Fezes/microbiologia , Adenoma/diagnóstico , Adenoma/genética , Adenoma/microbiologia , Reação em Cadeia da Polimerase em Tempo Real
13.
Sci Rep ; 12(1): 11424, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794137

RESUMO

The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL, GSDMD and LY6H was correlated with the abundance of Bacteroides, which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Microbiota , Bactérias/genética , Bacteroides/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Faecalibacterium/genética , Microbioma Gastrointestinal/genética , Humanos , RNA Ribossômico 16S/genética , Microambiente Tumoral
14.
BMC Gastroenterol ; 22(1): 313, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35752764

RESUMO

BACKGROUND: Gut pathological microbial imbalance or dysbiosis is closely associated with colorectal cancer. Although there are observable differences in molecular and clinical characteristics between patients with right- and left-sided colon cancer, differences in their gut microbiomes have not been thoroughly investigated. Furthermore, subsequent changes in microbiota status after partial colectomy remain unknown. We examined the human gut microbiota composition to determine its relationship with colon cancer and partial colon resection according to location. METHODS: Stool samples from forty-one subjects (10 in the control group, 10 in the right-sided colon cancer [RCC] group, 6 in the sigmoid colon cancer [SCC] group, 9 in the right colon resection [RCR] group and 6 in the sigmoid colon resection [SCR] group) were collected, and DNA was extracted. After terminal restriction fragment length polymorphism (T-RFLP) analysis, the samples were subjected to 16S rRNA gene amplicon sequencing, and the metabolic function of the microbiota was predicted using PICRUSt2. RESULTS: T-RFLP analysis showed a reduced ratio of clostridial cluster XIVa in the SCC patients and clostridial cluster IX in the RCC patients, although these changes were not evident in the RCR or SCR patients. 16S rRNA gene amplicon sequencing demonstrated that the diversity of the gut microbiota in the RCC group was higher than that in the control group, and the diversity in the SCR group was significantly higher than that in the RCR group. Principal coordinate analysis (PCoA) revealed significant differences according to the group. Analyses of the microbiota revealed that Firmicutes was significantly dominant in the RCC group and that the SCC group had a higher abundance of Verrucomicrobia. At the genus level, linear discriminant analysis effect size (LEfSe) revealed several bacteria, such as Ruminococcaceae, Streptococcaceae, Clostridiaceae, Gemellaceae, and Desulfovibrio, in the RCC group and several oral microbiomes in the SCC group. Metabolic function prediction revealed that cholesterol transport- and metabolism-related enzymes were specifically upregulated in the RCC group and that cobalamin metabolism-related enzymes were downregulated in the SCC group. CONCLUSION: Gut microbial properties differ between RCC and SCC patients and between right hemicolectomy and sigmoidectomy patients and may contribute to clinical manifestations.


Assuntos
Carcinoma de Células Renais , Neoplasias do Colo , Neoplasias Colorretais , Microbioma Gastrointestinal , Neoplasias Renais , Carcinoma de Células Renais/genética , Colectomia , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/cirurgia , Microbioma Gastrointestinal/genética , Genes de RNAr , Humanos , Neoplasias Renais/genética , RNA Ribossômico 16S/genética
15.
Front Cell Infect Microbiol ; 12: 830684, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663463

RESUMO

Background: There is no information on the commonality and specificity of oral and fecal microbiota in patients with gastric cancer (GC) and colorectal cancer (CRC). Methods: The high-throughput 16S rRNA gene V4 region sequencing was used to perform bioinformatics analysis of oral, fecal, and tissue microbiota in GC (76 subjects), CRC (53), and healthy controls (HC, 70). Furthermore, we determined the microbial characteristics of each part, constructed and verified three classifiers for GC and CRC, and evaluated curves of receiver operating characteristic and precision-recall with probability of disease. Results: Compared to HC, the microbial richness and diversity of GC and CRC decreased in oral cavity and increased in stool; additionally, these indexes in GC tissue were higher than those in CRC tissue. In GC and CRC patients, Haemophilus, Neisseria, Faecalibacterium, and Romboutsia were significantly reduced compared to the relative abundance value of oral or fecal bacterial genera in the HC group, while the Streptococcus, Gemella, Escherichia-Shigella, and Fusobacterium were significantly increased. The oral and tissue microbiota have similar and abundant shared bacterial networks. The single and combined microbial detection have good AUC values based on POD indices for predicting GC, CRC, and gastrointestinal (GI) cancers (GC and CRC). Conclusion: This study is the first to examine the characteristics of oral, fecal, and tumor microbiota in GC and CRC patients, and the similarities and differences in their microbial changes are reported. These oral or fecal bacteria (Haemophilus, Neisseria, Faecalibacterium, Romboutsia, Streptococcus, Gemella, Escherichia-Shigella, and Fusobacterium) may be involved in tumor evolution as potentially characteristic genera. In addition, both oral and fecal microbial detection may provide a solid theoretical foundation for the non-invasive prediction of these cancers.


Assuntos
Neoplasias Colorretais , Microbiota , Neoplasias Gástricas , Bactérias/genética , Biomarcadores , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/microbiologia , Fezes/microbiologia , Fusobacterium/genética , Humanos , Microbiota/genética , RNA Ribossômico 16S/genética , Neoplasias Gástricas/diagnóstico
16.
Phytomedicine ; 103: 154227, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35679795

RESUMO

BACKGROUND: A growing body of evidence reveals that dysregulation of Hedgehog signaling pathway and dysbiosis of gut microbiota are associated with the pathogenesis of colorectal cancer (CRC). Berberine, a botanical benzylisoquinoline alkaloid, possesses powerful activities against various malignancies including CRC, with the underlying mechanisms to be illuminated. PURPOSE: The present study investigated the potencies of berberine on CRC and deciphered the action mechanisms in the context of Hedgehog signaling cascade and gut microbiota. METHODS: The effects of berberine on the malignant phenotype, apoptosis, cell cycle and Hedgehog signaling of CRC cells were examined in vitro. In azoxymethane/dextran sulfate sodium-caused mouse CRC, the efficacies of berberine on the carcinogenesis, pathological profile, apoptosis, cell cycle and Hedgehog signaling were determined in vivo. Also, the influences of berberine on gut microbiota in CRC mice were assessed by high-throughput DNA sequencing analysis of 16S ribosomal RNA of fecal microbiome in CRC mice. RESULTS: In the present study, berberine was found to dampen the proliferation, migration, invasion and colony formation of CRC cells, without toxicity to normal colonic cells. Additionally, berberine induced apoptosis and arrested cell cycle at G0/G1 phase in CRC cells, accompanied by reduced Hedgehog signaling pathway activity in vitro. In mouse CRC, berberine suppressed tumor growth, ameliorated pathological manifestations, and potentially induced the apoptosis and cell cycle arrest of CRC, with lowered Hedgehog signaling cascade in vivo. Additionally, berberine decreased ß-diversity of gut microbiota in CRC mice, without influence on α-diversity. Berberine also enriched probiotic microbes and depleted pathogenic microbes, and modulated the functionality of gut microbiota in CRC mice. CONCLUSIONS: Overall, berberine may suppress colorectal cancer, orchestrated by down-regulation of Hedgehog signaling pathway activity and modulation of gut microbiota.


Assuntos
Berberina , Neoplasias Colorretais , Microbioma Gastrointestinal , Animais , Azoximetano , Berberina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos
17.
Front Cell Infect Microbiol ; 12: 804689, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493741

RESUMO

Although a dysfunctional gut microbiome is strongly linked to colorectal cancer (CRC), our knowledge of the mediators between CRC and the microbiome is limited. MicroRNAs (miRNAs) affect critical cellular processes, such as apoptosis, proliferation, and differentiation, and contribute to the regulation of CRC progression. Increasingly, studies found that miRNAs can significantly mediate bidirectional interactions between the host and the microbiome. Notably, miRNA expression is regulated by the gut microbiome, which subsequently affects the host transcriptome, thereby influencing the development of CRC. This study typically focuses on the specific functions of the microbiome in CRC and their effect on CRC-related miRNA production and reviews the role of several bacteria on miRNA, including Fusobacterium nucleatum, Escherichia coli, enterotoxigenic Bacteroides fragilis, and Faecalibacterium prausnitzii. Based on the important roles of miRNAs and the gut microbiome in CRC, strategies for modulating miRNA expression and regulating the gut microbiome composition need to be applied, such as bioactive dietary components and fecal microorganism transplantation.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , MicroRNAs , Neoplasias Colorretais/microbiologia , Faecalibacterium prausnitzii , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiologia , Humanos , MicroRNAs/genética
18.
Microbiol Spectr ; 10(3): e0105522, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35587635

RESUMO

Enterotoxigenic Bacteroides fragilis (ETBF) is consistently found at higher frequency in individuals with sporadic and hereditary colorectal cancer (CRC) and induces tumorigenesis in several mouse models of CRC. However, whether specific mutations induced by ETBF lead to colon tumor formation has not been investigated. To determine if ETBF-induced mutations impact the Apc gene, and other tumor suppressors or proto-oncogenes, we performed whole-exome sequencing and whole-genome sequencing on tumors isolated after ETBF and sham colonization of Apcmin/+ and Apcmin/+Msh2fl/flVC mice, as well as whole-genome sequencing of organoids cocultured with ETBF. Our results indicate that ETBF-induced tumor formation results from loss of heterozygosity (LOH) of Apc, unless the mismatch repair system is disrupted, in which case, tumor formation results from new acquisition of protein-truncating mutations in Apc. In contrast to polyketide synthase-positive Escherichia coli (pks+ E. coli), ETBF does not produce a unique mutational signature; instead, ETBF-induced tumors arise from errors in DNA mismatch repair and homologous recombination DNA damage repair, established pathways of tumor formation in the colon, and the same genetic mechanism accounting for sham tumors in these mouse models. Our analysis informs how this procarcinogenic bacterium may promote tumor formation in individuals with inherited predispositions to CRC, such as Lynch syndrome or familial adenomatous polyposis (FAP). IMPORTANCE Many studies have shown that microbiome composition in both the mucosa and the stool differs in individuals with sporadic and hereditary colorectal cancer (CRC). Both human and mouse models have established a strong association between particular microbes and colon tumor induction. However, the genetic mechanisms underlying putative microbe-induced colon tumor formation are not well established. In this paper, we applied whole-exome sequencing and whole-genome sequencing to investigate the impact of ETBF-induced genetic changes on tumor formation. Additionally, we performed whole-genome sequencing of human colon organoids exposed to ETBF to validate the mutational patterns seen in our mouse models and begin to understand their relevance in human colon epithelial cells. The results of this study highlight the importance of ETBF colonization in the development of sporadic CRC and in individuals with hereditary tumor conditions, such as Lynch syndrome and familial adenomatous polyposis (FAP).


Assuntos
Polipose Adenomatosa do Colo , Infecções Bacterianas , Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Infecções Bacterianas/patologia , Bacteroides fragilis/genética , Bacteroides fragilis/metabolismo , Colo/microbiologia , Neoplasias do Colo/genética , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Modelos Animais de Doenças , Escherichia coli/genética , Genes APC , Camundongos , Mutação
19.
Arch Microbiol ; 204(6): 348, 2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35616767

RESUMO

Human microbiome studies have shown diversity to exist among different ethnic populations. However, studies pertaining to the microbial composition of CRC among the Indian population have not been well explored. We aimed to decipher the microbial signature in tumor tissues from North Indian CRC patients. Next-generation sequencing of tumor and adjacent tissue-derived bacterial 16S rRNA V3-V4 hypervariable regions was performed to investigate the abundance of specific microbes. The expression profile analysis deciphered a decreased diversity among the tumor-associated microbial communities. At the phyla level, Proteobacteria was differentially expressed in CRC tissues than adjacent normal. Further, DeSeq2 normalization identified 4 out of 79 distinct species (p < 0.005) only in CRC, Bacteroides massiliensis, Alistipes onderdonkii, Bifidobacterium pseudocatenulatum, and Corynebacterium appendicis. Thus, the findings suggest that microbial signatures can be used as putative biomarkers in diagnosis, prognosis and treatment management of CRC.


Assuntos
Bifidobacterium pseudocatenulatum , Neoplasias Colorretais , Microbioma Gastrointestinal , Bactérias/genética , Bacteroides , Bacteroidetes , Bifidobacterium pseudocatenulatum/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/microbiologia , Corynebacterium , Microbioma Gastrointestinal/genética , Humanos , RNA Ribossômico 16S/genética
20.
Gut ; 71(12): 2439-2450, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35387878

RESUMO

OBJECTIVE: Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites. DESIGN: Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice. RESULTS: Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal­regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium. CONCLUSION: The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.


Assuntos
Fumar Cigarros , Neoplasias Colorretais , Microbioma Gastrointestinal , Animais , Camundongos , Microbioma Gastrointestinal/fisiologia , Disbiose/microbiologia , Fumar Cigarros/efeitos adversos , Camundongos Endogâmicos C57BL , Carcinogênese , Neoplasias Colorretais/microbiologia
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