RESUMO
BACKGROUND: The research aims to explore the characteristics of intestinal flora, nutritional status and immune function in patients with different types of obese colon cancer. METHODS: A retrospective analysis is conducted on 64 cases of obese colon cancer diagnosed from June 2018 to January 2020. According to the histological staging of the cancer, they are classified into adenocarcinoma, adenosquamous carcinoma and undifferentiated carcinoma, with corresponding cases of 24, 22 and 18, respectively. The intestinal flora (Bifidobacterium, Lactobacillus, Enterococcus faecalis, Escherichia coli, and yeast), nutritional status (Hb, Alb, PA, TFN, and PNI), immune function (IgG, IgM, IgA, CD4+, CD8+, and CD4+/CD8+) are analyzed in the different groups of patients. Survival curves are evaluated by Kaplan-Meier method and log-rank test for tumour death, local recurrence, and distant metastasis. RESULTS: There were no statistically significant differences in intestinal flora (Bifidobacterium, Lactobacillus, Enterococcus faecalis, Escherichia coli, and yeast), nutritional status (Hb, Alb, PA, TFN, and PNI) and immune function (IgG, IgM, IgA, CD4+, CD8+, and CD4+/CD8+) between different groups. There was a significant correlation between intestinal flora, nutritional status and immune function for all three. The survival curves of tumour death, local recurrence and distant metastasis in different groups of obese colon cancer patients were statistically significant. The tumor mortality rate, local recurrence, and distant metastasis rate in adenocarcinoma were 78.65%, 54.25% and 48.26% respectively. CONCLUSION: There are differences in intestinal flora, nutritional status and immune function among different types of obese colon cancer patients, but adenocarcinoma has the least benefit in intestinal flora, poor nutritional status, and weakest immune function.
Assuntos
Neoplasias do Colo , Microbioma Gastrointestinal , Estado Nutricional , Obesidade , Humanos , Microbioma Gastrointestinal/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias do Colo/imunologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Obesidade/complicações , Obesidade/imunologia , Idoso , Adenocarcinoma/imunologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , AdultoRESUMO
Recently, an increased number of reports have described pathogens of animal origin that cause a variety of infections and a rise in their transmission to humans. Streptococcus gallolyticus, a member of the Streptococcus bovis/Streptococcus equinus complex (SBSEC), is one of these pathogens and infects a wide range of hosts from mammals to poultry and has a broad functionality ranging from pathogenicity to food fermentation. As S. gallolyticus causes complications including bacteremia, infective endocarditis, and colorectal malignancy in humans, it is important to investigate its occurrence in various hosts, including geese, to prevent potential zoonotic transmissions. This study aimed to investigate the presence of S. gallolyticus in the droppings of clinically healthy and diarrheic geese, which were raised intensively and semi-intensively, by the in vitro culture method, characterize the isolates recovered by PCR and sequence-based molecular methods and determine their antibiotic susceptibility by the disk diffusion and gradient test methods. For this purpose, 150 samples of fresh goose droppings were used. Culture positivity for S. gallolyticus was determined as 8% (12/150). PCR analysis identified 54.55% (n = 6) of the isolates as S. gallolyticus subsp. gallolyticus and 45.45% (n = 5) as S. gallolyticus subsp. pasteurianus. Following the 16S rRNA sequence and ERIC-PCR analyses, S. gallolyticus subspecies exhibited identical cluster and band profiles that could be easily distinguished from each other and were clonally identified. High rates of susceptibility to florfenicol, penicillin, rifampicin, and vancomycin were detected among the isolates, regardless of the subspecies diversity. Both subspecies showed high levels of resistance to bacitracin, clindamycin, doxycycline, tetracycline, trimethoprim-sulfamethoxazole, and erythromycin and multiple MDR profiles, indicating their potential to become superbugs. This first report from Türkiye demonstrates the occurrence of the S. gallolyticus subspecies in geese. In view of the recent increase of geese production and the consumption of goose meat in Türkiye, the occurrence of S. gallolyticus in geese should not be ignored to prevent zoonotic transmission.
Assuntos
Reservatórios de Doenças , Gansos , Doenças das Aves Domésticas , Infecções Estreptocócicas , Streptococcus gallolyticus , Animais , Gansos/microbiologia , Streptococcus gallolyticus/genética , Infecções Estreptocócicas/veterinária , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/transmissão , Doenças das Aves Domésticas/microbiologia , Doenças das Aves Domésticas/transmissão , Reservatórios de Doenças/microbiologia , Reservatórios de Doenças/veterinária , Neoplasias do Colo/microbiologia , Neoplasias do Colo/veterinária , Humanos , Fezes/microbiologia , Antibacterianos/farmacologiaRESUMO
Cancer immunotherapy has been regarded as a promising strategy for cancer therapy by blocking immune checkpoints and evoking immunity to fight cancer, but its efficacy seems to be heterogeneous among patients. Manipulating the gut microbiota is a potential strategy for enhancing the efficacy of immunotherapy. Here, we report that MS-20, also known as "Symbiota®", a postbiotic that comprises abundant microbial metabolites generated from a soybean-based medium fermented with multiple strains of probiotics and yeast, inhibited colon and lung cancer growth in combination with an anti-programmed cell death 1 (PD1) antibody in xenograft mouse models. Mechanistically, MS-20 remodeled the immunological tumor microenvironment by increasing effector CD8+ T cells and downregulating PD1 expression, which were mediated by the gut microbiota. Fecal microbiota transplantation (FMT) from mice receiving MS-20 treatment to recipient mice increased CD8+ T-cell infiltration into the tumor microenvironment and significantly improved antitumor activity when combined with anti-PD1 therapy. Notably, the abundance of Ruminococcus bromii, which increased following MS-20 treatment, was positively associated with a reduced tumor burden and CD8+ T-cell infiltration in vivo. Furthermore, an ex vivo study revealed that MS-20 could alter the composition of the microbiota in cancer patients, resulting in distinct metabolic pathways associated with favorable responses to immunotherapy. Overall, MS-20 could act as a promising adjuvant agent for enhancing the efficacy of immune checkpoint-mediated antitumor therapy.
Assuntos
Linfócitos T CD8-Positivos , Microbioma Gastrointestinal , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Animais , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Humanos , Microambiente Tumoral/imunologia , Linfócitos T CD8-Positivos/imunologia , Transplante de Microbiota Fecal , Linhagem Celular Tumoral , Probióticos/administração & dosagem , Probióticos/farmacologia , Imunoterapia , Feminino , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/microbiologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro- and anti-tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA-producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial-derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)-induced proliferation and interleukin-6 (IL-6) expression in these cells. Gene expression correlations were assessed using the "Cancer Exploration" suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase-2 and IL-6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti-tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.
Assuntos
Proliferação de Células , Neoplasias do Colo , Microbioma Gastrointestinal , Receptores de GABA-A , Receptores de GABA-B , Transdução de Sinais , Ácido gama-Aminobutírico , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Ácido gama-Aminobutírico/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-B/metabolismo , Dinoprostona/metabolismo , Glutamato Descarboxilase/metabolismo , Interleucina-6/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Carcinogênese , Fezes/microbiologia , Receptores de GABA/metabolismo , Receptores de GABA/genética , Masculino , Camundongos Endogâmicos C57BL , FemininoRESUMO
BACKGROUND: The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent. The gut microbiota contributes to colorectal carcinogenesis (CRC), as demonstrated with colibactin-producing Escherichia coli (CoPEC). AIM: To evaluate the association between CoPEC prevalence and anxiety- and depressive-like behaviors with both preclinical and clinical approaches. METHODS: Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview. Results were compared according to the CoPEC colonization. In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain. Their behavior was assessed using the Elevated Plus Maze test, the Forced Swimming Test and the Behavior recognition system PhenoTyper®. RESULTS: In a limited cohort, all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis, whereas only one patient (17%) without CoPEC did. This result was confirmed in C57BL6/J wild-type mice and in a CRC susceptibility mouse model (adenomatous polyposis colimultiple intestinal neoplasia/+). Mice exhibited a significant increase in anxiety- and depressive-like behaviors after chronic infection with a CoPEC strain. CONCLUSION: This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.
Assuntos
Ansiedade , Depressão , Modelos Animais de Doenças , Infecções por Escherichia coli , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Peptídeos , Policetídeos , Animais , Humanos , Masculino , Policetídeos/metabolismo , Depressão/psicologia , Depressão/microbiologia , Ansiedade/psicologia , Ansiedade/microbiologia , Ansiedade/etiologia , Camundongos , Feminino , Idoso , Pessoa de Meia-Idade , Infecções por Escherichia coli/psicologia , Infecções por Escherichia coli/microbiologia , Peptídeos/metabolismo , Escherichia coli/isolamento & purificação , Neoplasias do Colo/psicologia , Neoplasias do Colo/microbiologia , Prevalência , Eixo Encéfalo-IntestinoRESUMO
Gut bacterial dysbiosis has been linked to several gastrointestinal diseases, including deadly colorectal cancer (CRC), a leading cause of mortality in cancer patients. However, perturbation in gut bacteriome during colon cancer (CC, devoid of colorectal malignancy) remains poorly explored. Here, 16S rRNA gene amplicon sequencing was carried out for fecal DNA samples targeted to hypervariable V3-V4 region by employing MiSeq platform to explore the gut bacterial community shift in CC patients. While alpha diversity indices predicted high species richness and diversity, beta diversity showed marked gut bacterial compositional dissimilarity in CC versus healthy controls (HC, n = 10 each). We observed a significant (p < 0.05, Wilcoxon Rank-Sum test) emergence of low-abundant anaerobic taxa, including Parvimonas and Peptostreptococcus, in addition to Subdoligranulum, Coprococcus, Holdemanella, Solobacterium, Bilophila, Blautia, Dorea, Moryella and several unidentified taxa, mainly affiliated to Firmicutes, in CC patients. In addition, we also traced the emergence of putative probiotic taxon Slackia, belonging to Actinomycetota, in CC patients. The emergence of anaerobic Firmicutes in CC is accompanied by a significant (p < 0.05) decline in the Klebsiella, as determined through linear discriminant analysis effect size (LEfSe) and heat tree analyses. Shifts in core microbiome and variation in network correlation were also witnessed. Taken together, this study highlighted a significant and consistent emergence of rare anaerobic Firmicutes suggesting possible anaerobiosis driving gut microbial community shift, which could be exploited in designing diagnostic and therapeutic tools targeted to CC.
Assuntos
Neoplasias do Colo , Disbiose , Fezes , Firmicutes , Microbioma Gastrointestinal , Klebsiella , RNA Ribossômico 16S , Humanos , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Neoplasias do Colo/microbiologia , Klebsiella/genética , Klebsiella/isolamento & purificação , Klebsiella/classificação , Fezes/microbiologia , Firmicutes/genética , Firmicutes/isolamento & purificação , Firmicutes/classificação , Disbiose/microbiologia , Masculino , Feminino , DNA Bacteriano/genética , Pessoa de Meia-Idade , Idoso , Filogenia , AnaerobioseRESUMO
Escherichia coli that harbor the polyketide synthase (pks) genomic island produce colibactin and are associated with sporadic colorectal cancer development. Given the considerable prevalence of pks+ bacteria in healthy individuals, we sought to identify strategies to limit the growth and expansion of pks+ E. coli. We found that culture supernatants of the probiotic strain E. coli Nissle 1917 were able to inhibit the growth of the murine pathogenic strain pks+ E. coli NC101 (EcNC101). We performed a nontargeted analysis of the metabolome in supernatants from several E. coli strains and identified putrescine as a potential postbiotic capable of suppressing EcNC101 growth in vitro. The effect of putrescine supplementation was then evaluated in the azoxymethane/dextran sulfate sodium mouse model of colorectal cancer in mice colonized with EcNC101. Putrescine supplementation inhibited the growth of pks+ E. coli, reduced the number and size of colonic tumors, and downmodulated the release of inflammatory cytokines in the colonic lumen. Additionally, putrescine supplementation led to shifts in the composition and function of gut microbiota, characterized by an increase in the Firmicutes/Bacteroidetes ratio and enhanced acetate production. The effect of putrescine was further confirmed in vitro using a pks+ E. coli strain isolated from a patient with colorectal cancer. These results suggest that probiotic-derived metabolites can be used as an alternative to live bacteria in individuals at risk of developing colorectal cancer due to the presence of pks+ bacteria in their colon. SIGNIFICANCE: Putrescine supplementation inhibits the growth of cancer-promoting bacteria in the gut, lowers inflammation, and reduces colon cancer development. The consumption of healthy foods rich in putrescine may be a potential prophylactic approach for individuals at risk of developing colorectal cancer due to the presence of pks+ bacteria in their colon.
Assuntos
Escherichia coli , Microbioma Gastrointestinal , Policetídeo Sintases , Putrescina , Putrescina/farmacologia , Putrescina/metabolismo , Animais , Escherichia coli/efeitos dos fármacos , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Policetídeo Sintases/metabolismo , Policetídeo Sintases/genética , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Humanos , Probióticos/farmacologia , Probióticos/administração & dosagem , Probióticos/uso terapêutico , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Suplementos Nutricionais , Policetídeos/farmacologia , Policetídeos/metabolismo , Modelos Animais de Doenças , Ilhas Genômicas , Colo/microbiologia , Colo/patologia , Colo/metabolismo , Colo/efeitos dos fármacos , Azoximetano , PeptídeosRESUMO
AIMS: Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation. METHODS AND RESULTS: C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16â s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice. CONCLUSION: We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.
Assuntos
Colo , Modelos Animais de Doenças , Disbiose , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Insuficiência Cardíaca , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Animais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/microbiologia , Insuficiência Cardíaca/microbiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/etiologia , Masculino , Colo/microbiologia , Colo/patologia , Ribotipagem , Neoplasias do Colo/patologia , Neoplasias do Colo/microbiologia , Bactérias/genética , Fezes/microbiologia , Interações Hospedeiro-PatógenoRESUMO
pks+ Escherichia coli (E. coli) triggers genomic instability in normal colon cells which leads to colorectal cancer (CRC) tumorigenesis. Previously, we reported a significant presentation of pks+ E. coli strains in CRC patients' biopsies as compared to healthy cohorts. In this work, using an in vitro infection model, we further explored the ability of these strains in modulating cell cycle arrest and activation of apoptotic mediators in both primary colon epithelial cells (PCE) and CRC cells (HCT-116). Sixteen strains, of which eight tumours and the matching non-malignant tissues, respectively, from eight pks+ E. coli CRC patients were subjected to BrDU staining and cell cycle analysis via flow cytometry, while a subset of these strains underwent analysis of apoptotic mediators including caspase proteins, cellular reactive oxygen species (cROS) and mitochondrial membrane potential (MMP) via spectrophotometry as well as proinflammatory cytokines via flow cytometry. Data revealed that all strains exerted S-phase cell cycle blockade in both cells and G2/M phase in PCE cells only. Moreover, more significant upregulation of Caspase 9, cROS, proinflammatory cytokines and prominent downregulation of MMP were detected in HCT-116 cells indicating the potential role of pks related bacterial toxin as anticancer agent as compared to PCE cells which undergo cellular senescence leading to cell death without apparent upregulation of apoptotic mediators. These findings suggest the existence of discrepancies underlying the mechanism of action of pks+ E. coli on both cancer and normal cell lines. This work propounds the rationale to further understand the mechanism underlying pks+ E. coli-mediated CRC tumorigenesis and cancer killing.
Assuntos
Neoplasias do Colo , Escherichia coli , Humanos , Escherichia coli/genética , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Apoptose , Carcinogênese , Citocinas , Linhagem Celular Tumoral , Ciclo CelularRESUMO
The intestinal microbiota plays an important role in colorectal cancer (CRC) progression. However, the effect of tissue-resident commensal bacteria on CRC immune surveillance remains poorly understood. Here, we analyzed the intratissue bacteria from CRC patient colon tissues. We found that the commensal bacteria belonging to the Lachnospiraceae family, including Ruminococcus gnavus (Rg), Blautia producta (Bp), and Dorea formicigenerans (Df), were enriched in normal tissues, while Fusobacterium nucleatum (Fn) and Peptostreptococcus anaerobius (Pa) were abundant in tumor tissues. Tissue-resident Rg and Bp reduced colon tumor growth and promoted the activation of CD8+ T cells in immunocompetent mice. Mechanistically, intratissue Rg and Bp degraded lyso-glycerophospholipids that inhibited CD8+ T cell activity and maintained the immune surveillance function of CD8+ T cells. Lyso-glycerophospholipids alone promoted tumor growth that was abrogated with Rg and Bp injection. Collectively, intratissue Lachnospiraceae family bacteria facilitate the immune surveillance function of CD8+ T cells and control colorectal cancer progression.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Animais , Camundongos , Neoplasias Colorretais/microbiologia , Linfócitos T CD8-Positivos , Carcinogênese , Neoplasias do Colo/microbiologia , Fusobacterium nucleatumRESUMO
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 , MutaçãoRESUMO
Faecal (FM) and colon mucosal associated microbiota (MAM) were studied in a model of colorectal cancer (CRC), the Apc-mutated Pirc rats, and in age-paired wt F344 rats. Principal Coordinates Analysis indicated that samples' distribution was driven by age, with samples of young rats (1 month old; without tumours) separated from older ones (11-month-old; bearing tumours). Diversity analysis showed significant differences between FM and MAM in older Pirc rats, and between MAM of both Pirc and wt rats and the tumour microbiota, enriched in Enterococcus, Escherichia/Shigella, Proteus and Bifidobacteriaceae. In young animals, Pirc FM was enriched in the genus Delftia, while wt FM was enriched in Lactobacillus and Streptococcus. Some CRC biomarkers and faecal short chain fatty acids (SCFAs) were also measured. Colon proliferation and DClK1 expression, a pro-survival mucosal marker, were higher in Pirc than in wt rats, while the mucin MUC2, was lower in Pirc rats. Branched SCFAs were higher in Pirc than in wt animals. By Spearman analysis CRC biomarkers correlated with FM (in both young and old rats) and with MAM (in young rats), suggesting a specific relationship between the gut microbiota profile and these functional mucosal parameters deserving further investigation.
Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Colo/microbiologia , Neoplasias do Colo/genética , Quinases Semelhantes a Duplacortina/genética , Mucina-2/genética , Fatores Etários , Animais , Bifidobacterium/crescimento & desenvolvimento , Bifidobacterium/isolamento & purificação , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Colo/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Quinases Semelhantes a Duplacortina/metabolismo , Enterococcus/crescimento & desenvolvimento , Enterococcus/isolamento & purificação , Escherichia/crescimento & desenvolvimento , Escherichia/isolamento & purificação , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Regulação da Expressão Gênica , Lactobacillus/crescimento & desenvolvimento , Lactobacillus/isolamento & purificação , Masculino , Mucina-2/metabolismo , Análise de Componente Principal , Proteus/crescimento & desenvolvimento , Proteus/isolamento & purificação , Ratos , Ratos Endogâmicos F344 , Shigella/crescimento & desenvolvimento , Shigella/isolamento & purificação , Streptococcus/crescimento & desenvolvimento , Streptococcus/isolamento & purificaçãoRESUMO
OBJECTIVE: In this study, we determined whether Helicobacter pylori (H. pylori) infection dampens the efficacy of cancer immunotherapies. DESIGN: Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of H. pylori-infected mice. In humans, we evaluated the correlation between H. pylori seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC). RESULTS: In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8+ T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8+ T cell proliferation. We performed retrospective human clinical studies in two independent cohorts. In the Dijon cohort, H. pylori seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy. The survival median for H. pylori seropositive patients was 6.7 months compared with 15.4 months for seronegative patients (p=0.001). Additionally, in the Montreal cohort, H. pylori seropositivity was found to be associated with an apparent decrease of NSCLC patient progression-free survival on anti-PD-1 therapy. CONCLUSION: Our study unveils for the first time that the stomach microbiota affects the response to cancer immunotherapies and that H. pylori serology would be a powerful tool to personalize cancer immunotherapy treatment.
Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Infecções por Helicobacter/complicações , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Animais , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Helicobacter pylori , Humanos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estudos RetrospectivosRESUMO
Mutations in mitochondrial genes impairing energy production cause mitochondrial diseases (MDs), and clinical studies have shown that MD patients are prone to bacterial infections. However, the relationship between mitochondrial (dys)function and infection remains largely unexplored, especially in epithelial cells, the first barrier to many pathogens. Here, we generate an epithelial cell model for one of the most common mitochondrial diseases, Leigh syndrome, by deleting surfeit locus protein 1 (SURF1), an assembly factor for respiratory chain complex IV. We use this genetic model and a complementary, nutrient-based approach to modulate mitochondrial respiration rates and show that impaired mitochondrial respiration favors entry of the human pathogen Listeria monocytogenes, a well-established bacterial infection model. Reversely, enhanced mitochondrial energy metabolism decreases infection efficiency. We further demonstrate that endocytic recycling is reduced in mitochondrial respiration-dependent cells, dampening L. monocytogenes infection by slowing the recycling of its host cell receptor c-Met, highlighting a previously undescribed role of mitochondrial respiration during infection.
Assuntos
Neoplasias do Colo/microbiologia , Listeria monocytogenes/fisiologia , Listeriose/prevenção & controle , Proteínas de Membrana/metabolismo , Mitocôndrias/fisiologia , Proteínas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Respiração , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Metabolismo Energético , Células HCT116 , Humanos , Listeriose/microbiologia , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
Recent evidence suggests that Fusobacterium nucleatum (Fn) is associated with the development and progression of colorectal cancer. We aimed to delineate the clinical implications of Fn in metastatic colon cancer. We performed quantitative polymerase chain reaction (qPCR) using DNA samples from synchronous metastatic colon cancer patients with either formalin-fixed paraffin-embedded (FFPE) archival primary site tumor samples or fresh colon tissues. Progression-free survival (PFS)1 and PFS2 were defined as PFS of first- and second-line palliative settings. qPCR for Fn was successfully performed using 112 samples (FFPE, n = 61; fresh tissue, n = 51). Forty-one and 68 patients had right-sided and left-sided colon cancer, respectively. Patients with Fn enriched right-sided colon cancers had shorter PFS1 (9.7 vs. 11.2 months) than the other subgroups (HR 3.54, 95% confidence interval [CI] 1.05-11.99; P = 0.04). Fn positive right-sided colon was also associated with shorter PFS2 (3.7 vs. 6.7 months; HR 2.34, 95% CI 0.69-7.91; P = 0.04). In the univariate analysis, PFS1 was affected by differentiation and Fn positive right-sided colon cancer. The multivariate analysis showed that differentiation (HR 2.68, 95% CI 1.40-5.14, P = 0.01) and Fn positive right-sided colon (HR 0.40, 95% CI 0.18-0.88, P = 0.02) were associated with PFS1. Fn enrichment in right sided colon was not associated with overall survival (OS). Fn enrichment has significantly worse prognosis in terms of PFS1 and PFS2 in patients with right-sided metastatic colon cancers.
Assuntos
Neoplasias do Colo/microbiologia , DNA Bacteriano/genética , Infecções por Fusobacterium/diagnóstico , Fusobacterium nucleatum/isolamento & purificação , Neoplasias Primárias Múltiplas/microbiologia , Neoplasias do Colo/patologia , DNA Ribossômico/genética , Feminino , Fusobacterium nucleatum/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Prognóstico , Intervalo Livre de Progressão , RNA Ribossômico 16S/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo , Microbioma Gastrointestinal/fisiologia , Prevotella/fisiologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/microbiologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Metabolômica , Camundongos , Compostos Organoplatínicos/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The microbial diversity and communities in the excrement of healthy and patients suffered from cancer were identified by 16SrDNA sequencing performed on the Illumina Hi Seq sequencing platform. The microbial difference was also analyzed. The sequencing results showed high quality of the data, and the microbial communities were more various in the excrement of cancer patients. And the abundance of Firmicutes phylum was significantly reduced in cancer group. The phylum of Fermicutes, Bacteroidetes in cancer group are significantly down-regulated and up-regulated compared with normal group. The species of Faecalibacterium prausnitzii, Bateroides vulgatus and Fusicatenibacter saccharivorans are significantly lower in cancer group than that in normal group (P< 0.05). The species of Prevetella copri, M. uniformis, and Escherichia coli are significantly higher in the cancer group than that in normal group. The comparative results indicated that beneficial bacterium significantly decreased in colorectal cancer (CRC) group, and harmful bacterium significantly increased in the colon cancer group, meanwhile the acidity, sugar increased whereas the oxygen content decreased to facilitate the growth of harmful bacterium. The results would provide microbial approaches for the treatment of colon cancer by the intake of beneficial microbial communities.
Assuntos
Bactérias , Neoplasias do Colo/microbiologia , Microbioma Gastrointestinal/genética , Bactérias/classificação , Bactérias/genética , Bactérias/patogenicidade , DNA Bacteriano/genética , Fezes/microbiologia , Humanos , Análise de Sequência de DNARESUMO
Due to chemotherapeutic drug resistance, tumor recurrence is common in patients with colorectal cancer (CRC) and chemo-resistant patients are often accompanied by defects in the mismatch repair system (MMR). Our previous study has shown that Candida tropicalis (C. tropicalis) is closely related to the occurrence and development of colorectal cancer, but whether this conditional pathogenic fungus is involved in chemotherapy needs further investigation. Here we found that C. tropicalis promoted chemotherapy resistance of colon cancer to oxaliplatin. Compared with oxaliplatin-treated group, the expression of functional MMR proteins in tumors were decreased in C.tropicalis/oxaliplatin -treated group, while the glycolysis level of tumors was up-regulated and the production of lactate was significantly increased in C.tropicalis/oxaliplatin -treated group. Inhibiting lactate production significantly alleviated the chemoresistance and rescued the decreased expression of MMR caused by C. tropicalis. Furthermore, we found that lactate down-regulated the expression of MLH1 through the GPR81-cAMP-PKA-CREB axis. This study clarified that C. tropicalis promoted chemoresistance of colon cancer via producing lactate and inhibiting the expression of MLH1, which may provide novel ideas for improving CRC chemotherapy effect.
Assuntos
Candida tropicalis/metabolismo , Neoplasias do Colo/genética , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Láctico/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Glucose/metabolismo , Glucose/farmacologia , Glicólise , Humanos , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína 1 Homóloga a MutL/metabolismo , Oxaliplatina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.
Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Progressão da Doença , Imunidade Inata , Imunoterapia , Linfócitos/imunologia , Animais , Comunicação Celular/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Neoplasias do Colo/microbiologia , Fezes/microbiologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade Inata/efeitos dos fármacos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Invasividade Neoplásica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Doadores de TecidosRESUMO
Spontaneous tumor regression following bacterial infection has been observed for hundreds of years. These observations along with anecdotal medical findings in 1890s led to the development of Coley's "toxins," consisting of killed Streptococcus pyogenes and Serratia marcescens bacteria, as the first cancer immunotherapy. The use of this approach, however, was not widely accepted at the time especially after the introduction of radiation therapy as a treatment for cancer in the early 1900s. Over the last 30-40 years there has been renewed interest in the use of bacteria to treat human solid tumors. This is based on the observation that various nonpathogenic anaerobic bacteria can infiltrate and replicate within solid tumors when given intravenously. Bacteria tested as potential anticancer agents include the Gram-positive obligate anaerobes Bifidobacterium and Clostridium, as well as the gram-negative facultative anaerobe Salmonella. Recent advances in synthetic biology and clinical success in cancer immunotherapy provide renewed momentum for developing bacteria-based cancer immunotherapy for cancer treatment and should allow greater potential for the development of novel therapeutic approaches for this devastating disease.