RESUMO
Fecal microbiota transplants (FMTs) recently entered the cancer therapeutics field as a method to resensitize treatment-resistant melanoma patients to immune checkpoint inhibitors (ICIs). In this issue of Cell Host & Microbe, Kim and colleagues extend its utility to other solid tumors, including esophageal and hepatocellular carcinomas.1.
Assuntos
Transplante de Microbiota Fecal , Imunoterapia , Transplante de Microbiota Fecal/métodos , Humanos , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Microbioma Gastrointestinal/imunologia , Melanoma/terapia , Melanoma/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/microbiologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Animais , Fezes/microbiologiaRESUMO
Hepatobiliary malignancies, which include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are the sixth most common cancers and the third leading cause of cancer-related death worldwide. Hepatic carcinogenesis is highly stimulated by chronic inflammation, defined as fibrosis deposition, and an aberrant imbalance between liver necrosis and nodular regeneration. In this context, the gut-liver axis and gut microbiota have demonstrated a critical role in the pathogenesis of HCC, as dysbiosis and altered intestinal permeability promote bacterial translocation, leading to chronic liver inflammation and tumorigenesis through several pathways. A few data exist on the role of the gut microbiota or bacteria resident in the biliary tract in the pathogenesis of CCA, and some microbial metabolites, such as choline and bile acids, seem to show an association. In this review, we analyze the impact of the gut microbiota and its metabolites on HCC and CCA development and the role of gut dysbiosis as a biomarker of hepatobiliary cancer risk and of response during anti-tumor therapy. We also discuss the future application of gut microbiota in hepatobiliary cancer management.
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Carcinoma Hepatocelular , Colangiocarcinoma , Disbiose , Microbioma Gastrointestinal , Neoplasias Hepáticas , Humanos , Microbioma Gastrointestinal/fisiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiologia , Colangiocarcinoma/microbiologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/etiologia , Neoplasias dos Ductos Biliares/microbiologia , Neoplasias dos Ductos Biliares/metabolismo , Ácidos e Sais Biliares/metabolismo , Fígado/metabolismo , Animais , Carcinogênese/metabolismoRESUMO
Background and Objectives: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing worldwide, alongside the epidemic of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Materials and Methods: Forty-one patients with MASH and nineteen with MASH-HCC participated in the study, completing survey questionnaires, undergoing periodontal examinations, and providing samples of saliva, mouth-rinsed water, feces, and peripheral blood. The oral and fecal microbiome profiles were analyzed by 16S ribosomal RNA sequencing. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The genus Fusobacterium had a significantly higher occupancy rate (p = 0.002) in the intestinal microflora of the MASH-HCC group compared to the MASH group. However, Butyricicoccus (p = 0.022) and Roseburia (p < 0.05) had significantly lower occupancy rates. The Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusions: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.
Assuntos
Carcinoma Hepatocelular , Microbioma Gastrointestinal , Neoplasias Hepáticas , Humanos , Microbioma Gastrointestinal/fisiologia , Masculino , Projetos Piloto , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas/microbiologia , Idoso , Boca/microbiologia , Teorema de Bayes , Fígado Gorduroso/microbiologia , Fígado Gorduroso/complicações , Adulto , Saliva/microbiologiaRESUMO
Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.
Assuntos
Carcinoma Hepatocelular , Disbiose , Microbioma Gastrointestinal , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/etiologia , Disbiose/microbiologia , Masculino , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/microbiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologiaRESUMO
BACKGROUND: The association between gut bacteria and the response to immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) has been studied; however, multi-kingdom gut microbiome alterations and interactions in ICI-treated HCC cohorts are not fully understood. METHODS: From November 2018 to April 2022, patients receiving ICI treatment for advanced HCC were prospectively enrolled. Herein, we investigated the multi-kingdom microbiota characterization of the gut microbiome, mycobiome, and metabolome using metagenomic, ITS2, and metabolomic data sets of 80 patients with ICI-treated HCC. RESULTS: Our findings demonstrated that bacteria and metabolites differed significantly between the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups, whereas the differences were smaller for fungi. The overall diversity of bacteria and fungi before treatment was higher in the DCB group than in the NDB group, and the difference in diversity began to change with the use of immunotherapy after 6-8 weeks. We also explored the alterations of gut microbes in the DCB and NDB groups, established 18 bacterial species models as predictive biomarkers for predicting whether immunotherapy is of sustained benefit (area under the curve=75.63%), and screened two species of bacteria (Actinomyces_sp_ICM47, and Senegalimassilia_anaerobia) and one metabolite (galanthaminone) as prognostic biomarkers for predicting survival in patients with HCC treated with ICI. CONCLUSIONS: In this study, the status and characterization of the multi-kingdom microbiota, including gut bacteria, fungi, and their metabolites, were described by multiomics sequencing for the first time in patients with HCC treated with ICI. Our findings demonstrate the potential of bacterial taxa as predictive biomarkers of ICI clinical efficacy, and bacteria and their metabolites as prognostic biomarkers.
Assuntos
Carcinoma Hepatocelular , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/microbiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Bactérias/efeitos dos fármacos , Bactérias/classificação , Estudos ProspectivosRESUMO
The exploration of the complex mechanisms of cancer immunotherapy is rapidly evolving worldwide, and our focus is on the interaction of hepatocellular carcinoma (HCC) with immune checkpoint inhibitors (ICIs), particularly as it relates to the regulatory role of the gut microbiome. An important basis for the induction of immune responses in HCC is the presence of specific anti-tumor cells that can be activated and reinforced by ICIs, which is why the application of ICIs results in sustained tumor response rates in the majority of HCC patients. However, mechanisms of acquired resistance to immunotherapy in unresectable HCC result in no long-term benefit for some patients. The significant heterogeneity of inter-individual differences in the gut microbiome in response to treatment with ICIs makes it possible to target modulation of specific gut microbes to assist in augmenting checkpoint blockade therapies in HCC. This review focuses on the complex relationship between the gut microbiome, host immunity, and HCC, and emphasizes that manipulating the gut microbiome to improve response rates to cancer ICI therapy is a clinical strategy with unlimited potential.
Assuntos
Carcinoma Hepatocelular , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , AnimaisRESUMO
Portal vein tumor thrombosis (PVTT) frequently leads to malignant ascites (MA) in individuals with hepatocellular carcinoma (HCC), remaining a bottleneck in the treatment. This study aimed to explore the differences in microbes in paired groups and provide novel insights into PVTT and MA-related treatments. Formalin-fixed paraffin embedding ascite samples were collected from MA secondary to HCC and benign ascites (BA) secondary to liver cirrhosis (LC). Ascitic microbiota profiles were determined in the HCC and LC groups by 16S rRNA sequencing. Prognostic risk factors were screened using survival analysis. The correlation between the significantly different microbial signatures in the groups with PVTT (WVT) and non-PVTT (NVT) and clinical characteristics was explored. The expression of different immune cells was determined by labeling four markers in the MA tissue chips using multiplex immunohistochemistry. A total of 240 patients (196 with HCC with MA and 44 with LC with BA) were included in this study. Microbial profiles differed between the HCC and LC groups. PVTT and Barcelona Clinic Liver Cancer stage were shown to be prognostic risk factors. Significant differences in the alpha and beta diversities were observed between the WVT and NVT groups. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC MA. Differences in microbial signatures between the WVT and NVT groups were correlated with the level of C-reactive protein and apolipoprotein A1. This study revealed the microbial differences in the tumor microenvironment of MA secondary to HCC and BA secondary to LC.IMPORTANCEFirst, we explored the alteration of the ascites ecosystem through the microbiota in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Second, this is the first clinical study to investigate the differences between patients with HCC with and without portal vein tumor thrombosis via 16S rRNA sequencing. These results revealed a decreased microbial diversity and metabolic dysregulation in individuals with HCC and portal vein tumor thrombosis. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC malignant ascitic fluid. Our study provides a new perspective on treating malignant ascites secondary to HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Microbiota , Veia Porta , RNA Ribossômico 16S , Carcinoma Hepatocelular/microbiologia , Humanos , Neoplasias Hepáticas/microbiologia , Masculino , Feminino , Veia Porta/microbiologia , Veia Porta/patologia , Pessoa de Meia-Idade , Prognóstico , RNA Ribossômico 16S/genética , Idoso , Ascite/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Trombose Venosa/microbiologia , Cirrose Hepática/complicações , Cirrose Hepática/microbiologia , AdultoRESUMO
Liver disease, a major health concern worldwide, is a serious and progressive disorder. Herein, we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome. As liver disease advanced, gut integrity was disrupted, and the mycobiota was disturbed in the mouse models. The metabolites associated with hepatocellular carcinoma (HCC) differed from those associated with the cirrhotic phase as follows: levels of stercobilin and aflatoxin B1 dialcohol were reduced, while levels of triterpenoids, bafilomycin A1, and DHEA were increased in the HCC group. The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC. Based on the results from clinical human samples, the genus Candida (Ascomycota) (in humans) and the genus Kazachstania (Ascomycota) (in mice) occupied a dominant position in the HCC group, while other fungi were depleted. The increased abundance of C. albicans and depletion of S. cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC. Moreover, the administration of C. albicans and S. cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC. Therefore, gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.
Assuntos
Biomarcadores , Carcinoma Hepatocelular , Progressão da Doença , Microbioma Gastrointestinal , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Biomarcadores/metabolismo , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/metabolismo , Masculino , Cirrose Hepática/microbiologia , Cirrose Hepática/metabolismo , Modelos Animais de Doenças , Ascomicetos , Camundongos Endogâmicos C57BL , Hepatopatias/microbiologia , Hepatopatias/metabolismo , Fungos/classificação , Fungos/metabolismo , Candida albicans/metabolismoRESUMO
Salmonella enterica is a zoonotic bacterium that not only causes serious economic losses to the livestock and poultry industries but also seriously endangers human health. Long-term indiscriminate use of antibiotics has led to drug resistance in Salmonella, and thus the identification of alternatives to antibiotics is crucial. In this study, the effects of puerarin on the S. enterica-infected chickens were investigated. A total of 360 chicks were randomly assigned as the control group (CON), the S. enterica group (S), and puerarin-treatment group (P). Chicks in the P group were fed the basal diet supplemented with 50 (P50), 100 (P100), 200 (P200), and 400 (P400) mg/kg puerarin, respectively. It was found that puerarin treatment markedly altered the serum activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and superoxide dismutase (SOD), together with the malondialdehyde (MDA) and total antioxidant capacity (T-AOC) contents in the serum. The mRNA expression of IL-6, IL-1ß, TNF-α, Bcl-2, and caspase-8 in the livers of S. enterica-infected chicks was increased after infection but significantly reduced after treatment with puerarin. Histologic analysis showed that puerarin effectively mitigated morphological damage in the liver caused by S. enterica. Proteomic analysis revealed that S. enterica infection led to metabolic disorders in the liver, resulting in oxidative stress, increased inflammation, and significantly elevated levels of hepatocellular carcinoma biomarkers. The findings of the filtered sequencing were verified by using quantitative PCR (qPCR). Treatment with 100 mg/mL puerarin thus effectively alleviated disordered liver metabolism, reduced inflammation and oxidative damage and significantly reduced the levels of hepatocellular carcinoma biomarkers in the liver. The results suggest that puerarin has the potential to replace antibiotics to control Salmonella infection in poultry and thus improve food safety.
Assuntos
Galinhas , Isoflavonas , Fígado , Salmonelose Animal , Animais , Antibacterianos/metabolismo , Biomarcadores/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/veterinária , Galinhas/metabolismo , Galinhas/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/microbiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/veterinária , Estresse Oxidativo , Proteômica , Salmonella/efeitos dos fármacos , Inocuidade dos Alimentos , Salmonelose Animal/complicações , Salmonelose Animal/tratamento farmacológico , Salmonelose Animal/microbiologia , Isoflavonas/administração & dosagemRESUMO
BACKGROUND: Gut microbial alterations have been linked to chronic liver disease and hepatocellular carcinoma (HCC). The role of the oral microbiome in liver cancer development has not been widely investigated. METHODS: Bacterial 16S rRNA sequences were evaluated in oral samples from 90 HCC cases and 90 controls who were a part of a larger U.S. case-control study of HCC among patients diagnosed from 2011 to 2016. RESULTS: The oral microbiome of HCC cases showed significantly reduced alpha diversity compared with controls (Shannon P = 0.002; Simpson P = 0.049), and beta diversity significantly differed (weighted Unifrac P = 0.004). The relative abundance of 30 taxa significantly varied including Cyanobacteria, which was enriched in cases compared with controls (P = 0.018). Cyanobacteria was positively associated with HCC [OR, 8.71; 95% confidence interval (CI), 1.22-62.00; P = 0.031] after adjustment for age, race, birthplace, education, smoking, alcohol, obesity, type 2 diabetes, Hepatitis C virus (HCV), Hepatitis B virus (HBV), fatty liver disease, aspirin use, other NSAID use, laboratory batch, and other significant taxa. When stratified by HCC risk factors, significant associations of Cyanobacteria with HCC were exclusively observed among individuals with negative histories of established risk factors as well as females and college graduates. Cyanobacterial genes positively associated with HCC were specific to taxa producing microcystin, the hepatotoxic tumor promotor, and other genes known to be upregulated with microcystin exposure. CONCLUSIONS: Our study provides novel evidence that oral Cyanobacteria may be an independent risk factor for HCC. IMPACT: These findings support future studies to further examine the causal relationship between oral Cyanobacteria and HCC risk.
Assuntos
Carcinoma Hepatocelular/microbiologia , Cianobactérias/isolamento & purificação , Neoplasias Hepáticas/microbiologia , Boca/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados UnidosRESUMO
OBJECTIVE: The aim of this paper was to discuss the potency of gut microbiome as a non-invasive predictive biomarker for early detection of pancreatic cancer and hepatocellular carcinoma. MATERIALS AND METHODS: We analysed the available up-to-date literature (PubMed, Embase, Google Scholar databases) regarding the link between gut microbiome and early detection of pancreatic cancer, as well as hepatocellular carcinoma. The following search linked to gut microbiome and aforementioned cancers was used: 'gut microbiome', 'gut microbiota', 'pancreatic cancer', 'pancreatic ductal adenocarcinoma', hepatocellular carcinoma', 'microbial biomarkers', 'fungal microbiota', 'mycobiota'. The search was conducted in English. RESULTS: The association between gut microbiota imbalance and development of pancreatic cancer and hepatocellular carcinoma has been recognized during last several years. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma, whose carcinogenesis is strongly related to oral microbial dysbiosis, H. pylori infection, bactibilia, hepatotropic viruses, and intrapancreatic microbiota. It is known that gut-liver axis exists and may affect hepatocarcinogenesis. Currently, the treatment strategies of these cancers are strongly limited and there are not well-recognized screening tools to early diagnose them. The growing attention towards the use of gut microbiome as a predictive non-invasive biomarker to detect pancreatic cancer and hepatocellular carcinoma in early stage has been observed. CONCLUSIONS: To conclude, the field regarding the link between gut microbiome as a non-invasive biomarkers and early detection of pancreatic cancer and hepatocellular carcinoma exists, however, it is not well-investigated. Additionally, many of the studies were conducted with small sample sizes, whereas biomarkers are ethnicity-dependent and should be validated in wide range of populations. Nevertheless, these aspects are promising and open up new diagnostic options.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Microbioma Gastrointestinal , Neoplasias Hepáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Disbiose/diagnóstico , Detecção Precoce de Câncer/métodos , Humanos , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/patologia , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/patologiaRESUMO
BACKGROUND: The gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers. METHODS: Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy. RESULTS: In total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance. CONCLUSIONS: We demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy.
Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , DNA Bacteriano/genética , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias do Sistema Biliar/imunologia , Neoplasias do Sistema Biliar/microbiologia , Neoplasias do Sistema Biliar/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , DNA Bacteriano/análise , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/patologia , Masculino , Metagenômica , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
METHOD: This study included 74 Chinese male patients with HCC. They were divided into early (n = 19), intermediate (n = 37), and terminal (n = 18) groups, referred to as Barcelona Clinic Liver Cancer stage 0+A, B, and C+D, respectively. Paired fecal and plasma samples were collected. Microbial composition and profiles were analyzed by 16S rRNA gene sequencing. The levels of gut damage marker (regenerating islet-derived protein 3α (REG3α)) and microbial translocation markers (soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), peptidoglycan recognition proteins (PGRPs)) were determined in plasma samples of patients by ELISA. Twenty plasma cytokine and chemokines were determined by Luminex. RESULTS: In early, intermediate, and terminal groups, the abundance of the Bifidobacteriaceae family decreased significantly (3.52%, 1.55%, and 0.56%, respectively, P = 0.003), while the abundance of the Enterococcaceae family increased significantly (1.6%, 2.9%, and 13.4%, respectively, P = 0.022). Levels of REG3α and sCD14 were markedly elevated only in the terminal group compared with the early (P = 0.025 and P = 0.048) and intermediate groups (P = 0.023 and P = 0.046). The level of LBP significantly increased in the intermediate (P = 0.035) and terminal (P = 0.025) groups compared with the early group. The PGRP levels were elevated only in the terminal group compared with the early group (P = 0.018). The ratio of Enterococcaceae to Bifidobacteriaceae was significantly associated with the levels of REG3α, LBP, sCD14, and PGRPs. With HCC progression, increased levels of inflammatory cytokines accompanied by a T cell-immunosuppressive response and microbial translocation were observed. CONCLUSION: Gut microbiota compositional and functional shift, together with elevated gut damage and microbial translocation, may promote HCC development by stimulating inflammatory response and suppressing T cell response.
Assuntos
Translocação Bacteriana/imunologia , Carcinoma Hepatocelular/imunologia , Disbiose/complicações , Microbioma Gastrointestinal/imunologia , Neoplasias Hepáticas/imunologia , Actinobacteria/genética , Actinobacteria/imunologia , Actinobacteria/isolamento & purificação , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , DNA Bacteriano/isolamento & purificação , Progressão da Doença , Disbiose/diagnóstico , Disbiose/imunologia , Disbiose/microbiologia , Enterococcaceae/genética , Enterococcaceae/imunologia , Enterococcaceae/isolamento & purificação , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16SRESUMO
The gut microbiota system plays a vital role in liver diseases. This study aimed to address the diversity of gut microbiota and its correlations with clinical parameters in healthy individuals, chronic liver disease (CLD), and hepatocellular carcinoma (HCC) patients. Fecal specimens of nine healthy individuals, 11 CLD, and 21 HCC were collected. The diversity of gut microbiota was examined by PCR and Illumina MiSeq sequencing and analyzed using 16S rRNA gene sequencing database. The correlations between gut microbiota and the clinical parameters of participants were also addressed. Compared to healthy individuals, Firmicutes at a phylum level decreased in CLD and HCC patients and Proteobacteria increased (p < 0.05). The composition of Blautia on a genus level in CLD and HCC patients significantly decreased compared to healthy controls (p < 0.05). Firmicutes composition was negatively associated with age and number of males (p < 0.05) and was positively associated with monocytes, high-density lipoprotein cholesterol (HDL-C), and estimated glomerular filtration rate (eGFR) levels (p < 0.05). At a genus level, Blautia composition was negatively associated with cirrhosis, age, and number of males (p < 0.01), while it was positively associated with red blood cells (RBCs), triglycerides, HDL-C, and lymphocyte levels (p < 0.05). Conclusively, there was a significant compositional difference in gut microbiota in CLD and HCC patients compared with healthy subjects. Firmicutes and Blautia in gut microbiota system lessened in CLD and HCC patients. Clinical biochemical parameters have an impact on the diversity of gut microbiota in liver diseases.
Assuntos
Carcinoma Hepatocelular/microbiologia , Clostridiales/classificação , Firmicutes/classificação , Hepatopatias/microbiologia , Neoplasias Hepáticas/microbiologia , Adulto , Idoso , Estudos de Casos e Controles , Clostridiales/genética , Clostridiales/isolamento & purificação , Fezes/microbiologia , Feminino , Firmicutes/genética , Firmicutes/isolamento & purificação , Microbioma Gastrointestinal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , RNA Ribossômico 16S/genética , Análise de Sequência de RNA , Caracteres Sexuais , Adulto JovemRESUMO
AIM: Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. METHODS: We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. RESULTS: The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, p = 0.85; and 7.6 vs. 7.5 months, p = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7-79.7%) in the viral infection group and 59.5% (95% CI 45.2-73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. CONCLUSIONS: Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/virologia , Feminino , Humanos , Imunoterapia , Infecções/diagnóstico , Neoplasias Hepáticas/virologia , Masculino , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Quinolinas/efeitos adversos , Estudos Retrospectivos , Viroses/diagnósticoRESUMO
Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.
Assuntos
Carcinoma Hepatocelular/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Hepáticas/imunologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologiaRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is associated with metabolic disorders such as obesity, insulin resistance, dyslipidemia, steatohepatitis, and liver fibrosis. Liver-resident (Kupffer cells) and recruited macrophages contribute to low-grade chronic inflammation in various tissues by modulating macrophage polarization, which is implicated in the pathogenesis of metabolic diseases. Abnormalities in the intestinal environment, such as the gut microbiota, metabolites, and immune system, are also involved in the pathogenesis and development of NAFLD. Hepatic macrophage activation is induced by the permeation of antigens, endotoxins, and other proinflammatory substances into the bloodstream as a result of increased intestinal permeability. Therefore, it is important to understand the role of the gut-liver axis in influencing macrophage activity, which is central to the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). Not only probiotics but also biogenics (heat-killed lactic acid bacteria) are effective in ameliorating the progression of NASH. Here we review the effect of hepatic macrophages/Kupffer cells, other immune cells, intestinal permeability, and immunity on NAFLD and NASH and the impact of probiotics, prebiotics, and biogenesis on those diseases.
Assuntos
Microbioma Gastrointestinal/imunologia , Hepatopatia Gordurosa não Alcoólica , Prebióticos , Probióticos , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/microbiologia , Humanos , Células de Kupffer/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/microbiologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/microbiologiaRESUMO
Liver cancer is the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) is a primary liver cancer that results from chronic hepatitis caused by multiple predisposing factors such as viral infection, alcohol consumption, and non-alcoholic fatty liver disease. Accumulating studies have indicated that dysfunction of the gut epithelial barrier and hepatic translocation of gut microbes may be implicated in the pathogenesis of HCC. However, the translocated bacteria in HCC patients remains unclear. Here, we characterised tumour-associated microbiota in patients with liver cancer and focused on HCC. We observed that the number of amplicon sequence variants in tumour-associated microbiota was significantly higher compared with that in non-tumour regions of the liver. The tumour-associated microbiota consisted of Bacteroidetes, Firmicutes, and Proteobacteria as the dominant phyla. We identified an unclassified genus that belonged to the Bacteroides, Romboutsia, uncultured bacterium of Lachnospiraceae as a signature taxon for primary liver cancer. Additionally, we identified Ruminococcus gnavus as a signature taxon for HCC patients infected with hepatitis B and/or hepatitis C viruses. This study suggests that tumour microbiota may contribute to the pathology of HCC.
Assuntos
Carcinoma Hepatocelular/microbiologia , Colangiocarcinoma/microbiologia , Clostridiales/isolamento & purificação , Neoplasias Hepáticas/microbiologia , Microbiota , Biomarcadores Tumorais , Hepatite Viral Humana/complicações , Humanos , Neoplasias Hepáticas/secundárioRESUMO
BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.