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ABSTRACT
Oral, gut, and tumor microbiota have been implicated as important regulators in the carcinogenesis and progression of gastrointestinal malignancies. However, few studies focused on the existence and association of resident microbes within different body regions. Herein, we aim to reveal the durability of the oral-gut-tumor microbiome and its diagnostic performance in hepatocellular carcinoma (HCC). Our study included two cohorts: a retrospective discovery cohort of 364 HBV-HCC patients and 160 controls with oral or fecal samples, a prospective validation cohort of 91 cases, and 124 controls for matching samples, as well as 48 HBV, and 39 HBV-cirrhosis patients for gut microbial patterns examined by 16S rRNA gene sequencing. With the random forest analysis, 10 oral and 9 gut genera that could distinguish HCC from controls in the retrospective cohort were validated among the prospective matching participants, with area under the curve (AUC) values of 0.7971 and 0.8084, respectively. When influential taxa were merged, the AUC of the consistent classifier increased to 0.9405. The performance continued to improve to 0.9811 when combined with serum levels of alpha-fetoprotein (AFP). Specifically, microbial biomarkers represented by Streptococcus displayed a constantly increasing trend during the disease transition. Furthermore, the presence of several dominant microbiota species was confirmed in hepatic tumor and non-tumor tissues with fluorescence in situ hybridization (FISH) and 5 R 16S rRNA gene sequencing. Overall, our findings based on the oral-gut-tumor microbiota provide a reliable approach for the early detection of HCC.
Acknowledgments
The authors would like to thank Peng Wu, Qingqing Liang, Wei Wang, and Gaoyang He of Lc-Bio Technologies Co., Ltd (Hangzhou, China) for their technical support in this work. We thank the anonymous reviewers and the editors for their helpful remarks and useful feedback that improved this paper.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, Gang Chen. The data are not publicly available due to their containing information that could compromise the privacy of research participants.
List of abbreviations
| HCC | = | hepatocellular carcinoma |
| AUC | = | area under the curve |
| AFP | = | alpha-fetoprotein |
| FISH | = | fluorescence in situ hybridization |
| OSCC | = | oral squamous cell carcinoma |
| IBD | = | inflammatory bowel disease |
| PCA | = | principal component analysis |
| PCoA | = | principal coordinates analysis |
| KEGG | = | Kyoto Encyclopedia of Genes and Genomes |
| STAMP | = | statistical analysis of metagenomic profiles |
| SEM | = | standard error of mean |
| LEfSe | = | linear discriminant analysis effect size |
| FDR | = | false discovery rate |
| RDA | = | redundancy analysis |
| ROC | = | receiver operating curve |
| LPS | = | lipopolysaccharide |
| ZO-1 | = | zonulin-1 |
| ELISA | = | enzyme-link immunosorbent assay |
| LAL | = | limulus amebocyte lysate |
| IHC | = | immunohistochemistry |
| LTA | = | lipoteichoic acid |
| RT | = | room temperature |
| GF | = | Germ-free |
| PPIs | = | proton-pump inhibitors |
| NSAIDs | = | nonsteroidal anti-inflammatory drugs |
| AAPs | = | atypical antipsychotics |
| ARB | = | angiotensin II receptor blocker |
| ACEI | = | angiotensin converting enzyme inhibitors |
| ANOSIM | = | analysis of similarities |
| BMI | = | body mass index |
| CCI | = | charlson comorbidity index |
| MELD | = | model for end-stage liver disease |
| HBV | = | hepatitis B virus |
| INR | = | international normalized ratio |
| PT | = | prothrombin time |
| HDL | = | high density lipoprotein |
| LDL | = | low density lipoprotein |
| ALT | = | alanine transaminase |
| AST | = | aspartate transaminase |
| PLT | = | platelet |
| Tchol | = | total cholesterol |
| TG | = | triglyceride |
| Tbil | = | total bilirubin |
| Cre | = | creatinine |
| Alb | = | albumin |
| GGT | = | γ-glutamyl transpeptidase |
| BAs | = | bile acids |
| SCFAs | = | short-chain fatty acids |
| LCA | = | lithocholic acid |
| DCA | = | deoxycholic acid |
| TLRs | = | toll-like receptors |
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2201159