Profiling of tumour-associated microbiota in human hepatocellular carcinoma
Open accessAbstract
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.
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Lachnoclostridium belongs to family Lachnospiraceae and is highly homologous to Ruminococcus gnavus.
“Lachnoclostridium belongs to family Lachnospiraceae and is highly homologous to Ruminococcus gnavus.34”
From Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor–treated unresectable hepatocellular carcinoma (2022) · cites this paper as [34]
The Results section ('Ruminococcus gnavus as a biomarker'; page unavailable) reports that sequences assigned to Lachnoclostridium were more than 97% identical to R. gnavus sequences, supporting the homology claim. The copy mentions Lachnospiraceae elsewhere in the Results but does not state that Lachnoclostridium belongs to that family. (LLM, conf=0.88)
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“Their findings demonstrated a significantly higher microbial load within tumor samples [99].”
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“Real-time quantitative PCR (qPCR) was performed to estimate the bacterial load, following a previously published protocol (44).”
InfluentialSelf-citationApproaches to spatially resolving the tumour immune microenvironment of hepatocellular carcinoma
Marsh‐Wakefield, F., Ferguson, A. L., Liu, K., Santhakumar, C., McCaughan, G. W., & Palendira, U. (2022) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359221113270 · Cited by 11 · see citing works
Feng, Y., Han, M.-Z., Zhou, Y., Wang, Y., Wang, Y., Sun, T., & Xu, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1575963 · Cited by 12 · see citing works
Zheng, H., Chen, X., Li, Q., Liu, Y., & Cai, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1084926 · Cited by 9 · see citing works
“Lachnospiraceae could be used as signature taxa for primary liver cancer (22).”
BackgroundCostante, F., Airola, C., Santopaolo, F., Gasbarrini, A., Pompili, M., & Ponziani, F. (2022) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v14.i9.1622 · Cited by 10 · see citing works
Predictive and Prognostic Roles of Gut Microbial Variation in Liver Transplant
Wong, H. J., Lim, W. H., Ng, C. H., Tan, D. J. H., Bonney, G. K., Kow, A. W. C., Huang, D. Q., Siddiqui, M. S., Noureddin, M., Syn, N. L. X., et al. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.873523 · Cited by 10 · see citing works
“Moreover, they discovered Ruminococcus gnavus as a signature microbe for hepatitis B and/or hepatitis C virus-related HCC (52).”
BackgroundCharacteristics and potential diagnostic value of gut microbiota in ovarian tumor patients
Gong, W., Jin, G., Bao, Y., Liu, Q., Ni, M., Wang, J., Mao, S., Zhang, Y., & Zheng, Z. (2025) · Scientific Reports · doi:10.1038/s41598-025-99912-x · Cited by 9 · see citing works
“R. gnavus abundance was also increased in patients with viral Hepatocellular carcinoma, which eventually induced tumor necrosis factor-α in dendritic cells and led to hepatocyte carcinogenesis 8 .”
Chen, M., & Bie, L. (2025) · Cancer Cell International · doi:10.1186/s12935-025-03745-7 · Cited by 10 · see citing works
“As major members of the gut commensal microbiota, Bacteroidetes, Firmicutes, and Proteobacteria have been detected in liver cancer [43, 51].”
InfluentialIntratumoral microbiota: an emerging force in diagnosing and treating hepatocellular carcinoma
Liu, H., Zhang, J., Rao, Y., Jin, S., Zhang, C., & Bai, D. (2024) · Medical Oncology · doi:10.1007/s12032-024-02545-9 · Cited by 8 · see citing works
“Komiyama et al. examined the microbiota in primary HCC and metastatic liver cancer and found an increased diversity of tumor tissues, especially in patients with HCC who were virally infected [26].”
Xu, J., Liu, Y., Cao, X., Guo, X., Wang, J., Liu, Y., Zhou, H., Ma, B., & Peng, S. (2024) · Stress Biology · doi:10.1007/s44154-024-00178-6 · Cited by 8 · see citing works
Kinashi, Y., Tanaka, K., Kimura, S., Hirota, M., Komiyama, S., Shindo, T., Hashiguchi, A., Takahashi, D., Shibata, S., Karaki, S.-I., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105256 · Cited by 7 · see citing works
Self-citationAcharya, S., & Thirunavukkarasu, C. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2902067 · Cited by 10 · see citing works
“[140], the microbiota that is associated with tumors includes Actinobacteria, Bac-teroidetes, Firmicutes, and Proteobacteria.”
BackgroundLiakina, V., Strainienė, S., Stundienė, I., Maksimaityte, V., & Kazėnaitė, E. (2022) · World Journal of Hepatology · doi:10.4254/wjh.v14.i7.1277 · Cited by 10 · see citing works
Nakatsu, G. (2021) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15715 · Cited by 8 · see citing works
Progress in the Study of Intratumoral Microorganisms in Hepatocellular Carcinoma
Song, Y., Tian, S., Li, Z., Miao, J., Wu, M., Xu, T., Wu, X., Qiao, J., Zhang, X., Zhao, H., et al. (2025) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s496964 · Cited by 7 · see citing works
Etiology-Dependent Microbiome Differences in Hepatocellular Carcinoma Development
Todorović, N., Martinelli, S., Nannini, G., Weiskirchen, R., & Amedei, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413510 · Cited by 8 · see citing works
Could intratumoural microbiota be key to unlocking treatment responses in hepatocellular carcinoma?
Yu, K. L., & Shen, S. (2024) · European Journal of Cancer · doi:10.1016/j.ejca.2024.115195 · Cited by 7 · see citing works
Golonka, R. M., Yeoh, B. S., Saha, P., Gohara, A. F., Tummala, R., Stepkowski, S. M., Tiwari, A. K., Joe, B., Gonzalez, F. J., Gewirtz, A. T., et al. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000166 · Cited by 8 · see citing works
“…analysis proposes it as a probable noninvasive biomarker for HCC. [15] The recent discovery of tumor-associated microbiota in HCC tissues [16 – 18] has expanded the concept of microbiota to also be a possible contributor to HCC. Theconnection between gut microbiota and HCC is constantly…”
Profiling of the tumor-associated microbiome in patients with hepatocellular carcinoma
Schulz, C., Vilchez‐Vargas, R., Öcal, E., Koch, N., Puhr‐Westerheide, D., Burnell, L. F., Hirner-Eppeneder, H., Benckert, J., Pech, M., Reimer, P., et al. (2025) · Gut Pathogens · doi:10.1186/s13099-025-00727-y · Cited by 7 · see citing works
“Whether an ASV was not previously described as inhabiting the human gut [30], it was considered an external contaminant, because of nonsterile paraffin or nonsterile environment during sample preparation [21, 28, 31].”
Liu, Q., Wang, J., Yao, Y., Sun, X., Fang, W. J., Zhang, Y., Liu, Z., & Zheng, Y. Z. (2025) · Current Research in Microbial Sciences · doi:10.1016/j.crmicr.2025.100428 · Cited by 5 · see citing works
Dolapchiev, L. I., Gonzales, K. A., Graham, L. C., Gagea, M., Stevenson, H. L., Kwan, S., & Beretta, L. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s485532 · Cited by 6 · see citing works
“44 In addition, diet can influence the gut microbiome as reviewed in the context of high fat diet and gastrointestinal cancers.”
BackgroundCrosstalk between Gut Microbiota and Hepatocellular Carcinoma
Xie, C., & Pocha, C. (2023) · Gastrointestinal Disorders · doi:10.3390/gidisord5020013 · Cited by 7 · see citing works
“Komiyama and colleagues [71] reported that Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria serve as tumor-associated microbiota.”
BackgroundUnveiling hidden players: the role of intratumoral microbiota in gastrointestinal cancer dynamics
Tang, W., Li, F., Zheng, H., Zhou, S., Li, C., Xu, X., & Fu, J. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06401-9 · Cited by 4 · see citing works
“In addition, gut bacteria can reach the hepatic parenchyma via portal circulation, and circulating tumour cells may further disseminate these microorganisms to liver metastases (Komiyama et al. 2021; Ponziani et al. 2019).”
Existence and distribution of the microbiome in tumour tissues of children with hepatoblastoma
Cui, J.-H., Li, X., Zhang, Q., Du, B., Ding, Z., Yan, C., Xue, G.-H., Gan, L., Feng, J.-X., Fan, Z., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e39547 · Cited by 4 · see citing works
“The upstream primers (5 ʹ - CCTACGGGNGGCWGCAG-3 ʹ ) and downstream primers (5 ʹ -GACTACHVGGGTATCTAATCC-3 ʹ ) were used, and the reaction details that were followed were as reported by Komiyama [11].”
InfluentialNajjary, S., Kros, J. M., Stricker, B. H. C., Ruiter, R., Shuai, Y., Kraaij, R., Steen, K. V., van der Spek, P. J., van Eijck, C. H. J., Ikram, M. A., et al. (2024) · Cancer Medicine · doi:10.1002/cam4.6860 · Cited by 3 · see citing works
“43 Alterations in the abundance of these microbes influence the initiation and progression of gastrointestinal carcinogenesis 44 but may also affect the immune system, which can lead to the development of extraintestinal malignancies.”
BackgroundImpact of Toxigenic Fungi: An Economic and Health Obstruction to Wellness in Mozambique
Fernandes, T. H., Ferrão, J., Guina, J. A., Chabite, I. T., Garrine, C. M. L. P., & Bell, V. (2021) · European Journal of Agriculture and Food Sciences · doi:10.24018/ejfood.2021.3.5.392 · Cited by 5 · see citing works
“lack of physical activity, chronic viral hepatitis, gut microbiota composition, or smoking [16], [17].”
BackgroundLee, D. J., Mun, D.-Y., Kang, M.-G., Kang, A., Choi, Y.-B., Seo, E., Son, S.-H., Yoon, J., Kim, A. J., Kwak, M.-J., et al. (2026) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.2602.02028 · Cited by 3
How the gut microbiome affects the immunotherapy response in hepatocellular carcinoma
Wu, M., Zhang, Y., & Yu, J. (2026) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2025.0761 · Cited by 3
“…shapes the TME in HCC. Tumor-associated microbiota are enriched in Bacteroidetes , Firmicutes , and Proteobacteria , with taxa, such as Ruminococcus gnavus and Stenotrophomonas maltophilia , linked to hepatic stellate cell activation and senescence-associated secretory phenotypes (SASPs) 53,54 .”
Kawai, S., Oguchi, H., Endo, M., Hase, K., & Kimura, S. (2025) · Biomedical Research · doi:10.2220/biomedres.46.61 · Cited by 3 · see citing works
“A library of 16S rRNA genes was constructed as previously described with some modifications (Komiyama et al. 2021).”
Self-citationIsmaiel, A., Almonajjed, M. B., Wardeh, M., Abdelghafar, A., Popa, Ş., Sabo, C., & Dumitrașcu, D. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1852380 · Cited by 2
Jinato, T., Khamjerm, J., Manprasong, S., Iadsee, N., Tangkijvanich, P., Nookaew, I., & Chuaypen, N. (2025) · Gut Pathogens · doi:10.1186/s13099-025-00782-5 · Cited by 2 · see citing works
“…as a characteristic bacterial signature in HCC tissues of patients with hepatitis B or C viruses [38] Another study also reported the enrichment of B. caeci-muris , Veillonella parvula , Clostridium bolteae , Bacteroides xylanisolvens , and Ruminococcus gnavus in patients with NAFLD-HCC [42].”
Li, X., Zuo-Quan, X., & Geng, M. (2026) · Acta Pharmacologica Sinica · doi:10.1038/s41401-026-01882-x · Cited by 1 · see citing works
Tang, B., Lin, Y. N., Jiang, T., Chen, Y., Zhao, Q., Wang, S., Shen, Y., Wang, S., Wu, Q., Xie, P., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-025-02303-y · Cited by 1 · see citing works
“More specifically, the Aspergillus phylum showed slightly higher proportions in hepatocyte populations, while Actinobacteria phylum abundance was significantly reduced [116, 118, 124].”
Fongmanee, J., Wanitsuwan, W., Wanna, W., Surachat, K., Saechan, C., Srinoun, K., Buncherd, H., Thanapongpichat, S., Kanjanapradit, K., & Tansila, N. (2025) · Genes to Cells · doi:10.1111/gtc.70008 · Cited by 1 · see citing works
“Moreover, the implication of this genus in hepatocellular carcinoma and hepatoblastoma has brought clinical significance as one of the potential bacterial markers (Feng et al. 2023; Komiyama et al. 2021).”
InfluentialFernandes, W. M., Harris, N., Zamalloa, A., Adofina, L., Srinivasan, P., Menon, K. V., Heaton, N. D., Miquel, R., Zen, Y., Kelly, G. P., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168924 · Cited by 1 · see citing works
“Furthermore, gut microbiota have been linked to treatment response to immunotherapy in melanoma and epithelial tumours [17–20], and a recent study showed that microbiota in the tumour itself may contribute to the pathology of HCC [21].”
BackgroundPanda, P., Mohanty, S., & Mohapatra, R. (2026) · Clinical Microbiology Newsletter · doi:10.1016/j.clinmicnews.2026.08.003
Xu, X.-T., Jiang, M.-J., Fu, Y.-F., & Meng, Q.-H. (2026) · BMC Gastroenterology · doi:10.1186/s12876-026-05027-6
Lu, J. J., Feng, F., Li, C., Yu, Z., Zhang, T., Liu, A., Gao, Q., Li, Z., Luo, L., Guan, X., et al. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.06.046
“The presence of bacteria has been reported in both normal liver tissue and hepatocellular carcinoma (HCC) 26,27 ; however, its impact on HCC treatment remains unclear.”
HBV and the Microbiome—PubMed Database Literature Review
Prince, A. M., Zeltiņa, I., Reinis, A., Valciņa, O., & Krūmiņa, A. (2026) · Infectious Disease Reports · doi:10.3390/idr18030038
“Emerging evidence supports a high prevalence of cancer type-specific microbiota residing within tumor tissues [2,86–89].”
Song, L., Zhou, Y., Zhan, Z., Pan, L., & Fang, L. (2026) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2026.100790
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“…enriched in the tumor tissues of patients with HBV-associated HCC. Compared with investigations on microbiome translocation in solid tumors [3, 4], we assumed that the unique enrichment of bacterial taxa in individual solid tumors could be attributed to an intricate adaptability effect by…”
InfluentialSong, S., Xu, L.-S., Wang, L.-Q., Zhou, X., Jiang, X., & Li, C.-P. (2025) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v17.i12.112936
“Komiyama et al [32] found significantly higher microbiome diversity in liver tumor tissues compared to adjacent tissues, a finding corroborated by He et al [21], who identified consistent patterns of increased microbial richness in HCC tissues.”
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Regulatory, diagnostic, and therapeutic roles of microRNAs in chronic liver diseases.
Kazemzadeh, R., Kheirollahi, M., Mard, S., Ahangarpour, A., & Savari, F. (2024) · Acta gastro-enterologica Belgica · doi:10.51821/87.2.12965
- Authors
- Komiyama, S., Yamada, T., Takemura, N., Kokudo, N., Hase, K., & Kawamura, Y. I.
- Affiliations
- Keio University (JP)
- National Center for Global Health and Medicine (JP)
- Corresponding author
- Hase, Koji
- Kawamura, Yuki I.
- Venue
- Scientific Reports
- Published
- 2021-05-19
- Volume
- 11
- Issue
- 1
- Pages
- 10589-10589
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8134445
- OpenAlex
- W3162026262
- Cited by
- 96
- References
- 40
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 21 · 2023: 22 · 2022: 17 · 2021: 5
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Center for Global Health and Medicine (30-1021, 30-1006, 20A1007)
- Japan Agency for Medical Research and Development (18gm1010004h0103, 19gm1010004s0104, 20gm1010004h0105, 20gm1310009h000)
- Takeda Science Foundation (FY2018)
- Asahi Glass Foundation (FY2017)
- Secom Science and Technology Foundation (FY2018, FY2019, FY2020)
- Yakult Foundation; The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Physical Sciences › Environmental Science › Ecology › Microbial Community Ecology and Physiology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hepatocellular carcinoma, gut microbiota, bacterial translocation, Ruminococcus gnavus, Bacteroides, Lachnospiraceae, hepatitis B virus, hepatitis C virus, amplicon sequence variants
- MeSH terms
- Clostridiales, Eubacteriales, Hepatitis, Viral, Human, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Biomarkers, Tumor, Cholangiocarcinoma, Microbiota
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