Advances in the study of intestinal microecology in the development of hepatocellular carcinoma and its implications for clinical diagnosis and treatment

doi:10.16139/j.1007-9610.2025.05.12

Abstract

Abstract:

The intestinal microecology is closely related to the occurrence and development of hepatocellular carcinoma (HCC). The intestinal microbiota and its metabolites can regulate the tumor immune microenvironment through the "gut-liver axis", promoting cancer progression. Therefore, the intestinal microbiome is gradually demonstrating the potential as a biomarker for early diagnosis of HCC and prediction of the efficacy of immunotherapy. Targeted intervention on the intestinal microecology (such as probiotics, fecal microbiota transplantation, dietary regulation, etc.) may enhance the efficacy of immune checkpoint inhibitors (ICIs) and is becoming a promising combination therapy strategy. In the future, HCC treatment will rely on multi-omics integration, artificial intelligence-assisted diagnosis, and synthetic biology tools to promote the translation of precise gut flora intervention strategies from basic research to the clinic. This article summarized the latest research progress of intestinal microecology in HCC, explored its potential value and development direction for precision diagnosis and treatment of HCC, and provided a theoretical basis for the clinical application of related intervention strategies.

Key words: Intestinal microecology, Hepatocellular carcinoma(HCC), Intestinal microbiome

CLC Number:

R735.7

ZHANG Tianqi, LIU Yang, WEI Yunwei. Advances in the study of intestinal microecology in the development of hepatocellular carcinoma and its implications for clinical diagnosis and treatment[J]. Journal of Surgery Concepts & Practice, 2025, 30(05): 450-455.

References 53

[1]	YANG J, YANG Y, ISHII M, et al. Does the gut microbiota modulate host physiology through polymicrobial biofilms?[J]. Microbes Environ, 2020, 35(3):ME20037.
[2]	MCKENNA P, HOFFMANN C, MINKAH N, et al. The macaque gut microbiome in health, lentiviral infection, and chronic enterocolitis[J]. PLoS Pathog, 2008, 4(2):e20. doi: 10.1371/journal.ppat.0040020 URL
[3]	THOMAS A M, FIDELLE M, ROUTY B, et al. Gut oncomicrobiome signatures (GOMS) as next-generation biomarkers for cancer immunotherapy[J]. Nat Rev Clin Oncol, 2023, 20(9):583-603. doi: 10.1038/s41571-023-00785-8 pmid: 37365438
[4]	许芳琪, 李博文, 刘洋, 等. 具核梭杆菌通过E-cadherin/β-catenin信号上调结直肠癌ABCG2表达诱导奥沙利铂耐药[J]. 中华肿瘤杂志, 2025, 47(4):329-339.
	XU F Q, LI B W, LIU Y, et al. Fusobacterium nucleatum upregulates ABCG2 by activating the E-cadherin/β-catenin signaling pathway to promote oxaliplatin resistance in colorectal cancer[J]. Chin J Oncol, 2025, 47(4):329-339.
[5]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[6]	BEHARY J, AMORIM N, JIANG X T, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma[J]. Nat Commun, 2021, 12(1):187. doi: 10.1038/s41467-020-20422-7 pmid: 33420074
[7]	TRIPATHI A, DEBELIUS J, BRENNER D A, et al. The gut-liver axis and the intersection with the microbiome[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(7):397-411. doi: 10.1038/s41575-018-0011-z pmid: 29748586
[8]	WANG X, FANG Y, LIANG W, et al. Gut-liver translocation of pathogen Klebsiella pneumoniae promotes hepatocellular carcinoma in mice[J]. Nat Microbiol, 2025, 10(1):169-184. doi: 10.1038/s41564-024-01890-9
[9]	PONTAROLLO G, KOLLAR B, MANN A, et al. Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling[J]. Nat Metab, 2023, 5(7):1174-1187. doi: 10.1038/s42255-023-00828-5 pmid: 37414930
[10]	MANFREDO VIEIRA S, HILTENSPERGER M, KUMAR V, et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans[J]. Science, 2018, 359(6380):1156-1161. doi: 10.1126/science.aar7201 pmid: 29590047
[11]	XING L, ZHANG Y, LI S, et al. A dual coverage monitoring of the bile acids profile in the liver-gut axis throughout the whole inflammation-cancer transformation progressive: reveal hepatocellular carcinoma pathogenesis[J]. Int J Mol Sci, 2023, 24(5):4258. doi: 10.3390/ijms24054258 URL
[12]	LIANG Z, LI S, WANG Z, et al. Unraveling the role of the Wnt pathway in hepatocellular carcinoma: from molecular mechanisms to therapeutic implications[J]. J Clin Transl Hepatol, 2025, 13(4):315-326. doi: 10.14218/JCTH.2024.00401 pmid: 40206274
[13]	LIN W, LI S, MENG Y, et al. UDCA inhibits hypoxic hepatocellular carcinoma cell-induced angiogenesis through suppressing HIF-1α/VEGF/IL-8 intercellular signaling[J]. Front Pharmacol, 2021,12:755394.
[14]	WILLEMSEN L E, KOETSIER M A, VAN DEVENTER S J, et al. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts[J]. Gut, 2003, 52(10):1442-1447. doi: 10.1136/gut.52.10.1442 pmid: 12970137
[15]	LOUIS P, FLINT H J. Formation of propionate and buty-rate by the human colonic microbiota[J]. Environ Microbiol, 2017, 19(1):29-41.
[16]	WANG W, DERNST A, MARTIN B, et al. Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation[J]. Cell Rep, 2024, 43(9):114736. doi: 10.1016/j.celrep.2024.114736 URL
[17]	HAN J, ZHANG S, XU Y, et al. Beneficial effect of antibiotics and microbial metabolites on expanded Vδ2Vγ9 T cells in hepatocellular carcinoma immunotherapy[J]. Front Immunol, 2020,11:1380.
[18]	CHEN W, WEN L, BAO Y, et al. Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2[J]. Proc Natl Acad Sci USA, 2022, 119(52):e2203894119. doi: 10.1073/pnas.2203894119 URL
[19]	SEYMOUR B J, TRENT B, ALLEN B E, et al. Microbiota-dependent indole production stimulates the deve-lopment of collagen-induced arthritis in mice[J]. J Clin Invest, 2023, 134(4):e167671. doi: 10.1172/JCI167671 URL
[20]	SHI Z, GAN G, GAO X, et al. Kynurenine catabolic enzyme KMO regulates HCC growth[J]. Clin Transl Med, 2022, 12(2):e697. doi: 10.1002/ctm2.697 pmid: 35184386
[21]	TANG H, WU L. MAMPs: a devil tamed becomes an angel[J]. Cell Host Microbe, 2023, 31(9):1422-1425. doi: 10.1016/j.chom.2023.08.009 pmid: 37708848
[22]	FITZGERALD K A, KAGAN J C. Toll-like receptors and the control of immunity[J]. Cell, 2020, 180(6):1044-1066. doi: S0092-8674(20)30218-X pmid: 32164908
[23]	SCHWABE R F, GRETEN T F. Gut microbiome in HCC - mechanisms, diagnosis and therapy[J]. J Hepatol, 2020, 72(2):230-238. doi: S0168-8278(19)30483-0 pmid: 31954488
[24]	YAMAGISHI R, KAMACHI F, NAKAMURA M, et al. Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma[J]. Sci Immunol, 2022, 7(72):eabl7209.
[25]	BHATT A P, SARTOR R B. 'Bugs on drugs': implications for gut health[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(5):287-288. doi: 10.1038/s41575-021-00437-1 pmid: 33692569
[26]	BAI W, XIAO J. Third international symposium on phytochemicals in medicine and food[J]. Crit Rev Food Sci Nutr, 2019, 59(sup1):S1-S3.
[27]	KIM S Y, AN J, LIM Y S, et al. MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma[J]. JAMA Oncol, 2017, 3(4):456-463. doi: 10.1001/jamaoncol.2016.3147 pmid: 27657493
[28]	XU F, ZHANG L, HE W, et al. The diagnostic value of serum PIVKA-Ⅱ alone or in combination with AFP in Chinese hepatocellular carcinoma patients[J]. Dis Mar-kers, 2021,2021:8868370.
[29]	ZHANG H, WU J, LIU Y, et al. Identification reprodu-cible microbiota biomarkers for the diagnosis of cirrhosis and hepatocellular carcinoma[J]. AMB Express, 2023, 13(1):35. doi: 10.1186/s13568-023-01539-6
[30]	ZHENG C, LU F, CHEN B, et al. Gut microbiome as a biomarker for predicting early recurrence of HBV-related hepatocellular carcinoma[J]. Cancer Sci, 2023, 114(12):4717-4731. doi: 10.1111/cas.v114.12 URL
[31]	FINN R S, QIN S, IKEDA M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20):1894-1905. doi: 10.1056/NEJMoa1915745 URL
[32]	YAU T, ZAGONEL V, SANTORO A, et al. Nivolumab plus cabozantinib with or without ipilimumab for advanced hepatocellular carcinoma: results from cohort 6 of the checkmate 040 trial[J]. J Clin Oncol, 2023, 41(9):1747-1757. doi: 10.1200/JCO.22.00972 URL
[33]	ZHOU C B, ZHOU Y L, FANG J Y. Gut microbiota in cancer immune response and immunotherapy[J]. Trends Cancer, 2021, 7(7):647-660. doi: 10.1016/j.trecan.2021.01.010 URL
[34]	SIMPSON R C, SHANAHAN E R, SCOLYER R A, et al. Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors[J]. Nat Rev Clin Oncol, 2023, 20(10):697-715.
[35]	ROUTY B, LE CHATELIER E, DEROSA L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J]. Science, 2018, 359(6371):91-97. doi: 10.1126/science.aan3706 pmid: 29097494
[36]	HU J, WANG C, YE L, et al. Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice[J]. J Biosci, 2015, 40(2):269-279. doi: 10.1007/s12038-015-9518-4 URL
[37]	PONZIANI F R, DE LUCA A, PICCA A, et al. Gut dysbiosis and fecal calprotectin predict response to immune checkpoint inhibitors in patients with hepatocellular carcinoma[J]. Hepatol Commun, 2022, 6(6):1492-1501. doi: 10.1002/hep4.1905 pmid: 35261212
[38]	GONG X, SHEN L, XIE J, et al. Helicobacter pylori infection reduces the efficacy of cancer immunotherapy: a systematic review and meta-analysis[J]. Helicobacter, 2023, 28(6):e13011. doi: 10.1111/hel.v28.6 URL
[39]	COUTZAC C, JOUNIAUX J M, PACI A, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer[J]. Nat Commun, 2020, 11(1):2168. doi: 10.1038/s41467-020-16079-x pmid: 32358520
[40]	MAGER L F, BURKHARD R, PETT N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy[J]. Science, 2020, 369(6510):1481-1489. doi: 10.1126/science.abc3421 pmid: 32792462
[41]	MIRJI G, WORTH A, BHAT S A, et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer[J]. Sci Immunol, 2022, 7(75):eabn0704.
[42]	ZHU X, HU M, HUANG X, et al. Interplay between gut microbial communities and metabolites modulates pan-cancer immunotherapy responses[J]. Cell Metab, 2025, 37(4):806-823.e6. doi: 10.1016/j.cmet.2024.12.013 pmid: 39909032
[43]	ZHANG Z, HUANG W, HU D, et al. E-twenty-six-specific sequence variant 5 (ETV5) facilitates hepatocellular carcinoma progression and metastasis through enhancing polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC)-mediated immunosuppression[J]. Gut, 2025, 74(7):1137-1149. doi: 10.1136/gutjnl-2024-333944 URL
[44]	LIU X, YANG W, PETRICK J L, et al. Higher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality[J]. Nat Commun, 2021, 12(1):6388. doi: 10.1038/s41467-021-26448-9 pmid: 34737258
[45]	KOMEIL I A, EL-REFAIE W M, GOWAYED M A, et al. Oral genistein-loaded phytosomes with enhanced hepatic uptake, residence and improved therapeutic efficacy against hepatocellular carcinoma[J]. Int J Pharm, 2021,601:120564.
[46]	PINATO D J, LI X, MISHRA-KALYANI P, et al. Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma[J]. JHEP Rep, 2023, 5(6):100747.
[47]	FESSAS P, NAEEM M, PINTER M, et al. Early anti-biotic exposure is not detrimental to therapeutic effect from immunotherapy in hepatocellular carcinoma[J]. Liver Cancer, 2021, 10(6):583-592. doi: 10.1159/000519108 URL
[48]	SHI K, ZHANG Q, ZHANG Y, et al. Association between probiotic therapy and the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis[J]. Front Cell Infect Microbiol, 2022,12:1104399.
[49]	ARAI N, MIURA K, AIZAWA K, et al. Probiotics suppress nonalcoholic steatohepatitis and carcinogenesis progression in hepatocyte-specific PTEN knockout mice[J]. Sci Rep, 2022, 12(1):16206. doi: 10.1038/s41598-022-20296-3 pmid: 36171333
[50]	CAMMAROTA G, IANIRO G, TILG H, et al. European consensus conference on faecal microbiota transplantation in clinical practice[J]. Gut, 2017, 66(4):569-580. doi: 10.1136/gutjnl-2016-313017 pmid: 28087657
[51]	LOPETUSO L R, DELEU S, GODNY L, et al. The first international Rome consensus conference on gut microbiota and faecal microbiota transplantation in inflammatory bowel disease[J]. Gut, 2023, 72(9):1642-1650. doi: 10.1136/gutjnl-2023-329948 URL
[52]	HUANG M, JI Q, HUANG H, et al. Gut microbiota in hepatocellular carcinoma immunotherapy: immune microenvironment remodeling and gut microbiota modification[J]. Gut Microbes, 2025, 17(1):2486519. doi: 10.1080/19490976.2025.2486519 URL
[53]	CHANG Z, GUO X, LI X, et al. Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization[J]. Cell, 2025, 188(7):1842-1857.e20. doi: 10.1016/j.cell.2025.02.002 URL