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Name of Journal:World Journal of Hepatology Manuscript NO: Manuscript Type: LETTER TO THE EDITOR Commentary: Multi-omics reveals the associations among the fecal metabolome,intestinal bacteria, and serum indicators in patients with hepatocellular carcinoma Biao Wen,Yin-Ping Wang Biao Wen,Yin-Ping Wang,Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610000, Sichuan Province, China Author contributions:Yin-Ping Wang wrote the original draft; Biao Wen contributed to conceptualization, writing, reviewing and editing; Yin-Ping Wang and Biao Wen participated in drafting the manuscript; and all authors have read and approved the final version of the manuscript. Supported by ORCID number：0000-0001-5226-5981 Corresponding author:Biao Wen,MD, PhD,Assistant Professor,Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College,No. 312, Middle Section of Baoguang Avenue, Xindu District, Chengdu 610000, Sichuan Province, China. 820695761@qq.com Received: Revised: Accepted: Published online: Abstract: Recently, Feng J et al. published an important study. The research team revealed the associations of fecal metabolomics, intestinal bacteria and serum indicators in patients with hepatocellular carcinoma (HCC) through multi-omics analysis. The research results indicate that the composition of the metabolome and intestinal bacteria in fecal samples is expected to become a potential biomarker for the diagnosis of HCC. After a thorough review of their work, we put forward two insights regarding the impact of hepatitis B virus and antiviral drugs on the intestinal flora of HCC, the changes in intestinal microbiota in HCC and healthy control groups. Key Words: Liver neoplasms; Gastrointestinal microbiome; Antiviral drug; Comment; Core Tip: We conducted a rigorous assessment of the research by Feng et al., and put forward expert suggestions regarding the changes of HCC in the gut microbiota and the impact of hepatitis B virus and related antiviral drugs on the microbiota, in order to advance this scientific field. TO THE EDITOR After reading the study titled "Multi-omics reveals the associations among the fecal metabolome, intestinal bacteria, and serum indicators in patients with hepatocellular carcinoma" by Feng et al. published in the World Journal of Gastroenterology, we found it highly insightful. The authors employed integrated metabolomic and microbiomic approaches to elucidate the linkages between fecal metabolites, gut microbiota, and serum biomarkers in hepatocellular carcinoma (HCC) patients, providing new perspectives for the early diagnosis of HCC. Here, we would like to share our perspectives on the following aspects: The impact of hepatitis B virus (HBV) and antiviral therapies on gut microbiota alterations in HCC; Gut microbial differences between HCC patients and healthy controls. The first point: The changes in the gut microbiota of HCC and healthy control groups vary in different studies and may be influenced by multiple factors More and more studies have shown that the intestinal microbiota is related to the occurrence of HCC and is expected to become a biomarker for the diagnosis of HCC. In the study by Feng et al., it was concluded that Lachnospira, Streptococcus and Veillonella are representative differential bacterial genera in the feces of HCC patients. These three bacterial genera and their related metabolites may serve as unique biomarkers [1]. Most studies have shown that there are differences in theα-diversity orβ-diversity of the intestinal microbiota between HCC patients and healthy control groups. However, these differences may vary when further studying the intestinal microbiota of HCC patients, such as at the genus level or species level. Zhang et al. found that Enterococcaceae, Lactobacillus, Bacillus and Gammaproteobacteria can be used as diagnostic markers for primary liver cancer (PLC). In addition, a correlation analysis was conducted, and the results showed that Veillonella was significantly positively correlated with alpha-fetoprotein (AFP) in PLC patients[2]. In 2023, Zhang et al. demonstrated that at the family level, the abundance of Lachnospiraceae, Coriobacteriaceae, Eggerthellaceae and Synergistaceae in the liver cancer group was significantly reduced compared with the normal group. The abundances of Enterobacteriaceae, Fusobacteriaceae, Lactobacillus and Erysierysiaceae increased significantly. At the horizontal level, compared with the normal group, The liver cancer groups included Blautia, Fusicatenibacter, Anaerostipes, Lachnospiraceae_ND3007_group, GG-56, Eggerthella, Lachnospiraceae_FCS020_group and The abundance of Olsenella was significantly reduced. The abundance of Escherichia coli - Shigella, Prevotella_2 Tyzzerella_4, Clostridium erysipelum and Prevotella_2 Tyzzerella ₄ increased significantly. Meanwhile, alpha-fetoprotein (AFP) is positively correlated with the abundance of Streptococcus[3];Yang et al. confirmed through a prospective study that in terms of intestinal samples, the average relative abundance of Proteobacteria in the HCC group was significantly higher than that in the control group. The abundance of Streptococcus in oral and fecal samples of HCC patients was higher than that in the control group. Meanwhile, during the transition from a healthy state to liver cirrhosis and HCC, the content of streptococcus in the hepatocellular carcinoma and liver cirrhosis groups was much higher than that in the control group, and showed an upward trend during the disease progression. From the analysis of microbial correlations and clinical characteristics and functions among each group, both Streptococcus and Virongella were identified in the microbial communities of oral and intestinal samples, and both were in key positions in the microbial correlation network of fecal samples. Streptococcus and Virongella showed a consistent trend. Among them, the microbiome distribution was positively correlated with MELD, Child-Pugh, age, CCI, AFP, AST, ALT, GGT, Cre, LDL, Tchol, PT and INR, and negatively correlated with ALB, BMI, HDL, TG and PLT in HCC patients. This study has similarities with that of Feng J et al[4];In 2024, the research results of Jinato et al. indicated that HCC was enriched with five genera, including Bacteroides, Streptococcus, Ruminococcus, Veronistella and Clostridium erysibiricum. And Romboutsia, UCG-002, Lachnospiraceae NK4A-136, Eubacterium hallii group, Lachnospiraceae ND-3007 group, Erysipelotrichaceae Seven genera such as UCG-003 and Bilophila have low abundance in HCC patients[5]. From the above, it can be known that some studies have mentioned the three bacterial genera, Streptococcus, Veronella, and Lachnospira, in the HCC and healthy groups, showing an increase in the abundance of Streptococcus and Veronella, while the relative abundance of Lachnospira has decreased. However, in different studies, The reasons for the incomplete similarity in the abundance and structure of the intestinal microbiota between HCC and the healthy control group may be related to the drug use, alcohol consumption, diet, racial and regional differences of HCC patients[6];A Western diet high in fat, cholesterol or sugar can induce dysbiosis of the gut microbiome, a reduction in symbiotic probiotics and an increase in opportunistic pathogens[7];For example, the formation of NAFLD-HCC induced by dietary cholesterol is related to intestinal flora imbalance, and the composition of the microbiota changes with the formation stage of NAFLD-HCC: Mucispirillum, Desulfovibrio, Anaerotruncus and Desulfovibrionaceae increased successively; Bifidobacterium and Bacteroides were depleted in mice fed with HFHC, which was also confirmed in patients with human hypercholesterolemia[8].Therefore, it is still necessary to further verify the unique biomarkers of HCC. The second point: Distinguish the independent effects of HBV infection and HCC and include data on the use of antiviral drugs Hepatitis B virus infection can directly disrupt the intestinal flora balance through systemic inflammatory responses and disorders of the hepatoenteric axis. The study by Shen et al. indicated that the flora composition of patients with HBV-CLD (such as enrichment of Streptococcus and reduction of Bifidobacterium) was significantly different from that of the healthy control group. It is suggested that HBV infection itself has unique microbiota characteristics; Meanwhile, antiviral drug treatment can partially reverse the dysbiosis caused by HBV[9-10]; Jinato et al. studied the changes in the gut microbiota between Viral (virus-HCC) and non-viral (NNC-HCC) -related hepatocellular carcinomas and found that compared with virus-HCC, the NNC-HCC subgroup significantly reduced various bacteria that produce short-chain fatty acids and the reduction of fecal butyrate[5];Liu et al. also analyzed the intestinal microbiota changes in hepatitis B virus-associated hepatocellular carcinoma. The research results showed that there were differences in the abundance of bacteria in the intestines of patients with B-HCC and NNBNC-HCC, and these bacteria were respectively involved in different functions or biological pathways[11]. Therefore, whether there is HBV infection and whether antiviral treatment is used may have an impact on the changes in the intestinal flora. In the study by Feng J et al., we found that HBV accounted for a high proportion (78.95%) in the HCC population. Based on previous studies, stratified comparison of HCC patients with HBV(+) and HBV(-), as well as recording the use of antiviral drugs and analyzing their effects, can more accurately clarify the microbiota characteristics of HCC itself. All in all, the changes in the gut microbiota are related to the occurrence and development of HCC. The inconsistency in the research on the gut microbiota related to HCC reflects the complexity of the disease and the dynamics of host-microbiota interactions. Future studies need to directly compare the microbiota, metabolome and immune characteristics of patients with HBV(+)HCC and HBV(-)HCC through larger sample cohorts of HCC, and combine animal models to verify the causal mechanism in order to reveal more robust microbiota characteristics and their mechanism of action in the occurrence and development of HCC. We look forward to the author team conducting follow-up research in this direction and promoting the innovation of early diagnosis techniques for HCC. Once again, we thank the authors for their outstanding work, which has opened up new ideas for HCC research. Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported. 1.Feng J, Wang J P, Hu J R, et al. Multi-omics reveals the associations among the fecal metabolome, intestinal bacteria, and serum indicators in patients with hepatocellular carcinoma[J]. World Journal of Gastroenterology, 2025, 31(15). 2.Zhang L, Wu YN, Chen T, Ren CH, Li X, Liu GX. Relationship between intestinal microbial dysbiosis and primary liver cancer. Hepatobiliary Pancreat Dis Int. 2019 Apr;18(2):149-157. doi: 10.1016/j.hbpd.2019.01.002. Epub 2019 Jan 4. PMID: 30661942. 3.Zhang W, Xu X, Cai L, Cai X. Dysbiosis of the gut microbiome in elderly patients with hepatocellular carcinoma. Sci Rep. 2023 May 13;13(1):7797. doi: 10.1038/s41598-023-34765-w. PMID: 37179446; PMCID: PMC10182990. 4.Yang J, He Q, Lu F, Chen K, Ni Z, Wang H, Zhou C, Zhang Y, Chen B, Bo Z, Li J, Yu H, Wang Y, Chen G. A distinct microbiota signature precedes the clinical diagnosis of hepatocellular carcinoma. Gut Microbes. 2023 Jan-Dec;15(1):2201159. doi: 10.1080/19490976.2023.2201159. PMID: 37089022; PMCID: PMC10128432. 5.Jinato T, Anuntakarun S, Satthawiwat N, Chuaypen N, Tangkijvanich P. Distinct alterations of gut microbiota between viral- and non-viral-related hepatocellular carcinoma. Appl Microbiol Biotechnol. 2024 Dec;108(1):34. doi: 10.1007/s00253-023-12845-1. Epub 2024 Jan 6. PMID: 38183473; PMCID: PMC10771587. 6.Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, Bray F. Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology. 2020 Jul;159(1):335-349.e15. doi: 10.1053/j.gastro.2020.02.068. Epub 2020 Apr 2. PMID: 32247694; PMCID: PMC8630546. 7.Pan Y, Zhang X. Diet and gut microbiome in fatty liver and its associated liver cancer. J Gastroenterol Hepatol. 2022 Jan;37(1):7-14. doi: 10.1111/jgh.15713. Epub 2021 Nov 3. PMID: 34664301. 8.Zhang X, Coker OO, Chu ES, Fu K, Lau HCH, Wang YX, Chan AWH, Wei H, Yang X, Sung JJY, Yu J. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut. 2021 Apr;70(4):761-774. doi: 10.1136/gutjnl-2019-319664. Epub 2020 Jul 21. PMID: 32694178; PMCID: PMC7948195. 9.Shen Y, Wu SD, Chen Y, Li XY, Zhu Q, Nakayama K, Zhang WQ, Weng CZ, Zhang J, Wang HK, Wu J, Jiang W. Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response. Gut Microbes. 2023 Jan-Dec;15(1):2155018. doi: 10.1080/19490976.2022.2155018. PMID: 36519342; PMCID: PMC9757487. 10.Li YG, Yu ZJ, Li A, Ren ZG. Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications: Molecular mechanisms and therapeutic inventions. World J Gastroenterol. 2022 Jul 28;28(28):3555-3572. doi: 10.3748/wjg.v28.i28.3555. PMID: 36161048; PMCID: PMC9372803. 11.Liu Q, Li F, Zhuang Y, Xu J, Wang J, Mao X, Zhang Y, Liu X. Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut Pathog. 2019 Jan 18;11:1. doi: 10.1186/s13099-018-0281-6. PMID: 30675188; PMCID: PMC6337822.

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