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. Author manuscript; available in PMC: 2024 Jan 1.
Published in final edited form as: Cancer J. 2023 Mar-Apr;29(2):57–60. doi: 10.1097/PPO.0000000000000646

The microbiome and liver cancer

Yuta Myojin 1, Tim F Greten 1,2
PMCID: PMC10168020  NIHMSID: NIHMS1866019  PMID: 36957974

Abstract

The gut-microbiome and liver are anatomically and functionally connected. The impact of the gut microbiota or microbial metabolites on liver cancer progression via immune cells has been recently revealed across various preclinical models. Commensal gut microbes of liver cancer patients differ from healthy controls and their composition is affected by the etiology of the HCC. The gut microbiota represents a potential novel target for intervention as shown in patients with melanoma, but we still lack data in patients with HCC. Fecal microbiota transplantation and dietary approaches may improve immunotherapy efficacy and a couple of clinical trials are ongoing. In liver cancer, the ongoing recognition of interactions between gut microbes and the tumor immune microenvironment provides an exciting therapeutic avenue to complement established immunotherapy.

Keywords: Liver cancer, immunotherapy, gut-microbiota

Liver Cancer

Liver cancer is one of the major causes of cancer related deaths worldwide 1. Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer2. The highest incidence and mortality of HCC are observed in East Asia and Africa, although HCC incidence and mortality are also increasing in different parts of Europe and in the USA 3. This may be due to an increase in non-alcoholic fatty liver disease (NAFLD) 4. Most HCC occur in patients with underlying liver cirrhosis and occur about 2.3-fold more frequently in men than in women in 2019 5. Early-stage HCC are treated with surgery, transplantation, or tumor ablation, while intermediate-stage cases undergo embolization and systematic therapy is the treatment of choice for patients with advanced disease 3 6 For a long time, sorafenib, a tyrosine kinase inhibitor, had been the only option for systematic therapy, but clinical trials revealed the efficacy of combined immunotherapies and become standard care of HCC patients7. However, the overall response is limited and needs to be improved. According to the latest report of the nation the overall death rate for HCC in the United States among males did not change between 2015 and 2019 8 with an estimated 5 year survival of 20 %9. Moreover, metabolic and inflammatory comorbidities, namely obesity, type 2 diabetes mellitus, and intestinal inflammation are factors driving HCC etiology, highlighting a critical gut-liver link10

The gut liver axis and liver cancer

The liver and the gastrointestinal tract communicate with each other bidirectionally along the gut-liver-axis. The portal vein represents a central component of the gut-liver-axis. It provides most of the liver’s blood supply 11. Gut derived commensal microbiota, microbial products and microbiota derived metabolites can reach the liver through the portal vein 12. The intestinal tract is continuously exposed to dietary antigens and microbes 12 with an estimated 3 × 103 bacterial species containing between 2 and 20 million different genes 13 residing within the colon.

In healthy conditions an intact gut barrier protects the human body from the gut commensal bacteria, and only negligible amounts of potentially pathogenic or toxic compounds such as dietary constituents or commensals enter the portal vein 12. However, various pathological conditions such as fatty liver disease 14,15, liver fibrosis and cirrhosis, inflammatory bowel disease, alcohol consumption, antibiotics or even dietary changes affect the composition of the gut bacteria leading to dysbiosis, likely via and impaired gut-barrier function. Indeed, the diversity of gut-microbiota decreases14 as liver disease progresses from chronic hepatitis, cirrhosis, to liver cancer. Increased intestinal barrier leakiness leads to improper hepatic exposure to microbiota-associated molecular patterns (MAMPs) and bacterial metabolites in chronic liver disease (CLD) promoting progression of CLD and the development of liver cancers as well as changes in local (gut) and distant (liver) immune function 16,17.

The characteristic of the microbiome in HCC

Various investigators have studied the composition of the gut derived microbiota. Many of these studies exhibit distinct microbiota compositions, likely due to distinct dietary and lifestyle factors that shape the human gut microbiome18. The composition of the gut microbiota of patients with hepatic cirrhosis differs from that of healthy individuals 19. Interestingly this difference may even promote HCC development. Enterococcus faecalis is abundant in the microbiota of patients with hepatitis C virus-related chronic liver disease. Fecal Microbiota Transplantation (FMT) studies using stool samples from patients with hepatitis C virus-related chronic liver disease promoted liver tumor growth in mice 20.

Ponziani and colleagues studied the gut microbiota in Italian patients with cirrhosis and NAFLD with and without HCC as well as healthy controls. Patients with cirrhosis showed higher abundance of Enterococcaceae, Gemellaceae at family level and Phascolarctobacterium, Enterococcus, Streptococcus, Gemella and Bilophila at genus level in patients with HCC. Contraly, they showed a reduction in Verrucomicrobiaceae, Bifidobacteriaceae Akkermansia, Bif idobacterium, Dialister, Collinsella Adlercreutzia in patients with HCC. . Plasma levels of interleukin 8 and 13 as well as chemokine (C-C motif) ligand 3, CCL4, and CCL5 were higher in the HCC group 14. The presence of hepatitis B infection is another factor affecting abundance of commensal gut bacteria in patients with HCC. Species richness at the level of genus of fecal microbiota of patients with HBV related HCC was much higher than in patients with non-viral induced HCC 21.

Emerging results from the analysis of intrahepatic microbiota in HCC reveals striking differences in bacterial composition. The authors studied tumor and normal adjacent tissue from 46 patients with HCC as well as hepatic tissue from 33 patients with hemangioma by 16S rRNA gene sequencing. The analysis of hepatic microbiota showed that HCC patients harbor a dysbiotic microbial community with a higher S. maltophilia abundance, a Gram-negative bacteria linked to poor hospital outcomes 22. In a different study from China, the authors studied samples from 11 HCC patients, 8 iCCA patients and 9 patients with combined HCC and intrahepatic cholangiocarcinoma (cHCC-CCA). The Bacterial phyla of Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes were the four dominant populations in both tumor and the matched adjacent nontumor tissues. Direct comparison of tumor with non-tumor tissue showed that Pseudomonas was significantly decreased in tumor tissues and both Rhizobiaceae at the family level and Agrobacterium at the genus level were significantly increased in tumor tissues 23.

Microbiome and immune responses in the liver

As mentioned before, dysbiosis can cause MAMPs and metabolite dislocation in the liver. MAMPs and metabolites of the gut microbiome can affect non-parenchymal cells, contributing on liver cancer pathophysiology through modulation of local immune responses.

To clarify the direct relationship of dysbiosis and immune responses, Nlrp6 knockout mice are used for spontaneously causing dysbiosis.. NLRP6 is the inflammasome sensor molecule and known to cause dysbiosis in NLRP6 knockout mice via TLR4 and TLR9. Toll-like receptor ligands bind to bacterial lipopolysaccharide (LPS) and CpG sequences, respectively 24. Recently, Schneider and colleagues demonstrated that dysbiosis increases the infiltration of mMDSC (CD45+ CD11b+ Ly6G − Gr1high cells) to the liver using Nlrp6 knock out mice, which promoted liver carcinogenesis and steatohepatitis in liver-specific NF-kappa B essential modulator (NEMO) knock out mice. Conditional NEMO knockout in liver parenchymal cells causes blocking the NF-kB signaling, which cause spontaneous hepatocyte cell death and steatohepatitis-hepatocaricinogenesis25. In the paper, Akkermansia muciniphila decrease in Nlrp KO mice was related to this phenotype26. Our group studied the connection between primary sclerosing cholangitis (PSC), colitis and cholangiocarcinoma. PSC induced dysbiosis led to an accumulation of LPS in the liver and an accumulation of PMN-MDSC 27. PMN-MDSC than suppressed anti-tumor immunity subsequently promoting cholangiocarcioma in this mouse model 27.

Beyond bacterial species, microbial metabolites also influence the hepatic immune landscape. Bile acids are produced in the liver and enhance lipid absorption in the intestine. Primary bile acids are converted to secondary bile acid by gut bacteria. Bile acids are reabsorbed in the intestine and this absorption is controlled by the gut microbiome28. Clostridial species change the balance of primary and secondary bile acids, which induce CXCL16 production of liver sinusoidal endothelial cells (LSEC). CXCL16 promotes CXCR6 expressing NKT cells accumulation in the liver and anti-tumor immunity 29. Deoxycholic acid, one of secondary bile acid induces hepatic stellate cells expressing senescence-associated secretory phenotype (SASP), which promote immune response to clear senescent cells and induce fibrosis and carcinogenesis30,31. In addition, anti-inflammmatory short-chain fatty acids (SCFAs) are produced by gut-microbiome from dietary fiber, including inulin. Oral inulin intake was shown to modulate the gut microbiome and improves anti-PD1 therapy via expansion of Tcf1+ PD1+ CD8+ T cell 32.

In addition to the effects from metabolites, bacteria itself can be found in human primary liver cancer22,23 and cirrhotic liver tissue26. Leinwand and colleagues studied the liver tissue resident bacteria and immune response in human and mouse. In that, Bacteroides in liver tissue produce glycosphingolipid, which is presented to iNKT cells and cause expansion of CD45+ leukocytes33. Consequently, dysbiosis or impaired exposure to the gut microbiota or microbial metabolites influence hepatic disease, driving liver inflammation, fibrosis, carcinogenesis, and tumor progression (Figure 1).

Figure 1. Gut-Liver axis in terms of gut-microbiota.

Figure 1

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The metabolites and bacteria from the intestine translocate to the liver via the portal vein and the bile duct transfer the metabolites such as primary bile acid from the liver.

The microbiome as a potential treatment target in liver cancer

Combined immunotherapy has become standard of care first and second line option for patients with HCC 6. However, the efficacy of immunotherapy remains limited and varies between patients, likely due to tumor heterogeneity and a tolerogenic tumor immune microenvironment. However, recent experimental models and a clinical melanoma cohort suggests the gut microbiome also influences therapeutic potential (CITE).

Clinically, the gut microbiome is associated with improved response to immunotherapy in patients with melanoma34–36, RCC, and NSCLC37. A recently performed meta-analysis including 6 retrospective studies covering 1056 HCC patients of which 352 received antibiotic treatment could not reveal that antibiotic use would impair response to immunotherapy in HCC 38. A different study including 20 patients with unresectable HCC showed fecal microbiota and bile acids were associated with outcomes of immunotherapy from a single center cohort in Asia. The authors showed that the coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival 39. Further prospective studies are needed to identify whether specific gut bacteria or bacterial metabolites shape hepatic immunotherapy.

The mechanism investigations for the relation of gut-microbiome and immunotherapy is examined in mice studies and proceed to clinical trials. The efficacy of anti-CTLA4 treatment is impaired both in antibiotic treated mice and germ-free mice. Colonizing mice with a bacterial cocktail of Bacteroides thetaiotaomicron, Bacteroides fragilis, or Burkholderia cepacian restored immunotherapy outcomes40. Furthermore, metabolites from gut microbiota also affect efficacy. Inosine modulated by Bifidobacterium pseudolongum promotes anti-CTLA4 therapy response in mouse models of intestinal cancer, which is dependent on adenosine receptor A2a receptor on T cells 41. Enterococcus-derived secreted antigen A (SagA) improves anti-PD-1 therapy and elicits an adaptive immune response42 and mice transplanted with stool derived from PD-1 therapy responder melanoma patients exhibited improved responses to anti-PD-1 therapy in contrast to mice that were transplanted with stool from NR patients34,37,43.

FMT studies are currently under way in melanoma 44,45. In addition to FMT, dietary alternations might be an useful option to improve immunotherapy efficacy as changes in diet rapidly affect the human gut microbiome46. In melanoma patients treated with immune checkpoint inhibitors the efficacy of anti-PD1 treatment was better in patients on high-fiber diet intake and no-probiotic use compared to low-fiber diet intake or probiotic use47. Dietary intake of lower fiber and omega 3 fatty acid are linked to decreased bacterial diversity of the gut microbiome, as well as poor response to immune checkpoint inhibitor in melanoma patients 48.

Based on these findings, Figure 2 provides an overview of potential therapeutic applications to change the gut microbiome and microbiota derived metabolites to improve the outcome to immunotherapy in HCC.

Figure 2. Gut-microbiome as a biomarker and therapeutic target combined with immunotherapy.

Figure 2

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Diet or antibiotics change the gut-micro biome. The microbiome of HCC patients might be a biomarker and target to treat combined with immune therapy.

Summary

The gut-microbiota has a significant impact on the immune environment in the liver controlling tumor development and progression. Interventions targeting the gut-microbiome might be a novel, and needed, therapeutic target of HCC combined with immunotherapy.

Acknowledgments

The authors thank Chi Ma and Kylynda Bauer for editing and proofreading the review.

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