Gut microbiota-mediated gut-liver axis: a breakthrough point for understanding and treating liver cancer

Abstract

The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Keywords: Clinical translation; Gut microbiota; Gut-liver axis; Intratumoral microbiota; Liver cancer.

Figure 1.

Origin and outcomes of gut dysbiosis in the gut-liver axis. (A) Environmental factors such as the Western diet, alcohol consumption, drugs, and genetic predispositions are primary contributors to gut dysbiosis in the context of liver diseases. (B) This dysbiosis disrupts microbial metabolism, leading to intestinal barrier dysfunction and subsequent translocation of microorganisms and microbial products to the liver. These events typically occur early in the pathogenic process.

Figure 2.

Gut microbiome evolves with liver carcinogenesis from different etiologies. Hepatocellular carcinoma developing from different etiologies exhibits diverse fecal microbiome profiles. Similarly, iCCA is associated with specific changes in gut bacteria and metabolites. Blue boxes represent bacterial genus, yellow boxes species, red boxes fungi and green boxes metabolites. CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GUDCA, glycoursodeoxycholic acid; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; PSC, primary sclerosing cholangitis; SCFAs, short-chain fatty acids; TUDCA, tauroursodeoxycholic acid.

Figure 3.

Underlying mechanisms by which aberrant gut-liver axis promotes hepatobiliary carcinogenesis. (A) As a result of gut leakiness, the liver is exposed to a large number of gut-derived inflammatory signals, including pathogen-associated molecular patterns (PAMPs), exotoxins and live microorganisms. Cytolysin directly causes hepatocyte death by inducing cell lysis and contributes to subsequent fibrosis. Lipopolysaccharide (LPS) stimulates Kupffer cells to produce pro-inflammatory cytokines and exerts pro-proliferative and anti-apoptotic effects on hepatocytes through Toll-like receptor 4 (TLR4). Muramyl dipeptide (MDP) induces DNA damage and secretion of inflammatory cytokines in hepatocytes by binding to nucleotide-binding oligomerization domain 2 (NOD2). Senescent hepatic stellate cells (HSCs) provoked by lipoteichoic acid (LTA) and deoxycholic acid (DCA) also exacerbate hepatic inflammation by releasing several senescence-associated secretory phenotype (SASP) factors. (B) Gut microbiota mediates the effects of high dietary fructose intake on pro-carcinogenic metabolic reprogramming. Tumor necrosis factor (TNF) upregulates the expression of key genes in lipid synthesis through the activation of TNF signaling, thereby promoting de novo lipogenesis. High fructose diet elevates the levels of microbiota-derived acetate, which promotes HCC cell proliferation by enhancing glutamine synthesis and O-GlcNAcylation of downstream proteins. (C) Gut dysbiosis induces an immunosuppressive microenvironment in the liver. Senescent HSCs suppress anti-tumor immunity by producing prostaglandin E2 (PGE2) and interleukin-33 (IL-33), which inhibit the expansion of cytotoxic CD8⁺ T cells and activate T_reg cells, respectively. Activation of LPS-TLR4 signaling in hepatocytes promote the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Secondary bile acids inhibit hepatic NKT cells accumulation by downregulating the expression of C-X-C motif chemokine ligand 16 (CXCL16) in liver sinusoidal endothelial cells (LSECs). Gut dysbiosis also restrains immune activation and promotes immunosuppression by reducing acetate levels. CCA, cholangiocarcinoma; DAMPs, damage associated molecular patterns; HCC, hepatocellular carcinoma; IFN-γ, interferon-γ.

Figure 4.

Clinical implications of gut microbiota in liver cancer prevention, diagnosis and therapy. The gut microbiome can serve as a non-invasive biomarker for the diagnosis of liver cancer. Gut microbiota-based therapeutic strategies, such as antibiotics, probiotics, and fecal microbiota transplantation (FMT), have the potential to prevent the malignant progression of liver cancer from benign liver diseases and enhance the efficacy of liver cancer treatments, including targeted therapy, chemotherapy, and radiotherapy, by restoring gut homeostasis. A novel approach, the nano-delivery system, can transport gut microbial metabolites to tumor sites, improving both efficacy and safety.