Hepatocellular Carcinoma: How the Gut Microbiota Contributes to Pathogenesis, Diagnosis, and Therapy

Abstract

The gut microbiota is gaining increasing attention, and the concept of the "gut-liver axis" is gradually being recognized. Leaky gut resulting from injury and/or inflammation can cause the translocation of flora to the liver. Microbiota-associated metabolites and components mediate the activation of a series of signalling pathways, thereby playing an important role in the development of hepatocellular carcinoma (HCC). For this reason, targeting the gut microbiota in the diagnosis, prevention, and treatment of HCC holds great promise. In this review, we summarize the gut microbiota and the mechanisms by which it mediates HCC development, and the characteristic alterations in the gut microbiota during HCC pathogenesis. Furthermore, we propose several strategies to target the gut microbiota for the prevention and treatment of HCC, including antibiotics, probiotics, faecal microbiota transplantation, and immunotherapy.

Keywords: diagnosis; gut microbiota; gut-liver axis; hepatocellular carcinoma; treatment.

FIGURE 1

Distribution of microorganisms in the gastrointestinal tract. CFU, colony-forming units.

FIGURE 2

Mechanisms by which BAs mediate HCC. (A) Bile acids, as important metabolites of the gut microbiota, can cause inflammatory responses, cell death, ROS accumulation, reduction of apoptosis, and so on, mainly by mediating complex signalling pathways within hepatocytes, ultimately leading to the development of HCC. (B) BAs can also act on other liver cells such as HSC, LSEC, NKT cell, and so on, thereby affecting HCC progression. BAs, bile acids; TRAILR, TNF-related apoptosis inducing ligand receptor; cFLIP, Cellular FLICE-like inhibitory protein; mtDNA, mitochondrial DNA; Bcl-2, B cell lymphoma-2; ROS, reactive oxygen species; TLR, Toll-like receptor; ER, endoplasmic reticulum; CaMKII, calcium/calmodulin-dependent protein kinase II; CHOP, C/EBP homologous protein; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; JAK, Janus kinase; STAT3, signal transducer and activator of transcription 3; PLA2, phospholipase A2; AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; Egr-1, early growth response gene 1; EGFR, epidermal growth factor receptor; vcm-1, vascular endothelial cell adhesion molecule 1; FXR, Farnesoid X receptor; TDCA, taurodeoxycholic acid; TCA, taurocholic acid; SIRT1, sirtuin 1; FasL, fas ligand; HNF 1α, hepatocyte nuclear factor 1α; TGR5, Takeda G protein-coupled receptor 5; HSC, hepatic stellate cell; LTA, lipoteichoic acid; SASP, senescence-associated secretory phenotype; DCs, dendritic cells; NKT cell, natural killer T cell; CXCR, C-X-C chemokine receptor type; LSEC, liver sinusoidal endothelial cell; LCA, lithocholic acid; ω-MCA, ω-muricholic acid; NK cell, natural killer cell.

FIGURE 3

Mechanisms by which TLR4 mediates HCC. (A) For hepatocytes, TLR4 can lead to angiogenesis (activation of VEGF), invasiveness (through multiple inflammatory mediators), EMT, degeneration (activation of PREX-2) and downregulation of miR122, ultimately promoting the development of HCC. (B) In other liver cells, TLR4 expression also activates signals (such as NF-κB, interleukin and TNF-α) that promote HCC development. LPS, lipopolysaccharide; HMGB1, high-mobility group box 1; MKK4, MAP kinase 4; JNK, c-Jun N-terminal kinase; MMP, matrix metallopeptidase; EMT, epithelial mesenchymal transition; PREX-2, phosphatidylinositol-3, 4, 5-trisphosphate RAC exchanger 2; VEGF, vascular endothelial growth factor; SP1, specificity protein 1; miR-122, microRNA-122; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; BAMBI, bone morphogenetic protein and activin membrane bound inhibitor; TGF, transforming growth factor; NLRP3, NLR family pyrin domain-containing 3; Th17 cell, T helper 17 cell; Pten, phosphatase and tensin homologue; Treg cell, regulatory T cell; CCL22, C-C class chemokine 22; SOX2, SRY-box containing gene 2; CSC, cancer stem cell.

FIGURE 4

Possible future strategies for targeting the gut microbiota in the treatment of HCC. ➀Antibiotics such as rifaximin, norfloxacin, and others are capable of scavenging specific gut microbes to inhibit HCC progression. ➁Specific probiotics, prebiotics, and postbiotics may inhibit the development of HCC by maintaining the gut microecological environment and improving gut barrier functions. ➂Modified FMT (adjustment of components, delivery frequency, delivery route, etc.) can bring the gut microbiota of HCC patients closer to those of normal people. ➃The immunosuppressive environment shaped by harmful species of the gut microbiota can be improved by immunotherapy targeting CTLA-4 and PD-1. ➄FXR agonists (such as obeticholic acid) and TLR4 inhibitors (such as eritoran) can affect bile acid metabolism and immune response signalling, respectively, both of which might inhibit HCC development by indirectly altering the gut microbiota. FMT, faecal microbiota transplantation; FXR, Farnesoid X receptor; TLR4, Toll-like receptor 4; HCC, hepatocellular carcinoma.