Gut microbiome in gastrointestinal cancer: a friend or foe?

Abstract

The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.

Keywords: GI cancer; carcinogenesis; chemotherapy; gut microbiota.

Figure 1

The influence of gut microbiome on the development of GI cancer. Shown are the main mechanisms through which the gut microbiota is proposed to affect the tumorigenesis across GI cancer types, including esophagus, stomach, colon, liver, pancreas and bile duct.

Figure 2

A summarized figure demonstrating the linkage between the gut microbiome and gastric cancer and esophageal cancer. Section 1 Gastric cancer: HtrA protease secreted by H.pylori produce CagA protein by cleaving occludin, claudin-8 and E-cadherin. The cagA protein promotes EMT by activating the YAP pathway and inducing tumorigenesis through activation of NF-κB, PTEN, and SHP2 pathways. The production of ROS induced by H.pylori via the NF-κB pathway and inflammation contributes to DNA damage. H. pylori infection induces gastric stem cells to proliferate and stimulate gland hyperplasia through R-spondin 3 and Axin2. The interaction of CagA and PAR1b induces genomic instability by inhibiting the nuclear translocation of BRCA1 and YAP. The hypermethylation of USF1 by H. pylori degrades the p53 proteasome to promote gene instability. H.pylori-induced inflammation upregulates NOX1/ROS signaling pathway to promote the stemness of gastric cancer. H. pylori promotes the proliferation of cancer cell infection by activating the RASAL2/β-catenin signaling pathway. Section 2 ESCC: P. gingivalis trigger activation of NF-κB to induce EMT through the Smad/YAP/TAZ signaling pathway.

Figure 3

A summarized figure demonstrating the mechanisms of gut microbiome regulating HCC development. Section 1 Commensal bacteria regulate the metabolism of primary and secondary bile acids to control NKT accumulation via CXCL16. Section 2 LPS arising from gram-negative bacteria activate the NF-κB signaling pathway and produce a variety of pro-inflammatory cytokines. LTA in gram-positive bacteria collaboratively with DCA upregulate SASP and COX-2 through TLR2 in HSCs, COX2 mediated PGE₂ attenuate anti-tumor immunity through PTGER4.

Figure 4

Diagram summarizing the oncogenic interaction between the gut microbiome and CRC. The Fap2 protein combined with Gal-GalNAc is enriched on the surface of CRC cells to promote the colonization of F.nucleatum. F. nucleatum binds to E-cadherin on intestinal epithelial cells through FadA , activates the β-catenin signaling pathway, induces NF-κB pathway activation and upregulates pro-inflammatory cytokines, produces Fap2 to bind to TIGIT receptors on NK cells and other TILs. F.nucleatum activate NF-κB pathway via TLR4 and MYD88 to promote cell proliferation and invasion. Peptostreptococcus anaerobius increase the level of ROS via TLR2 and/or TLR4 signaling pathways. ETBF induce IL-17 and NF-κB pathway to enhance the production of C-X-C chemokine. MDSCs recruited by ETBF via IL-17 to inhibit the activity of cytotoxic CD8 + T cells. ETBF enhances the expression of MMP9 and VEGFA to induce neovascularization through IL-17. E. coli can also increase the level of ROS and promote the accumulation of spontaneous mutations. B. fragilis induces DNA damage.

Figure 5

Evidence of the gut microbiota enriched in GI cancer playing a crucial role in carcinogenesis. Circos plots illustrating the correlation of bacteria with tumorigenesis in GI cancer. The red ribbons represent the harmful effects of bacteria on GI cancer development. The blue ribbons represent the beneficial effects of bacteria on GI cancer development. The causality of the microbiota in GI cancer has not yet been fully elucidated. Different taxa are divided into six groups and colored by their phylum. Numbers indicate the references that highlight these relationships.