Potential effects of gut microbiota on host cancers: focus on immunity, DNA damage, cellular pathways, and anticancer therapy

Abstract

The symbiotic bacteria that live in the human gut and the metabolites they produce have long influenced local and systemic physiological and pathological processes of the host. The gut microbiota are increasingly being recognized for its impact on a range of human diseases, including cancer, it may play a key role in the occurrence, progression, treatment, and prognosis of many types of cancer. Understanding the functional role of the gut microbiota in cancer is crucial for the development of the era of personalized medicine. Here, we review recent advances in research and summarize the important associations and clear experimental evidence for the role of the gut microbiota in a variety of human cancers, focus on the application and possible challenges associated with the gut microbiota in antitumor therapy. In conclusion, our research demonstrated the multifaceted mechanisms of gut microbiota affecting human cancer and provides directions and ideas for future clinical research.

Fig. 1. Gut microbiota metabolites are involved in innate and adaptive host immunity.

The gut microbiota and metabolites in the intestinal lumen are sensed by dendritic cells (DCs), which then induce the transformation of naive T-cells into various effector T-cells. In this process, butyrate inhibits DC activation of naive T-cells and secretion of IL-6, −8, and −12, and other factors, while promoting the transformation of naive T-cells into Treg. Bacteroides fragilis toxin (BFT) promoted the transformation of naive T-cells into Tfh cells and Th17. Staphylococcal enterotoxin B promotes the transformation of naive T-cells into Th9 cells. Inosine and short-chain fatty acids promote the transformation of naive T-cells into Th1 cells, and trimethylamine N-oxide promotes the secretion of IL-2 and −3, and other factors by Th1 cells. In terms of innate immunity, myeloid-derived suppressor cells reach the intestinal tract through the blood and secrete cancer-promoting factors, such as Arg-1, nitric oxide synthase (NOS), and reactive oxygen species. In this process, FAP2 plays a promoting role. Simultaneously, FAP2 binds and blocks the receptor TIGIT on NK T-cells, thus inhibiting the NK T-mediated tumor cell attack process. Secondary bile acid decreases the expression of CXCL16 on the surface of antigen-presenting cells (APCs) and prevent the aggregation of CXCR6⁺ NK T-cells. Intracellular RIG-I on APCs recognizes the abnormal DNA of the bacterial community and transmits the signal to mitochondrial anti-viral signaling proteins (MAVS) on the mitochondrial membrane, which in turn activates the NF-kB signal and releases IFN-α, a process in which MAVS plays a catalytic role.

Fig. 2. DNA mismatch-repair imbalance, DNA damage, chromosomal instability, and abnormal histone acetylation caused by gut microbiota.

Gut microbiota such as Shigella flexneri (S. flexneri), Escherichia coli (E. coli), Bacteroides fragilis (B. fragilis), Enterococcus faecalis (E. faecalis), Morganella morganii (M. morganii), and Helicobacter pylori (H. pylori) block the normal cell cycle by affecting oxidative environment-dependent DNA damage and disrupting the DNA mismatch-repair process, thus increasing the tendency of epithelial cells to become cancerous. Additionally, toxins secreted by E. coli interfere with histone acetylation, while butyrate and propionic acid, metabolites of Butyrivibrio fibrisolvens (B. fibrisolvens) and Propionibacterium, as inhibitors of deacetylase, can increase the degree of acetylation and have an opposite anticancer effect. E. faecalis releases oxidants through a macrophage-dependent manner, causing chromosomal instability.

Fig. 3. Gut microbiota are involved in the regulation of several intracellular signaling pathways.

CagA binds to SHP-2 and activates it to promote Ras/MAPK signaling and trigger the abnormal proliferation of host T-cells. Gingipains is the main virulence factor of Porphyromonas gingival, it up-regulate phosphorylation of MEK and ERK, the core components of the RAS/RAF/MEK/ERK pathway, promoting cancer cell proliferation. E-cadherin is a transmembrane glycoprotein that exists in cell membranes and binds epithelial cells together to maintain their normal morphology and polarity. Normally, the intracellular peptide of E-cadherin is linked to β-catenin to ensure that it does not transmit signals to the nucleus, while the intracellular free β-catenin exists in the form of a complex. CagA and FadA destroy the function of E-cadherin, affect the intercellular connection and the binding force of β-catenin, and switch on the WNT/β-catenin signal when the WNT signal activates the cell membrane receptor FRZ. TLR-4 recognizes bacterial metabolites, such as Bacteroides fragilis toxin (BFT), gingipains, lipopolysaccharides, and butyrate, and activates the NF-kB and NFAT signaling pathways to promote abnormal proliferation of cancer cells.