Dysbiosis of gut microbiota in promoting the development of colorectal cancer

Shaomin Zou, Lekun Fang, Mong-Hong Lee, Shaomin Zou, Lekun Fang, Mong-Hong Lee

Abstract

Gastrointestinal microbiome, containing at least 100 trillion bacteria, resides in the mucosal surface of human intestine. Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases, including colon tumorigenesis. Colorectal cancer (CRC), the third most common cancer, is the disease resulting from multi-genes and multi-factors, but the mechanistic details between gut microenvironment and CRC remain poorly characterized. Thanks to new technologies such as metagenome sequencing, progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible, which has facilitated studies about microbiota composition, taxonomic alterations and host interactions. Different bacterial species and their metabolites play critical roles in the development of CRC. Also, microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC. This review summarizes current studies regarding the association between gastrointestinal microbiota and the development of CRC, which provides insights into the therapeutic strategy of CRC.

Keywords: colorectal cancer; gut microbiota; microbiome dysbiosis; tumorigenesis.

Figures

Figure 1.
Figure 1.
Influence of TLR signaling on carcinogenesis by microbiota. (A) Dysbiosis of the luminal microbiota, such as the increase of Fusobacterium, induces the expression of TLR4, which activates the calcium-dependent calcineurin and NFAT. In addition, once the TLR4 is activated, it leads to the activation of NF-κb, resulting in the change of several miRNA expressions, including miR21. Finally, tumor growth is promoted. (B) TLR5 could recognize bacterium flagellin and induce the activation of NF-κb, regulating the expression of some inflammation-associated cytokines. (C) Bacteroides fragilis produces polysaccharide A and suppresses anti-microbial immune responses via TLR2 signaling, which promotes the inflammatory T-helper 17 responses whilst inhibiting the Foxp3+ regulatory T cells. TLR, Toll-like receptor; NF-κb, nuclear factor κb; NFAT, nuclear factor of activated T cells; ILC3, Innate lymphoid cells 3.
Figure 2.
Figure 2.
Microbiome affects immunotherapy efficacy. (A) Anti-CTLA4 antibodies impair function of Treg and increase Bacteroides, thereby improving the anti-tumor response mediated by immune checkpoint blockade (Anti-CTLA4). Antibiotics treatment can dampen the T-cell-mediated anti-tumor immune responses. (B) Bifidobacterium promotes DC activation and subsequent anti-tumor T-cell responses of anti-PD-L1 therapy. CTLA4, cytotoxic T-lymphocyte-associated antigen-4; Treg, regulatory T cells; DC, dentric cells; PD-L1, programmed cell death protein ligand 1.
Figure 3.
Figure 3.
Bacterial metabolites affect inflammation and gene expression. Bacterial metabolites, including SCFAs, interact with GPR41, GPR43 and GPR109A on host cells. Butyrate interacts with GPR109A, promoting the differentiation of Treg and activating macrophages and CD+ T cells to induce IL10 and TGFβ, thereby blocking inflammation. Butyrate and propionate, after being transported into host cells, cause HDAC inhibition, resulting in hyperacetylation of histones. The HDAC inhibition leads to cell cycle arrest, apoptosis induction and angiogenesis suppression. SCFAs, short-chain fatty acids; GPR, G protein-coupled receptor; Treg, regulatory T cells; IL10, interleukin 10; TGFβ, tumor growth factor β; HDAC, histone deacetylase.

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