The Role of Cyclomodulins and Some Microbial Metabolites in Bacterial Microecology and Macroorganism Carcinogenesis

Abstract

A number of bacteria that colonize the human body produce toxins and effectors that cause changes in the eukaryotic cell cycle-cyclomodulins and low-molecular-weight compounds such as butyrate, lactic acid, and secondary bile acids. Cyclomodulins and metabolites are necessary for bacteria as adaptation factors-which are influenced by direct selection-to the ecological niches of the host. In the process of establishing two-way communication with the macroorganism, these compounds cause limited damage to the host, despite their ability to disrupt key processes in eukaryotic cells, which can lead to pathological changes. Possible negative consequences of cyclomodulin and metabolite actions include their potential role in carcinogenesis, in particular, with the ability to cause DNA damage, increase genome instability, and interfere with cancer-associated regulatory pathways. In this review, we aim to examine cyclomodulins and bacterial metabolites as important factors in bacterial survival and interaction with the host organism to show their heterogeneous effect on oncogenesis depending on the surrounding microenvironment, pathological conditions, and host genetic background.

Keywords: bacterial metabolites; carcinogenesis; cyclomodulins; genotoxins; microecology.

Figure 1

The role of cyclomodulins in carcinogenesis. CNF1, activating Rho GTPases, causes changes in the actin cytoskeleton, which leads to blocking of cytokinesis and the occurrence of aneuploidy and the epithelial-mesenchymal transition of cells. GTPases suppress the expression of cyclin B1 by arresting the cell cycle in the G2/M phase and increasing the transcription of Bcl-2 and Bcl-XL factors without triggering apoptosis. Aneuploidy, senescence, and the acquisition of a mesenchymal phenotype by cells lead to the development and progression of cancer. CIF, by binding to the ubiquitin-like protein NEDD8, inhibits the activity of CRL ubiquitin ligase. As a result, p21 and p27 accumulate in the cell, which leads to cell cycle arrest, prevention of eukaryotic cell proliferation, and delayed apoptosis. The genotoxins colibactin and CDT cause DNA damage resulting in cell cycle arrest at the G1/S and G2/M checkpoints. Cell growth and cell renewal arrest facilitate bacterial colonization. The cellular response to significant DNA damage consists either in the development of apoptosis or in the formation of a cellular senescence phenotype. Incomplete DNA repair of surviving cells leads to genomic instability, initiation of tumor development, and/or increased tumor growth. (Figure 1 was created using the images from Servier Medical Art https://smart.servier.com/ 26 June 2022).

Figure 2

Contribution of commensal bacteria microbial metabolites to carcinogenesis. By stimulating the proteasomal degradation of p53 and inducing cancer stem cells (CSC), secondary BAs lead to malignant transformation of cells. Oxidative damage to DNA by secondary BA and butyrate is associated with the formation of ROS, which cannot be restored in genetically modified cells, which leads to the formation of resistance to apoptosis, increased autophagy, and cancer development. Butyrate inhibits HDAC in normal and cancer cells. The action of butyrate upon HDAC3 of intestinal macrophages reduces the activity of the mTOR protein, as a result of which autophagy in macrophages is enhanced. This is how butyrate-producing bacteria maintain the optimal level of their population. By inhibiting HDAC, butyrate induces the expression of p21, which arrests the cell cycle at the G1-S stage: cells can undergo apoptosis or acquire a senescence-associated secretory phenotype leading to the development or progression of cancer. By inhibiting the production of cyclic adenosine monophosphate (cAMP), lactic acid activates autophagy in vaginal epithelial cells, protecting them from intracellular microorganisms. Protective autophagy in tumor cells prevents apoptosis, promoting tumor metastasis. By blocking HDAC, lactic acid increases the production of NGAL by epithelial cells, which inhibits the growth of other microorganisms, inducing selective transcription of genes in malignantly transformed cells, which contributes to their survival and stimulates oncogenesis. (Figure 2 was created using images from Servier Medical Art https://smart.servier.com/ 26 June 2022).