The role of gut microbiota in tumor occurrence and diagnosis, and the anti-tumor mechanisms of probiotics.

China is a major country for cancer, with the incidence and mortality rates of common cancers generally higher than the global average. Malignant tumors are caused by the transformation of normal cells into uncontrolled abnormal cells after proto-oncogenes in normal cells are activated by mutagens, and cancer mutations are essentially the result of DNA damage. There is a large number of microbial communities in the normal human intestine, and the gut microbiota is closely related to human health and the occurrence of tumors. Certain intestinal bacteria can induce tumor occurrence through colonization at specific sites and dysbiosis of the gut microbiota, while the gut microbiota can also play a role in tumor treatment. The anti-tumor effect of probiotics has attracted widespread attention from scholars at home and abroad due to their non-damaging effect on normal tissue cells and has been studied in depth.

Gut microbiota and tumor occurrence

1. Helicobacter pylori

Helicobacter pylori is commonly found in various regions of the stomach and duodenum and can cause gastritis, peptic ulcers, and even gastric cancer. The International Agency for Research on Cancer of the World Health Organization has classified Helicobacter pylori as a Group 1 carcinogen, meaning it is a confirmed human carcinogen. Helicobacter pylori first secretes HtrA protease, which cleaves tight junction proteins Claudin-8 and E-cadherin, disrupting the protective layer of gastric epithelial cells, and then secretes CagA protein, reprogramming the host cell DNA, leading to the mutation of host cells into cancer cells. Additionally, Helicobacter pylori can activate gastric epithelial stem cells by increasing the expression of R-spondin 3 or promote DNA damage by reducing the expression of the USF1/p53 complex, thereby promoting the occurrence of gastric cancer.

2. Escherichia coli and Bacteroides fragilis

Colorectal cancer is a common malignant tumor of the digestive tract, ranking fourth among malignant tumors in China, with an increasing trend. Escherichia coli and Bacteroides fragilis in the gut microbiota can damage the colonic mucosal protective layer by releasing toxins, forming carcinogenic viscous biofilms in colonic epithelial cells, damaging DNA, and activating cancer pathways in colonic epithelial cells. On the other hand, the synergy of these two bacteria can also increase the likelihood of IL-17-induced colorectal cancer.

3. Fusobacterium nucleatum

Fusobacterium nucleatum is a common symbiotic bacterium in the oral cavity and has also been detected in tissues of colorectal cancer. As research progresses, more and more evidence suggests that Fusobacterium nucleatum can promote the occurrence and development of colorectal cancer. Fusobacterium nucleatum can activate the nuclear factor κB signaling pathway and increase the expression of microRNA-21, which promotes tumor cell transformation by inhibiting the tumor suppressor gene programmed cell death factor. At the same time, Fusobacterium nucleatum produces two lectins, FadA protein and Fap2 protein. FadA protein interacts with E-cadherin, activating the Wnt/β-catenin signaling pathway in colorectal cancer cells to promote the production and spread of cancer cells, while Fap2 protein mediates the binding of Fusobacterium nucleatum to overexpressed Gal-GalNAc in colorectal cancer cells, facilitating their transfer.

4. Dysbiosis of gut microbiota

The occurrence of tumors is a complex process, not caused by a single species, but rather influenced and acted upon by multiple microorganisms in the gut microbiota. A healthy and stable gut microbiota can maintain the normal physiological activities of the host, but once the gut microbiota becomes imbalanced, it can lead to abnormalities in the host, such as high methylation of host genes, resulting in precancerous lesions.

Gut microbiota and tumor diagnosis

In recent years, gut microbiota analysis has been applied to disease prediction and diagnosis. By analyzing the gut microbiota and its metabolites in tumor patients, the characteristics of the gut microbiota in tumor patients have been summarized, with the hope of using gut microbiota for tumor diagnosis.

1. Specific microorganisms

Ren et al. compared the fecal microbiota of healthy individuals, cirrhosis patients, and liver cancer patients, summarizing the gut microbiota characteristics of early liver cancer patients and constructing a diagnostic model, proving the potential of gut microbiota in predicting early liver cancer. Dai et al. analyzed the metagenomic data of colorectal cancer patients' gut microbiota in different populations and identified seven bacteria enriched in the intestines of colorectal cancer patients that could serve as potential diagnostic markers. A study by Zheng et al. also discovered and validated 13 high-precision biomarkers that can predict lung cancer, while establishing specific gut microbiota characteristics for the initial prediction of lung cancer.

2. Specific genomes

Xia et al. discovered a protein that can cause DNA damage through their research, which, when overexpressed in cells, can lead to DNA damage. The RNA expressing these proteins can be used to predict tumor mutations. Another summary analysis of the original metagenomes of differential microorganisms indicated the presence of a large number of microbial lyase genes in the fecal samples of colorectal cancer patients, which can convert choline into harmful metabolites for the human body. This finding provides a possibility for predicting the occurrence of colorectal cancer through the examination of gut microbial characteristics in fecal samples, positively impacting the prevention, screening, and treatment of colorectal cancer.

Anti-tumor mechanisms of probiotics

1. Immune activation

The anti-tumor effect of probiotics mainly relies on their immune activation in the body. Most probiotics are Gram-positive bacteria, and their cell walls are primarily composed of peptidoglycan, polysaccharides, and lipoteichoic acid. The main component of the cell wall peptidoglycan is muramyl dipeptide (MDP), which can activate macrophages to release interleukin-1 (IL-1) and interleukin-6 (IL-6), inducing lymphocytes to produce gamma-interferon (IFN-γ). IL-1 enhances the killing effect of natural killer (NK) cells, which can kill various tumor cells and play an important role in preventing tumor occurrence. IL-6 promotes the differentiation and maturation of B cells, can directly induce T cell proliferation, and participates in the activation of T cells and NK cells, inhibiting various tumors such as breast cancer and cervical cancer. The anti-tumor effect of lactic acid bacteria is achieved by activating immune effector cells such as macrophages, NK cells, and B cells through the muramyl dipeptide and lipoteichoic acid in their cell walls, leading to the secretion of cytotoxic effector molecules with tumor-killing activity.

2. Induction of Nitric Oxide (NO) Production

There is substantial research evidence indicating that the induced synthesis of nitric oxide is one of the main mechanisms by which activated macrophages kill tumor cells. It is currently widely believed that NO kills tumor cells through the following two pathways: (1) NO binds to the active site of key metabolic enzymes within tumor cells, forming iron-nitrosyl complexes that deactivate the enzymes, leading to cytotoxicity; (2) NO combines with oxygen to form hydroxyl radicals and NO2, which can strongly kill cells. Sekine et al. co-cultured whole peptidoglycan (WPG) from infant Bifidobacterium with mouse peritoneal exudate cells (which contain a large number of macrophages) and found that the supernatant from WPG-activated macrophages produced a large amount of NO. Lonchamp et al. further confirmed that another component of the Bifidobacterium cell wall, lipoteichoic acid, is an inducer of nitric oxide synthase. In summary, Bifidobacterium can induce the formation of NO in the body to kill tumor cells.

3. Promotion of Tumor Cell Apoptosis

Apoptosis is a series of cascaded active cell death processes that occur in response to various death signal stimuli. Wang Lisheng et al. found that after treatment with Bifidobacterium, tumor-bearing mice showed a significant increase in the expression rate of pro-apoptotic genes and the density of positive cells in the colorectal cancer transplant tumor group, indicating that Bifidobacterium enhances the expression of pro-apoptotic genes as a pathway to induce tumor cell apoptosis. Nuclear factor kappa B (NF-κB) is a multifunctional protein that can regulate the expression of various genes, inhibit tumor cell apoptosis, and is closely related to the occurrence and development of tumors. In a nude mouse model of colorectal cancer transplantation, the density of positive NF-κB cells in the Bifidobacterium injection group was significantly lower than that in the tumor control group, indicating that Bifidobacterium can prevent the activation of NF-κB in vivo, promoting tumor cell apoptosis.

4. Inhibition of Telomerase

Telomerase is a special ribonucleoprotein polymerase that is undetectable in differentiated somatic cells but is reactivated in the vast majority of tumor cells, leading to cellular immortality. Wang Yue et al. compared the telomerase activity of HL-60 leukemia cell lines before and after treatment with lipoteichoic acid from Bifidobacterium and found that after treatment, telomerase activity was significantly reduced, and the growth of HL-60 leukemia cells was inhibited. The anti-tumor mechanism of Bifidobacterium may be related to the inhibition of telomerase in tumor cells.

Conclusion

Identifying microorganisms related to tumor treatment can further enhance the efficacy of tumor therapies, and probiotics are also an important adjunct in tumor treatment. However, individual differences in the gut microbiome pose a major challenge for large-scale validation of the gut microbiome, and gut microbiology requires further exploration.

Note: This article is intended as a popular science article and should not be considered medical guidance.