The human body is an ecosystem consisting of not just human eukaryotic cells, but also an array of viruses and microorganisms that we call the human virome and microbiome1. They are important in human health. Dietary fiber and polyunsaturated fats help cultivate a healthy gut microbiome. This can help prevent many types of cancer and other diseases. Recent advances in technology allow us to see connections that were previously not recognized. For example, we knew that cytomegalovirus (CMV) is abundant in gliomas (brain cancer) but thought that the cancer cells were separate from CMV, as well as other viruses and bacteria.

The brain was thought to be sterile (germ-free) and protected by the blood-brain barrier. We now know that it is not. Viruses and bacteria have been found, not just in biopsies but also in individual brain cells2. They are found under non-inflammatory and non-traumatic conditions. Certain pathogenic bacteria can lead to a variety of diseases. Gram-negative bacterial biochemicals and Porphyromonas gingivalis were detected in the brains of Alzheimer’s disease patients. They were also linked to the accumulation of the tau protein that causes Alzheimer’s disease.

CMV has also been found in glioblastoma multiforme, breast cancer, and ovarian epithelial cancer, especially high-grade serous ovarian cancer3. Human CMV gene products control tumorigenic cellular pathways and processes associated with all the hallmarks of cancer. Chronic CMV infection contributes to immunosenescence4. This is one reason why COVID-19 vaccines are often not as effective in the elderly5. CMV, a member of the herpesvirus family, has the remarkable capacity to establish lifelong persistence in the human host, often remaining asymptomatic. Although this virus can coexist with its host for decades, its presence has been linked to profound changes in the neuroimmune endocrine system. Latent CMV infection exerts a profound influence on the aging immune system, potentially contributing to age-related diseases. CMV plays a major role in pathologies such as cardiovascular diseases, cancer, neurodegenerative disorders, COVID-19, and long COVID.

The microbiomes of tumor and adjacent normal brain tissues from 50 glioma patients were analyzed. Six genera were found to be significantly enriched in glioma tissues compared to adjacent normal brain tissues, including Fusobacterium, Longibaculum, Intestinimonas, Pasteurella, Limosilactobacillus, and Arthrobacter.

So, there is a microbiome within tumor tissues, and the tumor ecosystem6. The intratumoral microbiome can suppress the growth of some tumors and promote growth in others. It is important to include the virome and microbiome when treating cancer patients. We hope to learn how to predict tumorigenesis, modulate the efficacy and toxicity of tumor immunotherapy, and predict the prognosis of patients.

The intratumoral microbiome influences tumorigenesis and progression through immunomodulation. It can increase tumorigenesis by inhibiting the neuroendocrine immune system. Bacteria can affect the responses of immune effector cells to malignant cells. For example, Fusobacterium nucleatum (F. nucleatum) suppresses the immune response, which promotes tumor growth. F. nucleatum can also promote colorectal cancer, breast cancer, esophageal squamous cell carcinoma, and oral squamous cell carcinoma.

Also, Helicobacter pylori (H. pylori) in the stomach can induce chronic inflammation and gastric cancer. There is also Porphyromonas gingivalis (P. gingivalis). It emerges and thrives in an inflammatory environment, such as the gums in periodontal disease. This leads to a dysregulated inflammatory microenvironment, which is a big risk factor for cardiovascular diseases and many types of cancer, including pancreatic cancer. So, oral health is very important, requiring regular dental check-ups. There are other harmful microbial species. In colorectal cancer, Eubacterium rectale endotoxin exacerbates colitis and induces tumorigenesis. Similarly, Actinomyces promotes colorectal cancer, and Methylobacterium contributes to gastric cancer.

Although most studies emphasize the negative role played by the intratumoral microbiome, there are also some intratumoral bacteria that can prevent tumors by stimulating the immune system. Akkermansia muciniphila (A. muciniphila) is a good example. It is a gut probiotic with many healthy effects. This includes weight loss, slowing down aging, inhibiting neurodegenerative diseases, and predicting the efficacy of immunotherapy. A. muciniphila has been found within the tumor microenvironment, where it can remodel the immune milieu to inhibit inflammation-associated tumorigenesis. In colorectal cancer, A. muciniphila suppresses tumor growth.

Lactobacillus can also bolster anti-cancer efficacy through immune modulation. In breast cancer, the probiotic Lactobacillus plantarum promotes butyrate production, which suppresses inflammation, and helps form a healthy microbiota. This inhibits tumor growth. Lactobacillus reuteri (L. reuteri) in melanoma enhances the efficacy of antitumor immunity by secreting a dietary tryptophan catabolite. The antitumor immune response of L. reuteri can be further increased by a tryptophan-rich diet. Moreover, Lactobacillus johnsonii (L. johnsonii) can enhance the responsiveness of many types of cancer to immune checkpoint inhibitor therapy.

All of this is consistent with One Health, which recognizes that the health of humans, domestic and wild animals, plants, and the wider environment (including ecosystems) are closely linked and interdependent7. Our health is linked to not just the external environment, but our internal virome and microbiome. Modern analytical technologies allow researchers to analyze single cells. Previously, biopsies collected many cells. When analyzed, the results showed the average of all the cells. By analyzing single cells, new differences were detected in the genome, epigenome, transcriptome, metabolome, virome, and microbiome. The goal is to learn why some cancer cells die when exposed to chemo- and/or radiotherapy while others thrive, metastasize, and kill the patient.

Notes

1 Dietary Fiber, the Gut Microbiome and Health, Smith, R.E. on Meer.
2 Li, Ting, et al., Multi-omics analysis reveals the interplay between intratumoral bacteria and glioma on ASM Journals.
3 El Baba, Ranim, et al. Formation of Polyploid Giant Cancer Cells and the Transformative Role of Human Cytomegalovirus IE1 Protein on ScienceDirect.
4 Müller, Ludmila, and Svetlana Di Benedetto. Immunosenescence and cytomegalovirus: exploring their connection in the context of aging, health, and disease om International Journal of Molecular Sciences.
5 Kadambari, Seilesh, Paul Klenerman, and Andrew J. Pollard. Why the elderly appear to be more severely affected by COVID‐19: the potential role of immunosenescence and CMV on Reviews in medical virology.
6 Wang, Na, et al. Intratumoral microbiome: implications for immune modulation and innovative therapeutic strategies in cancer on Journal of Biomedical Science.
7 One Health on World Health Organization.