The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View

Abstract

The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.

Figure 1.. The Human Microbiome May Interact with a Cancer through Intricate Feedback Loops, and Investigating the Interaction Networks May Require a Systems Biology Approach.

The effect of a microbiome on a cancer may be direct or indirect, and this is an important distinction. Direct interaction could take place between microbiomes residing in tissues where the cancer emerges, such as the hypothetical roles illustrated here of the skin microbiome interacting directly with melanoma; indirect interactions could occur between a microbiome and a cancer residing in a different tissue. For example, the gut microbiome alters circulating metabolites which in turn affect general host physiology and could have an indirect effect on the progression of skin cancer or its response to therapy. Diet will also play a role because it affects the circulating levels of metabolites and the microbiome composition.

Figure 2.. Microbiome Engineering Could Reduce Pain in Cancer Patients.

In a mouse model, the probiotic Lactobacillus acidophilus NCFM strain decreased pain relative to controls and potentiated the effect of opioid analgesics [23].

Figure 3.. Metastases Can Carry Bacteria from the Microbiome of Primary Tumors to Distal Tissues.

A recent study [42] investigated patient biopsies from colorectal cancer and liver metastases from the same patients. Bacteria found in primary tumors, including Fusobacterium nucleatum, were also found in metastases, suggesting they had traveled with the metastatic cells. Experiments with mice validated these findings and showed that antibiotic treatment could reduce tumor load.

Figure 4.. Many Cancer Therapies such as Chemotherapy and Pelvic Irradiation Can Damage Healthy Microbiomes.

Transplants of intestinal microbiota such as autologous fecal microbiota transplant (auto-FMT), where a stool sample is collected, cleared for safety, and stored to then be given as a treatment after microbiota damage, could be used to safely remediate the microbiome of a patient. Auto-FMT has been applied to cancer patients receiving hematopoietic cell transplantation. Applications to other cancer patients should proceed with caution because we do not fully understand the link between the gut microbiome and cancer; auto-FMT raises a concern that restoring the pretreatment microbiome composition could increase the odds of cancer recurrence.

Figure I.. Cervical Cancer Comes with a Shift in the Composition of the Cervicovaginal Microbiome.

The microbiome changes from a Lactobacillus-dominated community to a community enriched in strict anaerobes such as Sneathia sanguinigens and Gardnerella vaginallis. Bacterial vaginosis - a dysbiotic phenotype - is associated with higher risk of HIV and human papillomavirus (HPV) acquisition and transmission, preterm births, and pelvic inflammatory disease and cancer.

Figure I.. Migration to the USA Can Lower the Diversity of the Gut Microbiota.

This could explain why the incidence of particular diseases - including obesity and some cancers - increases in some populations of US immigrants. Studying this intriguing phenomenon could provide new clues to the role of microbiomes in cancer.