Cancer and the microbiota

Abstract

A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications.

Fig. 1. The path from health to solid tumor malignancies at mucosal sites and the microbiota’s contribution

Human body surfaces are subject to constant environmental insult and injury. Infections, trauma, dietary factors, and germline mutations can contribute to breach of the body’s mucosal barriers. In most individuals, barrier breaches are rapidly repaired and tissue homeostasis is restored. Impaired host or microbial resiliency contributes to persistent barrier breach and a failure to restore homeostasis. In these settings, the microbiota may influence carcinogenesis by (i) altering host cell proliferation and death, (ii) perturbing immune system function, and (iii) influencing metabolism within a host.

Fig. 2. Mechanisms by which microbes influence cancer development and progression

(A) Bacterial toxins can directly damage host DNA. Bacteria also damage DNA indirectly via host-produced reactive oxygen and nitrogen species. When DNA damage exceeds host cell repair capacity, cell death or cancer-enabling mutations occur. (B) β-Catenin signaling alterations are a frequent target of cancer-associated microbes. Some microbes bind E-cadherin on colonic epithelial cells, with altered polarity or within a disrupted barrier, and trigger β-catenin activation. Other microbes inject effectors (e.g., CagA or AvrA) that activate β-catenin signaling, resulting in dysregulated cell growth, acquisition of stem cell–like qualities, and loss of cell polarity. (C) Proinflammatory pathways are engaged upon mucosal barrier breach in an evolving tumor. Loss of boundaries between host and microbe engages pattern recognition receptors and their signaling cascades. Feedforward loops of chronic inflammation mediated by NF-κB and STAT3 signaling fuel carcinogenesis within both transforming and nonneoplastic cells within the tumors.

Fig. 3. Dietary fiber, microbiota, butyrate, and tumorigenesis

Metabolism of fiber by colonic microbes results in generation of butyric acid. When genetic mutations in Msh2 and Apc are present, butyrate increases cell proliferation and enhances tumorigenesis. Data from another model of colorectal carcinogenesis indicate the opposite outcome: Neoplastic colonocytes engage in glycolysis for cellular energy, unlike healthy colonocytes (which favor fatty acid oxidation). As a result, butyrate accumulates in the nucleus of neoplastic cells, engaging tumor-suppressive pathways and apoptosis.

Fig. 4. How the microbiota modulate chemotherapy and immunotherapy efficacy in mouse models

The gut microbiota stimulate immune cells to produce reactive oxygen species (ROS). ROS enhance DNA damage caused by oxaliplatin, blocking DNA replication and transcription and resulting in cell death. Cyclophosphamide can cause small intestinal barrier breach. This barrier disruption results in bacterial translocation that potentiates antitumor T_H1 and T_H17 responses. CpG oligonucleotides are a microbial-associated molecular pattern and are used in immunotherapy. Antibiotic disruption of the gut microbiota in mice compromised the efficacy of CpG in a mouse subcutaneous tumor model.