How Gut Bacteria Influence Cancer Progression and Immunity

Two new studies from Weill Cornell Medicine reveal how gut bacteria can either suppress or fuel anti-tumor immunity—opening the door to microbiome-based therapies and personalized dietary strategies for cancer patients.

Study 1: Chronic Stress Drives Gut Bacteria into Tumors

The Mechanism

A study published in Cancer Cell (June 25) by Dr. Melody Zeng and Dr. Hilal Bashir investigated how chronic psychological stress affects the relationship between gut bacteria and tumor immunity in mouse models.

Key Findings

• Chronic stress caused specific gut bacteria—primarily Enterococcus gallinarum—to migrate from the GI tract into tumors.
• Once inside tumors, bacteriophages (viruses that infect bacteria) from E. gallinarum activated cancer-associated fibroblasts (CAFs) via the DNA-sensing receptor TLR9.
• Activated CAFs produced stress hormones that suppressed local antitumor immunity, specifically B-cell-mediated responses.
• Germ-free mice and mice treated with broad-spectrum antibiotics showed reduced immune suppression.
• Blocking TLR9 signaling or injecting antibiotics directly into tumors prevented immune suppression in mice.

"Detection of phages in tumors may serve as a prognostic indicator, while blocking TLR9 signaling represents a potential therapeutic target."

Implications for Patients

• Stress management may be particularly relevant for cancer patients.
• The findings raise questions about the use of glucocorticoids in certain treatments.
• Localized antibiotics offer a potential new approach to preserving antitumor immunity.

Funding: National Institutes of Health, the Hartwell Foundation, and other sources.

Study 2 & 3: Gut Bacteria Control Asparagine—Fueling or Fighting Tumors

The Core Discovery

Two reports published in Cell Microbe and Host (January 2) by Dr. Chunjun Guo, Dr. David Artis, and Dr. Nicholas Collins examined how gut bacteria influence whether the amino acid asparagine promotes tumor growth or activates immune cells.

The Role of Bacteroides ovatus

The researchers focused on Bacteroides ovatus, a common gut bacterium containing the bo-ansB gene, which encodes an enzyme that breaks down asparagine.

• When the bo-ansB gene was present, B. ovatus consumed more asparagine in the gut, reducing the amount reaching tumors.
• When the gene was inactivated, bacteria could not deplete asparagine, leading to higher levels in circulation and within tumors.

Impact on Tumor Growth and Immune Response

In mouse models of colorectal cancer fed asparagine-supplemented diets:

• Mice with bo-ansB-containing bacteria showed increased tumor growth when fed extra dietary asparagine.
• Mice with bo-ansB-deleted bacteria on the same diet showed higher asparagine reaching the tumor—which was absorbed by CD8+ T cells.
• Higher asparagine levels triggered CD8+ T cells into a "stem-like" state associated with sustained anti-tumor responses.
• Insufficient asparagine reduced the effectiveness of CD8+ T cells in suppressing tumor growth.
• Higher asparagine levels prompted CD8+ T cells to express more SLC1A5 protein transporters on their surface—critical for cancer-fighting capabilities. Blocking SLC1A5 negated these effects.

"Enzymes and metabolites produced by gut microbiota may serve as biomarkers for cancer progression."

Future Directions

The researchers envision a future where cancer care integrates:

• Immunotherapy with personalized diets
• Microbiome-targeted strategies such as specific probiotics
• Engineered gut bacteria
• Dietary plans designed to regulate amino acid availability

The Guo lab intends to explore additional pathways that affect tumor burden through growth inhibition or enhanced anti-tumor activity.

Researcher Emphasis: The co-lead researchers stressed the importance of continued study of interactions among diet, microbiota, and the immune system. The goal is to develop personalized therapies that synergize specific diets with an individual's microbiota to enhance immune response against cancer.