Reshaping the gut microbiome or diet with asparagine may limit cancer growth

Researchers suggest that gut bacteria can help determine whether dietary asparagine, an amino acid, will boost tumor growth or activate immune cells against the disease. The team at Weill Cornell Medicine, US, notes that their findings could lead to a novel treatment approach in which clinicians may reshape the gut microbiome or diet to starve tumors while supercharging immune cells. 

Using mouse models, the researchers discovered that higher asparagine levels in a tumor microenvironment drove immune cells to express more of a protein transporter on their cell surface, which was important in fighting cancer cells. These can help immune cells turn into cancer-killing T cells that help destroy tumor cells. 

“Our study suggests that we need to think about how the interplay of diet, gut microbiota, and tumor-infiltrating immune cells could affect cancer growth and response to therapy. We can’t overlook this key level regulation,” says co-lead researcher Dr. Chunjun Guo, research scholar in Metabolic Health and associate professor of Immunology.

Depleting amino acids

Using mouse models transplanted with human gut microbiota, the team determined that some bacteria could deplete amino acids and affect tumor growth. They focused on asparagine because it supports protein synthesis and promotes cell survival.

Cancer cells in the nutrient-poor environment of tumors and cytotoxic immune cells (CD8+ T cells) that attack and destroy tumor cells require asparagine to be active.

In the study in Cell Host & Microbe, the researchers worked with Bacteroides ovatus, a common gut bacterium that carries the bo-ansB gene, which encodes an enzyme that breaks down asparagine. In mouse models, the team showed that when the bo-ansB gene is present, B. ovatus consumes more asparagine in the gut, reducing the amount of the amino acid absorbed into the bloodstream and delivered to tumors.

Without this gene, the bacteria could not deplete asparagine in the gut, so more of the amino acid reached tumors via blood circulation. According to the researchers, this showed that the bacteria control the levels of asparagine that leave the gut.

In mice with colorectal cancer that were fed extra dietary asparagine, bacteria with bo-ansB genes helped tumors grow. But in mice lacking these bacteria, an asparagine-rich diet led to more asparagine reaching the tumor and being absorbed by CD8+ T cells.

The findings could lead to a novel treatment approach of reshaping the gut microbiome or diet to starve tumors while supercharging immune cells.As a result, the immune cells were triggered into a “stem-like” state, associated with long-lasting, effective anti-tumor responses. Without sufficient asparagine, the cells were less effective at suppressing tumor growth.

Removing bo-ansB drove CD8+ T cells to express more SLC1A5, a cell-surface protein transporter. The team explains that resulting stem-like CD8+ T cells serve as a renewable source of immune cells that can mature into “cancer-killing T cells.”

Once activated, these cells attack tumors by producing strong immune factors that help destroy cancer cells. The team found that blocking SLC1A5 erased the gains from higher asparagine levels.

Boosting antitumor activity

The researchers say they’re also interested in exploring other pathways that may impact tumor burden by suppressing growth or boosting antitumor activity, beyond asparagine.

“Many studies suggest that enzymes produced by our microbiota, as well as the metabolites like small molecules and proteins, could be potential biomarkers for cancer progression,” says Guo.

The team notes that this finding raises the possibility that future cancer care could pair immunotherapy with tailored diets and microbiome-targeted strategies, such as probiotics, engineered gut bacteria, or personalized dietary plans to fine-tune amino acid availability.

“We think it’s critical to continue studying interactions between diet, the microbiota, and the immune system because different diets may enhance the immune system of one individual but not another, depending on the type of microbiota they have,” says co-author Dr. Nicholas Collins, assistant professor of Immunology.

“Our goal is personalized therapy, where we can tailor a specific diet that will synergize with the microbiota of an individual to boost the immune system against cancer.”

Earlier research also suggested that diverse communities of resident bacteria can protect the human gut from harmful pathogens by competing for the same nutrients. Nutrition Insight discussed the findings’ potential to support new strategies for optimal gut health with one of the authors.

Meanwhile, another paper revealed that vitamin D promoted the growth of gut bacteria in mice, thereby improving their immunity to cancer. Mice consuming a vitamin D-rich diet responded better to transplanted cancers and immunotherapy treatments.

Beyond academic research, the Danish biotech company Bactolife has developed binding proteins that help maintain gut balance by neutralizing undesired metabolites. The company recently raised funds to commercialize these products and execute a human study program.