Preclinical Study: How Gut Metabolites May Stop Tumor Growth

Cedars-Sinai Cancer investigators have identified metabolites produced by gut bacteria that help the body’s immune system fight cancer. These chemicals, called indoles, are produced when the bacteria break down nutrients, and their identification could eventually lead to a new cancer therapy.

The preclinical study was published in Cell Reports Medicine. 

“Our study is the first to show how metabolites produced by select bacteria can induce changes in the body’s immune response when the body is fighting cancer,” said Ze’ev Ronai, PhD, director of the Translational Research Institute at Cedars-Sinai, professor of Surgery and senior author of the study. “Previous research established that gut bacteria affect the immune system and can help fight cancer. Our new findings are an important step forward because they give us a specific metabolite that can be used for future therapies.” 

The investigators focused on B. rodentium in the guts of mice and a related bacteria species, B. uniformis, in the guts of humans. When these bacteria break down the amino acid tryptophan, they produce different forms of metabolites called indoles. 

In laboratory mice, investigators found that treatment with B. rodentium restricted the growth of melanoma and colon, breast and pancreatic cancers, and that treatment with indole on its own restricted the growth of melanoma.

“Indole was more effective against these tumors than other metabolites produced by tryptophan breakdown, which are used in immunotherapies,” said Ximena Diaz Olea, a research scientist in the Ronai Lab and first author of the study. 

The investigators also looked at data from human patients who were responding well to immunotherapy for melanoma. In these patients, investigators found increased levels of the enzymes used to produce indole, suggesting higher levels of indoles were contributing to the patients’ good outcomes. 

“We are now evaluating whether increasing the levels of indoles in the gut would be sufficient to inhibit cancer,” Ronai said. “We hope to turn these findings into a therapy that will benefit patients.”

Investigators say this might be possible by giving patients capsules containing B. uniformis, then following up with nutrients to increase the bacteria’s reproduction and indole levels in the gut.

While this study focused on B. uniformis and B. rodentium, as many as 20 different bacteria species produce the enzyme that creates indole, opening further avenues for exploration, Ronai said. 

“These findings provide the foundation for modes of treatment that could complement or replace existing ones,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “This type of translational science paves the way toward new options for patients.” 

If investigators are successful at translating their findings into an anticancer therapy, Ronai said that it would likely be useful against many cancer types, as the immune cells bolstered by indole are effective against many cancers.

Additional Cedars-Sinai authors include Ximena Diaz Olea, Aagam Shah, Hyungsoo Kim, Ashok Kumar Sharma, Anthony Martin, Mark B. Faries, Omid Hamid, Suzanne Devkota, and Simon Knott.

Other authors include Kristin Beede, Gabriel Pereira, David Scott, Christopher Petucci, Eric Martens, Dmitri Rodionov, Miguel P. Martinez, Tongwu Zhang, Andrei Osterman, Emile E. Voest, Nadim J. Ajami, Jennifer Wargo, and Amanda E. Ramer-Tait.

Funding: This work was supported by the Cedars-Sinai shared resources in genomics, vivarium and microbiome studies; NCI grant R35CA197465 (to ZAR); the Hervey Family / San Diego Foundation (to ZAR); grant R21CA249822 (to ART and HK); and the Buffett Cancer Center funds (to ART) via NCI grant CA036727.

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