Gut Bacterium and Its Indole Metabolites Boost Anti-Tumor Immunity, Nebraska-Led Study Finds

In a facility at the University of Nebraska–Lincoln, mice raised with no gut bacteria of their own gave researchers a clean test of a question that has hung over cancer treatment for years: why do some patients respond to immunotherapy while others do not? The answer the team reports, in a study published in Cell Reports Medicine, points to a single gut microbe and the compounds it makes.

The bacterium is Bacteroides uniformis. It takes the amino acid tryptophan and converts it into molecules called indoles. In mice with melanoma, those indoles boosted the immune system's attack on the tumor and helped suppress its growth. The researchers describe the work as the first to show that metabolites made by certain gut bacteria can positively shape the body's immune response to cancer.

The work was co-led by Amanda Ramer-Tait, the Maxcy Professor of Food Science and Technology at Nebraska, and Ze'ev Ronai, director of the Translational Research Institute at Cedars-Sinai and a professor of surgery. Ramer-Tait has worked with collaborators at Cedars-Sinai and other institutions for years. The study was supported by Nebraska's Gnotobiotic Mouse Program, which she directs, and Kristin Beede, the program's research lab manager, is among the authors.

That program is what let the team separate the effect of tryptophan breakdown from everything else a gut community does. Only the indole-producing bacterial strain produced anti-tumor immunity. In a decisive test, the researchers introduced a genetically modified Bacteroides uniformis, one that could no longer turn tryptophan into indoles, into germ-free mice. The anti-tumor effect vanished, and the tumors developed normally.

The team then looked at people. They analyzed samples from cancer patients receiving immunotherapy and found higher levels of the enzymes used to produce indoles in those who were responding well. That suggests, though it does not prove, that the same mechanism was contributing to patient outcomes.

Ramer-Tait said the study offers one possible reason patients differ in how they respond to treatments such as immune checkpoint inhibitors: a specific microbe and the metabolites it produces. Ronai noted that earlier research had already established that gut bacteria affect the immune system and can help fight cancer. What the new findings add, he said, is a specific metabolite that could be used in future therapies.

The researchers see two possible routes forward. One is manipulating the gut microbiome itself. The other is providing the beneficial bacterial metabolites directly. Ramer-Tait described the longer-term idea as microbiome- or diet-based interventions that supply either the helpful microbes or the dietary substrates they need, in order to strengthen a patient's response to immunotherapy. She added that the approach could extend beyond melanoma, because indoles play a role in improving immune responses to other cancers as well.

Funding came from the National Institutes of Health and the University of Nebraska Medical Center's Fred and Pamela Buffett Cancer Center. The tumor-suppressing results were shown in mice, and the patient data are an association in samples, so the next question is whether indole-based strategies can be tested in people.