The human body carries a far greater number of symbiotic microorganisms than we can imagine. Cells are the basic units that make up the human body, and the total number of cells in an adult is on the order of tens of trillions. However, the gut flora, which is symbiotic with the human intestinal tract, is ten times the number of cells in the body, and its composition is quite complex, with roughly 500 to 1,000 different species of bacteria in each individual's body.

Among them, gut microorganisms are the main components of the human symbiotic microorganisms. Recent studies have shown that gut microbes affect humans in many ways, including disease, fitness, personality, and even longevity. The interaction between the gut flora and the human body is quite complex, and perhaps we can treat certain intractable diseases, such as cancer, through the gut flora.

On April 6, 2023, researchers from the University of Pittsburgh published a research paper in the journal Cell entitled "Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment".

The study showed that a probiotic, Lactobacillus reuteri, is able to stimulate killer T cells by secreting indole-3-carboxaldehyde (I3A). When mice were fed a tryptophan-rich diet, which is metabolized by Lactobacillus reuteri to I3A, it was able to improve the effectiveness of cancer immunotherapy, suppress tumor size, and prolong survival.

This study lays the groundwork for testing in clinical trials whether I3A treatment or a combination of probiotics and diet can improve cancer immunotherapy outcomes.

The gut is not only an important digestive organ but also the largest immune organ in the body. Since the gut microflora colonizes the human gut, it is easy to assume that the gut flora is likely to be inextricably linked to the human immune system and profoundly influence its function.

In fact, a number of studies in recent years have confirmed that gut microbes are an important influence on the effectiveness of tumor immunotherapy. Recently, a study also found a link between probiotics and immunotherapy responses in melanoma patients.

To understand this process, the research team fed Lactobacillus reuteri, a common probiotic, to germ-free mice with melanoma. The team found that Lactobacillus reuteri metastasized from the gut into the tumor tissue of the mice, where it grew and persisted in the tumors over time.

What's more, mice injected with Lactobacillus reuteri had more CD8+ T-cells (killer T-cells) at the tumor site, the tumors shrank more dramatically, and the mice lived longer compared to control mice. Not only that, but in addition to melanoma, Lactobacillus reuteri inhibited tumor growth in mice with a variety of hormonal tumors, including adenocarcinoma, fibrosarcoma, and breast cancer.

In-depth studies have shown that Lactobacillus reuteri stimulates anti-tumor immune responses through the secretion of indole-3-carboxaldehyde (I3A), a compound that activates the AhR signaling pathway in CD8+ T-cells, promotes their production of interferon gamma, and kills cancer cells. Although this receptor is present in almost every cell in the body, I3A specifically acts on CD8+ T cells to enhance their anti-cancer ability.

Corroborating this, Lactobacillus reuteri no longer induced an anti-tumor immune response when the team removed the AhR receptor from CD8 T cells. In addition, the team used a strain of Lactobacillus reuteri that does not produce I3A, demonstrating that this compound is essential for the bacteria to enhance antitumor immunity and suppress tumors.

It's worth noting that in order to secrete I3A with anti-tumor effects, Lactobacillus reuteri needs to ingest tryptophan, an amino acid found in foods such as chicken, soybeans, oats, nuts, and seeds. When the research team fed tryptophan-rich food to mice with melanoma, their tumors grew more slowly and they lived longer than control mice (whose food was low in tryptophan). In addition, the tryptophan-rich diet also enhanced the tumor-suppressing effects of immunotherapy.

To see if I3A could play a role in human responses to immunotherapy, the team analyzed blood samples from melanoma patients treated with immune checkpoint inhibitors. They found that patients who responded well to immunotherapy had higher levels of I3A, and that higher levels of I3A before treatment were also associated with a better chance of survival.

"Based on these findings, it is likely that I3A levels will be used in the future as a biomarker to predict which patients are likely to respond to immunotherapy and that I3A will also be used as an adjuvant to immunotherapy to improve the prognosis of patients," according to Professor Marlies Meisel, the corresponding author of the study.

The findings are still in the early stages, and further studies are needed to confirm them, including clinical trials, to see if a tryptophan-rich diet actually affects the prognosis of tumor patients.