Colorectal cancer is the third most commonly diagnosed cancer globally. A patient’s chances of survival can be predicted by their immunoscore, which is calculated from the density of cell-death-inducing cells (CD8+ cells) inside tumors.
Recent studies show that concentrated forms of urolithin A (UA), a natural product of pomegranate digestion, induce mitophagy — the breakdown of old or redundant “cellular powerhouses” known as mitochondria. In turn, this encourages the creation of new mitochondria and slows the progression of age-related diseases.
Other studies have found that UA has immunomodulatory effects in cells that reduce inflammation alongside cells that enhance immune function.
Further study of the effects of UA on immune function could lead to the development of anti-tumor treatments.
Recently, researchers explored the effects of UA on colorectal cancer in mice. They found that UA induced “strongly protective” anti-tumor T cell immunity in mice both when consumed in food and when used alongside CAR-T cell therapy, a treatment in which T cells — a type of immune cell — are altered to attack cancer cells.
“Our findings are particularly exciting because the focus is not on the tumor cell but on the immune system, the natural defense against cancer,” said Dr. Dominic Denk, physician at Frankfurt University Hospital, in Germany, and first author of the current study.
“This is where reliable therapeutic approaches are still lacking in the reality of colorectal cancer patients. By possibly improving the combination therapy with existing immunotherapies, the study opens up meaningful possibilities for further application in the clinic. We hope to use this to sustainably improve the therapy of colorectal cancer, but also of other cancers,” he added.
The study appeared in Immunity.
“[UA] is a metabolite of ellagitannins which are a type of polyphenol. Polyphenols are known to have antioxidant and anti-inflammatory properties,” Dr. Thomas M. Holland, physician-scientist at the Rush Institute for Healthy Aging, Rush University Medical Center, not involved in the study, told MNT.
“The ellagitannins are predominantly found in pomegranates but also strawberries, raspberries, and nuts, most notably walnuts,” he explained.
“Additionally, these foods contain a plethora of nutrients and bioactives that are broadly beneficial for overall health. That being said, ellagitannins are converted to UA by gut bacteria. Thus, one must have an intact and appropriately diverse gut microbiome to allow for this conversion to take place,” he added.
For the study, the researchers gave mouse models of colorectal cancer a UA-containing diet or control diet for 18 weeks.
In the end, they found that mice on UA diets experienced a significant decrease in tumor incidence and size, alongside a higher level of T cells in the inner lining of the colon.
From further experiments, they found that UA’s positive immune effects were neither present in mice without mature T and B cells, nor those depleted of CD8+ T cells. They thus wrote that UA’s positive effects are dependent on the presence of certain T cells.
“[This study suggests that] beyond the expected general anti-inflammatory properties that UA has, it may also allow for greater immunomodulation wherein the body can detect and manage early tumor growths in the gastrointestinal tract, like those seen in colorectal cancer,” noted Dr. Holland.
The researchers next examined the effects of UA on human T cells from five donors.
“Although it was observed in vitro, (meaning either a test tube, petri dish, etc.) UA was shown to have the capability to induce CD4 memory T cell production. This function allows for a rapid response in the event of re-exposure to an antigen- in this case, those would be tumor-specific antigens,” noted Dr. Holland.
In other experiments, the researchers found that UA may also increase the efficacy of CAR-T cell therapy, a promising new immunotherapy to treat colorectal cancer.
The researchers noted that while their study produced promising results, the exact underlying mechanisms remain unknown.
Dr. Holland added that as the study was conducted in mice, it remains to be seen whether the results translate over to humans. “[T]his is where many studies begin, and as the authors say, the study yields interesting and exciting results that warrant further investigation,” he noted.
When asked about the study’s implications, Dr. Jing Chen, director of the Cancer Metabolomics Research Center at the University of Chicago Medicine, not involved in the study, told MNT: “The authors suggested that UA could be considered as a dietary supplement to enhance anti-tumor immunity for immunotherapy to treat colon cancer.”
Dr. Holland added:
“This study lends further evidence that a well-rounded diet, inclusive of diverse fruits and vegetables that contain various nutrients and bioactives is not only beneficial for overall health and longevity but also has the potential to decrease infection and cancer risk.”
“Furthermore, an overall healthy lifestyle — including diet, physical activity, good sleep hygiene, socialization, stress reduction, etc. — is paramount to optimizing physical and cognitive functionality,” he concluded.
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