The gut has a big role to play in our susceptibility to having good health and how well we respond to various forms of medical treatment. Within the gut lies trillions of living microorganisms that make up the gut microbiota. The role that microorganisms play within gut health has been recognized in scientific areas including autoimmunity, Parkinson’s disease and even depression.
Dr. Shahla Bari, a fellow in the Malignant Hematology Program at Moffitt Cancer Center, has been fascinated with the gut microbiome for more than a decade. Personally, she has suffered from Hashimoto’s disease for 12 years. Hashimoto’s is an autoimmune disease that occurs when the body makes antibodies that attack thyroid cells. This experience ignited her passion for studying this kind of autoimmunity, the kind where the gut microbiota can make an immune system overactive.
Past studies have shown that gut microbiota can predict which patient will respond to immunotherapy, a common form of treatment now used across almost every solid tumor cancer. Additionally, preclinical models in mice have shown that changing the gut microbiota can also change the response to treatment.
When Bari learned of this, her passion for learning about gut microbiota shifted from a personal interest to dedicated research and full-time career. She sought to find a biomarker that could predict if patients with cancer would respond to therapy, and if they don’t respond is there a way to change the microbiota to facilitate a therapeutic response.
At the 2022 American Society of Clinical Oncology Annual Meeting, Bari and her team presented findings from their study detailing the association of gut microbiome on responses to first-line immune checkpoint inhibitors in patients with recurrent metastatic head and neck squamous cell cancer.
“With the science currently available, it’s difficult to change your genes,” said Bari. “But the beautiful thing about the microbiota is that you can change it with even minor tweaks to your diet.”
Metabolites Offer Clues
Bari’s team identified that approximately 25% to 30% of head and neck patients respond to first-line therapy, or the best treatment available. For 70% of patients the disease progresses and they will receive a second-line therapy. For many, that second-line treatment doesn’t work as well.
Through the collection of patient stool and blood before and at three months into treatment, Bari’s team was able to evaluate the bacterial signature between responders versus nonresponders.
“The bacteria between two people can be very different,” said Bari. “We only share about 40% of bacteria, but we share about 85% of the metabolites that these bacteria produce. The same bacterial metabolites can be produced from different bacteria within different people, and these metabolites can enter the blood and affect our immune system.”
Evaluating the microbiota of these patients revealed that some bacterial metabolites were differentially expressed between responders and nonresponders. To confirm this, they reviewed responders over the last five years.
“There is a rare subset of patients who will respond and continue to respond for a long time,” said Bari. Her team identified those patients who responded for longer than six months and collected stool samples. What they found was that the microbial metabolite signatures were even further enhanced.
Opportunity to Improve Responses
One of the metabolites of significance they identified was inosine. Bari’s team found that within responders, inosine was decreasing with response while in nonresponders, inosine was increasing. They hypothesized that immune cells can use inosine (if available) as an energy source, activating the immune system to fight cancer. This hypothesis has already been evaluated in mice. Their study was the first to show it in humans.
The other significate microbial metabolite that Bari’s team found to be differentially expressed was tryptophan kynurenine. “In responders, tryptophan was not being converted to kynurenine,” said Bari. “In nonresponders, it was.”
The significance of this finding is that the downstream metabolites activate a pathway that is immunosuppressive when tryptophan is converted to kynurenine. This means there is a higher chance of immunosuppression and therefore, less response to therapy.
Ultimately, by laying the groundwork for future gut microbiome and microbial metabolite modulation research, this study can improve responses to immunotherapy for patients with recurrent metastatic head and neck squamous cell cancer. Most importantly, drugs already exist to help with this.
“These two metabolites, inosine and tryptophan kynurenine, are important because, right now, we have existing drugs that allow us to modulate these pathways,” said Bari. “If these drugs can be repurposed from mice models, they can one day help humans.”