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How “Good” Gut Health Promotes Response to Immunotherapy Treatments

By Madison Nguyen 

 We are just beginning to understand the intricate community of microorganisms that exist within us and the impact they have on our health and wellness. These new discoveries can change how we view medicine as they lead to new challenges and new ways to improve and develop treatments. The discovery of the host microbiome as a mutualistic relationship between humans and microbes challenged our ideas of immunity and immune response. It questioned the established self and non-self theory of immunity in which the immune system only recognizes the host from foreign antigens, however the immune system can even further distinguish between commensal microbes (good bacteria) and pathogens. This ability to distinguish friend from foe allows the immune system to decide when to act against harmful pathogens or bypass beneficial microbes.  

We are still uncovering the mechanisms behind the relationship between host microbiota and cancer, but we do know that certain microbes are associated with response to immunotherapy. Immunotherapy is a cancer treatment that wields the patient’s immune system against the tumor, relying on the body’s immune cells to recognize and attack the cancer cells.  Patients who did not respond to immunotherapy had lower abundance of “good” bacteria compared to responding patients. These “good” bacteria consist largely of the Ruminococcaceae family, which are able to induce family-specific metabolic pathways that promote better host immunity. Researchers have demonstrated in mice models that using broad spectrum antibiotics prior to immunotherapy significantly decreases the overall response and chances of progression-free survival. Fecal Matter Transplants (FMT) have been performed on mice to transplant the gut microbiome from one mouse into another to further determine if restoring the depleted microbiomes could improve mice's response to immunotherapy.  

With successful results, these preliminary findings have major implications for the large role bacteria have on our health and wellness that we are just beginning to chip away at. One researcher leading this is an oncologist at UPMC Hillman Cancer Center and associate professor of medicine at the University of Pittsburgh, Dr. Diwakar Davar. With a clinical interest in melanoma and non-melanoma skin cancers, his research focuses on the role of the gut microbiome in patients receiving immunotherapy. His research lab, referred to as the Davar FMT lab, works to apply these research goals in a clinical setting. As a clinician and a researcher, Davar educates his patients about the important role their gut microbiome plays in their treatment. He also emphasizes how the microbiome is important to their health and wellness and why we need to maintain a good diet to feed our gut microbiota. Davar explains that “increasing intake of fiber and fermented foods favorably augment the function of anticancer therapy…as well as the negative and deleterious role of artificial sweeteners, such as sucralose, inhibiting the effect of anticancer therapy.” This applies to both cancer patients and the general population that may want to promote good gut health, as a healthy gut microbiome helps defend the host from pathogens. The host microbiome exists in a steady state with commensal bacteria, or beneficial microbes, out-competing the dangerous and harmful pathogens for space and resources. This is colonization resistance, and it helps to restrain pathogen growth, in not just our gut bacteria, but also on our skin and mucus linings.  

It is important to acknowledge the role the environment has on the gut microbiome, and there is still much more to be done to determine if the research being done here in Western Pennsylvania can be applied across the United States, or even the world. The environment that we are exposed to from birth dictates the microbes that colonize us. This leads people with different lifestyles and raised in different environments to be exposed to exceedingly different microorganisms. Studies have shown that growing up with exposure to a wider variety of microbes in children’s early development is associated with a lower risk of asthma and the development of allergies. This is because exposure to more diverse microbes in early childhood allows for these microbes to trigger the innate immune system, and thus activate certain T cells of the adaptive immune system that are associated with regulating asthma and allergies. This echoes the close and intricate relationship between our commensal microbes and immune systems, as they are constantly communicating with each other. Davar’s research team targets this relationship as he and his lab focus on how to harness the potential of the gut microbiome to improve patient response to immunotherapy. Advanced melanoma patients receiving single immune checkpoint inhibitor (ICI) therapy have a response rate of 30–40%, however recent findings point to altering the gut microbiome as a way to boost patient response to immunotherapy.  

In a trial published in 2021, Davar and fellow physician and researcher, Dr. Hassane Zarour, demonstrated that altering the gut microbiome improved advanced melanoma patients’ response to anti-PD-1 immunotherapy. Anti-PD-1 drugs inhibit programmed cell death protein-1 (PD-1), promoting the T cells’ ability to attack the tumor. The trial performed FMTs from melanoma patients who previously responded to their immunotherapy to melanoma patients who had not yet responded to their anti-PD-1 therapy. They found that by changing the gut composition to mirror that of a patient who responded to treatment, they were able to overcome prior resistance to therapy, as those patients who previously did not respond to therapy began to respond to anti-PD-1 therapy post-FMT administration. The gut microbiota that are largely present in these non-responding patients are gram-negative bacteria that contain lipopolysaccharide, which is known to augment an immune cascade of “myeloid cells that are known to be hostile towards the function of effector T cells,” as Davar explains. Gram-negative bacteria are a type of bacteria characterized for having an outer membrane making them more resistant to antibiotics. Additionally, several of these microbes can produce metabolites that further suppress the function of T cells. Nurturing the steady state of commensal bacteria is crucial in boosting the immune system and this is especially true for patients receiving immunotherapy.  

The future of this research relies on the ability to collect and access large datasets of patient populations to account for the diversity of gut microbiota across various groups that combine “patient data, dietary data, and metabolomic data” to better distinguish the trends that we are seeing and apply it to larger patient populations, according to Davar. The work that is being done at the Davar FMT lab within UPMC Hillman Cancer Center is very promising, as it reveals new ways to improve treatments for patients and further develops our understanding of an intersection of two seemingly unrelated fields in novel ways.