Investigating the role of the gut microbiota on immune checkpoint inhibitor-mediated colitis

<p>Immune checkpoint inhibitors (ICIs) have been revolutionary in the fight against cancer by recruiting the host immune system as an agent for attack on malignant cells. Unfortunately, immune-related adverse events (irAEs), including ICI-mediated colitis (IMC), are common side effects that result from immune cell mediated damage on healthy tissues. Recent studies have highlighted a role for the gut microbiota in modulating ICI-mediated anti-tumor responses, but less is known regarding how the gut microbiota may impact on irAEs. Considering that the gastrointestinal tract harbors thousands of unique microbial species, many of which are known to modulate the immune system, microbes and microbe-derived factors are likely important modulators of IMC risk and severity.</p> <p>In two related studies, we used clinical samples to first profile the gut microbial composition to better understand which taxa are associated with IMC. The first study is a case series of IMC patients (n=12) that received fecal microbiota transplant (FMT) as a salvage therapy for treatment of refractory IMC. A majority of patients (83%) achieved symptom improvement after one FMT treatment, while 92% achieved IMC clinical remission by the end of the study following repeat FMT. We found that patients with a composition more dissimilar to donors at baseline were more likely to respond favorably to FMT. Symptom resolution and complete response to FMT was marked by significant increases in alpha diversity as well as increases in taxa including <em>Bifidobacterium</em> and <em>Collinsella</em>. Additional insights from the study include a decrease in CD8+ T cells in complete responders. In a separate study, fecal samples were prospectively collected from IMC patients at onset of toxicity presentation (n=31). An examination of the microbiota composition of these samples revealed two major subsets of IMC patients, including a larger one with a more dysbiotic gut microbiota at baseline, characterized by loss of obligately anaerobic species and expansion of potential pathobionts such as <em>Streptococcus</em> and <em>Escherichia</em>. Patients from this subset went on to have poor clinical outcomes post-IMC onset, including reduced overall survival and a higher incidence of infectious complications. A metabolomic evaluation demonstrated that short chain fatty acids (SCFAs), including acetate, propionate and butyrate, were significantly depleted in this group of IMC patients. In a murine model of IMC, we found that a brief, five-day administration of an antibiotic cocktail led to loss of obligately anaerobic species and expansion of aerotolerant taxa like <em>Enterococcus, Lactobacillus</em>, and <em>Escherichia</em>, similar to the subset of patients with poor clinical outcomes. Interestingly, examining these mice demonstrated increased bacterial translocation to mesenteric lymph nodes, indicating that intestinal microbial dysbiosis in this setting led to an impairment in intestinal barrier function. Gained knowledge through patient profiling and pre-clinical mouse models will better our understanding of factors related to IMC and subsequent related poor outcomes for patients in the future.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Halsey, Taylor
• Jenq, Robert
• <p>0000-0001-8601-9949</p>

Contributors dc:contributor

• Robert Jenq, MD
• James Allison, PhD
• Michael Curran, PhD

• gut microbiome
• immune checkpoint inhibitors
• microbiology
• clinical research
• Bacteria
• Medical Immunology
• Medical Microbiology
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1331

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2388