The use of oral antibiotics has significantly increased in recent years. Although antibiotics destroy pathogenic bacteria, they also affect beneficial ones — creating a state of microbial imbalance called dysbiosis. Notably, we and others have shown that states of dysbiosis cause severe changes in immune responses. Many patients with advanced stages of cancer, metastatic melanoma included, are treated with cellular immunotherapy, yet only 50% of the patients respond. 

We hypothesized that antibiotic-induced dysbiosis of the gut microbiota suppresses the efficacy cellular immunotherapy, by changing the tumor microenvironment. We found that the induced dysbiosis was characterized by alterations in bacterial abundance, composition, and diversity in our animal models of melanoma and lung cancer. On the host side, antibiotic-induced dysbiosis caused elongated small intestines and ceca, and B16-F10 melanoma and Lewis lung carcinoma progressed more quickly than in control mice.  Mechanistic studies revealed that this progression was mediated by suppressed expression of tumor endothelial adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), and a subsequent decrease in the number of activated and effector CD8 T cells in the tumor. Current studies are under way in order to therapeutically overcome dysbiosis-induced ICAM-1 suppression, thereby enhancing the effectiveness of cellular immunotherapy. Overall, these results demonstrate the importance of commensal bacteria in supporting anticancer immune surveillance and immunotherapy, define an important role of tumor endothelial cells within these processes, and suggest adverse consequences of antibiotics on cancer control. 

Citation/Acknowledgements. Representing AR COBRE: Center for Microbial Pathogenesis and Host Inflammatory Responses  (PI: Dr. Mark Smeltzer, PhD; P30 GM145393) 

The host endocannabinoid system is comprised of lipid hormones known as endocannabinoids that interact with host cannabinoid receptors to modulate intestinal physiology and immunity. Numerous studies using various colitis models have linked dysregulated endocannabinoid signaling with inflammation and an altered gut microbiome. Our work further demonstrates that manipulation of gut endocannabinoid tone also impacts infectious disease caused by gut bacterial pathogens through two distinct mechanisms. Chronic elevation of tissue endocannabinoid tone promotes earlier pathogen clearance, which corresponds with attenuated disease during peak infection. This effect requires pathogen expression of the pro-virulence receptor QseC, which functions to activate a key pathogenicity island that maximizes pathogen colonization and virulence during gut infection. We further show that endocannabinoids directly repress pathogen virulence by inhibiting QseC activation by host catecholamines. In contrast, acute augmentation of gut endocannabinoid tone during infection onset accelerates pathogen gut colonization, resulting in earlier and more aggressive colitis development. Ongoing studies suggest this effect is likely mediated through host, and not pathogen, sensing of endocannabinoids. Taken together, endocannabinoids can clearly impact the outcomes of infectious colitis through host- and bacteria-dependent mechanisms, thus highlighting the complexity of this interkingdom signaling network in modulating host-pathogen interactions within the gut.  

Citation/Acknowledgements. Representing: USC COBRE: Center for Alternative Medicine (PI: Drs. Mitzi and Prakash Nagarkatti, P20GM103641)

Microbial therapeutics have great promise in treatment of various infectious diseases and other gastrointestinal conditions. Despite the success of one such treatment method, fecal microbiota transplantation (FMT), in treating recurrent Clostridioides difficile infection (CDI), it is still unclear how a certain environment influences the ability of a microbial community to produce metabolites hypothesized to combat C. difficile. In a mouse model of recurrent CDI, we observed that clearance of C. difficile was correlated with the production of butyrate. An in vitro model to investigate the effect of butyrate on C. difficile directly demonstrated that while butyrate could attenuate growth, it increased toxin and spore production. Exogenously delivered butyrate could not independently clear C. difficile in mice. We also observed that successful clearance of C. difficile using FMT required a fecal source from the same species, independent of engraftment of microbial species typically associated with clearance. Exposing ex-germ-free mice to microbiota from a human fecal source, which did not clear C. difficile in our regular model, prior to infection was able to rescue clearance of C. difficile again, suggesting host involvement in successful FMT treatment for C. difficile. Our current aims include identifying microbial and host factors that stimulate beneficial microbes to colonize, grow, and produce distinct metabolites, with the ultimate goal of advancing manipulation of the microbiome for our benefit.