Role of the gut microbiota in cancer and host anti-tumor response
Gut microbiota are critical for host immune education and activation. The gut microbiome (both microbiota and microbiota-derived metabolites) has been associated with cancer development/progression and responses to cancer therapy. Further, specific gut microbiota or metabolites can modulate these phenotypes in preclinical models. Our group and others were the first to identify distinct gut microbiome signatures in human cancer patients who responded favorably to immune checkpoint inhibitory therapy (ICT). Interestingly, the gut microbiota we identified in our clinical study do indeed enhance ICT efficacy in a preclinical melanoma model, whereas a probiotic commonly found in yogurt does not.
We are now in the process of further elucidating the potential mechanisms by which these specific gut microbiota and metabolites may augment host response to cancer therapy by using in vitro functional immune assays with mouse and human immune cells, multiomics approaches, and preclinical cancer models (including humanized mice). We are also extending our studies to elucidate the impact of gut microbiota on other immunotherapies such as CAR-T.
Recent work has focused on developing novel gut microbiome-derived therapeutics for enhancing cancer immunotherapy efficacy – efforts that have resulted in the filing of two patents (UTSD 3245, UTSD 3772) and co-founding of a startup company, Aumenta Biosciences.
Understanding the molecular mechanisms regulating microbial (bacteria and fungi) colonization and dissemination in the mammalian gastrointestinal tract
Bacterial and fungal colonization of the gut precedes serious mucosal or systemic disease, particularly in immunocompromised and surgical patients. The mammalian host has developed extensive defense mechanisms for limiting intestinal pathobionts (microbes that can cause disease under specific circumstances) from escaping the gut. The interplay between the pathobiont, host immune effectors, and/or the resident gut microbiota and microbiota-derived metabolites dictates whether bacteria or fungi can colonize the gut.
We use a variety of model pathobionts (including Candida albicans, Pseudomonas aeruginosa, and Escherichia coli) in in vitro and preclinical models. As an illustrative example, we have shown that specific commensal anaerobic bacteria are critical for inducing gastrointestinal epithelial cells to produce gut immune effectors (such as hypoxia- inducible factor-1α, HIF-1α, and the antimicrobial peptide LL-37/CRAMP) that are essential for maintaining C. albicans colonization resistance. When commensal bacterial populations are disrupted via antibiotic therapy, gut immune effectors are markedly diminished, and Candida populations can overgrow and subsequently cause invasive disease. Finally, by administering a pharmacologic HIF-1α agonist, we can induce Candida gut level reduction and significantly decrease mortality from disseminated infection.
We are now using specific antibiotics and diets to induce distinct changes in gut microbiomes of mice that result in distinct pathobiont colonization phenotypes and then utilize unbiased multiomics approaches (see below) to identify key drivers of colonization resistance. By gaining insight into these mechanisms, we hope to apply these findings to human patients with hopes of preventing invasive pathobiont infections and pathobiont-induced diseases.
Role of the gut microbiota in modulating autoimmune complications (e.g. graft-versus-host-disease) in cancer and stem cell transplant patients
There is mounting evidence that gut dysbiosis (disturbances in gut microbiome populations) are associated with autoimmune diseases such as inflammatory bowel disease. Further, specific gut microbiota can exacerbate or mitigate autoimmunity in preclinical models.
For example, graft-versus-host-disease (GVHD), a complex immune-mediated process in which the transplanted immune system (graft) attacks the organs of the recipient (host), resulting in 20% to 50% of stem cell transplant (SCT) patients. Our group and others have shown that specific commensal anaerobic bacteria are associated with protection from GVHD. Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, what we term anti-inflammatory Clostridia (AIC), that were significantly depleted in pediatric GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Specific antibiotics that deplete AIC exacerbate GVHD in mice, whereas oral AIC supplementation increases gut AIC levels and mitigates GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients.
We are now in the process of further elucidating the mechanisms by which AIC modulate GVHD. Further, we are cultivating specific AIC from human samples in order to identify gut microbiota strains which are most effective in attenuating inflammation. By gaining insight into these mechanisms, we hope to apply these findings to human patients with hopes of preventing autoimmune complications in cancer and SCT patients.
Using multiomics approaches to identify microbial-dependent effectors which drive disease phenotypes
In an effort to move beyond focusing on gut microbiota taxa, our group is utilizing several ‘omics approaches to identify functional effectors that are driving phenotypes. Using infection, autoimmunity, and cancer preclinical model, we induce distinct gut microbiomes (via use of specific antibiotics or diets) that result in distinct phenotypes. Then we perform concurrent taxonomic, metabolomic, proteomic, and immune functional profiling. These high dimensional data are then analyzed to identify key biological (taxa, metabolites, proteins, immune effectors) drivers of the phenotypes in question. Subsequent experiments are then pursued to confirm causality in the in vitro and preclinical models described above.