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Research

Candida albicans Gastrointestinal Colonization and Dissemination

Candida albicans, the most common human fungal pathogen, colonizes up to 80% of humans and is now the 4th leading cause of hospital-acquired infections. Surgical patients, premature babies, and cancer patients are particularly prone to developing invasive Candida infections.

We are particularly interested in how commensal anaerobic gut microbiota maintain C. albicans colonization resistance in the mammalian gut. 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.

We are now in the process of further elucidating both the direct bacterial-fungal and bacterial-host mechanisms that prevent C. albicans from colonizing the mammalian GI tract. By gaining insight into these mechanisms, we hope to apply these findings to human patients with hopes of preventing invasive C. albicans infections.

Role of the gut microbiota in modulating graft-versus-host-disease

Between 20-50% of patients undergoing allogeneic stem cell transplantation (SCT) develop 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 HSCT patients.

Commensal gut bacteria have long been implicated in initiating and perpetuating GVHD. 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. By gaining insight into these mechanisms, we hope to apply these findings to human patients with hopes of preventing GVHD in patients.

Role of the gut microbiota in modulating host anti-tumor response

One of the major functions of the gut microbiome is the activation and education of host immune responses[7, 8]. Interestingly, in preclinical mouse models, the composition of the host gut microbiota is a major factor determining response to cancer therapy, both cytotoxic chemotherapy and immune checkpoint inhibitory therapy (ICT). In fact, germ-free or antibiotic treated tumor bearing mice do not respond to cancer therapy. But introducing specific gut microbiota in the murine GI tract results in improved cancer therapy response.

We recently completed a pilot study in adult melanoma patients receiving immune checkpoint inhibitor therapy (ICT). We performed gut microbiome and gut metabolome profiling on pre-therapy fecal samples. We identified unique gut microbiota and gut metabolites that were significantly enriched in ICT responders versus those who developed progressive disease.

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 and a preclinical melanoma model. By gaining insight into these mechanisms, we hope to apply these findings to cancer patients with hopes of optimizing response to cancer therapy.

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.