• Koh Lab Banner

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.