Debaryomyces species as an indicator of non-healing ulcers in Crohn's disease

Inventors

Stappenbeck, Thaddeus • JAIN, Umang

Assignees

Washington University in St. Louis

Abstract

Methods for treating, selecting a treatment, and monitoring a treatment for an inflammatory bowel disease in a patient in need are disclosed. Treatments include administering an antifungal compound. The method for selecting and monitoring a treatment includes detecting a biomarker indicative of an amount of the fungus Debaryomyces hansenii within the sample. The treatment is administered if the biomarker is above a threshold level and the biomarker may be monitored before and during treatment. Biomarkers include abundance of fungal DNA in the patient's gut microbiota and anti-fungal antibodies in the blood of the patient.

Core Innovation

The disclosure provides methods to diagnose, select, and monitor inflammatory bowel disease, with a focus on Crohn’s disease, using biomarkers that reflect intestinal burden of the fungus Debaryomyces hansenii. The biomarker evidence includes detecting Debaryomyces hansenii deoxyribonucleic acid (DNA) sequences in an inflamed intestinal biopsy sample or an inflamed excised intestinal tissue sample, or measuring an increased concentration of antibodies against Debaryomyces hansenii in blood or serum of a patient relative to healthy controls. The disclosure further links these biomarker readouts to treatment selection and monitoring.

The disclosure states that a therapeutically effective amount of an antifungal compound is administered to treat Crohn’s disease, and that such administration reduces Debaryomyces in the gut microbiome to improve mucosal and wound healing. Antifungal compounds described include caspofungin, fluconazole, and flucytosine, and the disclosure also discusses amphotericin B in experiments. The mechanistic rationale presented connects Debaryomyces hansenii localization to inflamed wound beds with impaired crypt regeneration via a myeloid/type I interferon axis and CCL5, including mitigation of the healing defect by CCL5 neutralization or loss of CCR5.

The disclosure supports the mechanistic link and clinical relevance using models and human evidence. It describes enrichment of Debaryomyces and Debaryomyces hansenii in inflamed CD tissue and elevated serum IgA against Debaryomyces hansenii, with correlation involving CCL5. It also describes that in mouse models, conditions that cause defective healing are rescued by antifungal administration, and that direct inoculation of Debaryomyces hansenii impairs repair, including additional evidence from DSS and gnotobiotic model contexts.

Claims Coverage

The provided independent claim is directed to treating Crohn’s disease by biomarker detection for Debaryomyces hansenii followed by administering a therapeutically effective amount of an antifungal compound. The main inventive features are expressed through two alternative biomarker detections and an antifungal treatment step, with dependent claims refining the detection modality and specifying example antifungal compounds and microbiome-targeting treatment effects.

Across the independent claim, the inventive concept is to identify Crohn’s disease patients using either Debaryomyces hansenii DNA sequences in inflamed intestinal samples or elevated antibodies against Debaryomyces hansenii in blood/serum compared to healthy controls, and to treat the patient by administering a therapeutically effective amount of an antifungal compound.

Stated Advantages

Documented Applications