Microbial infection impairs healing in Crohn's disease

A US research team has discovered an infection that prevents healing in Crohn’s disease — a breakthrough that may point to much-needed new treatment or prevention approaches for the common inflammatory bowel disease.

The work was led by Dr Thaddeus Stappenbeck, Chair of the Cleveland Clinic Lerner Research Institute’s Department of Inflammation & Immunity, and also included researchers from Washington University in St. Louis, Cedars-Sinai Medical Center and Dartmouth College. Together, they found that levels of the yeast Debaryomyces hansenii — commonly found in cheese and processed meat — are higher in Crohn’s disease patients, particularly abundant within chronically inflamed regions of the colon and small intestine, indicative of unhealed intestinal wounds. Their work has been published in the journal Science.

“Impaired wound healing can promote chronic inflammation, both of which are key features of inflammatory bowel diseases,” said Dr Stappenbeck. “The significance of our study is that we found an infectious component for Crohn’s disease. Targeting this infection may be a viable approach to treat the disease or develop diet-based prevention strategies, which are greatly needed as current therapies fail in about 50% of our patients.”

The researchers analysed biopsied intestinal tissue from patients with and without Crohn’s disease, finding that D. hansenii was detected in most diseased samples compared to only 10% of healthy samples. Additionally, in an unrelated cohort of patients, researchers sequenced genomic DNA biopsied from various intestinal regions of individuals with Crohn’s disease. They found that D. hansenii was elevated in inflamed regions on the intestines compared to non-inflamed regions sampled from the same patient.

To identify the specific mechanisms at play, Dr Stappenbeck and colleagues studied mouse models of impaired wound healing consistent with injuries observed in Crohn’s patients, finding that D. hansenii levels were significantly higher only within unhealed wounds. They went on to find that the fungus preferentially localised within these wounds to a specific type of immune cell, called macrophages.

They determined that D. hansenii is not broadly pro-inflammatory but rather contributes to disease pathology by increasing the levels of a specific cytokine called CCL5 (chemokine ligand 5). Chemokines such as CCL5 are needed to recruit other inflammatory cells.

“Taken together, our findings suggest that targeting CCL5 or the yeast itself may be viable therapeutic approaches to improve intestinal healing in patients with Crohn’s disease who are infected with D. hansenii,” Dr Stappenbeck said.

Follow-up clinical studies will be important to test additional patients of various ages and geographic locations. It also will be important to follow patients with D. hansenii infections over time to determine the clinical importance with respect to disease severity, progression and response to Crohn’s treatments.

“As microbiome research has exploded in the last decade or so, our understanding of its role in human health and disease has expanded tremendously,” Dr Stappenbeck said. “Our study supports that D. hansenii is safe in healthy individuals, but may be problematic in Crohn’s patients. Our goal is to now understand how D. hansenii interacts with other components of the microbiome and the host immune system in Crohn’s disease patients to affect its ability to infect damaged areas of the intestine.”

Image caption: An infected macrophage. Image courtesy Washington University.

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