How do interactions between intestinal bacteria and fungi exacerbate Crohn's disease?

Scientists knew that bacteria in the intestine, as well as environmental and genetic factors, contributed to the debilitating bowel disease of Crohn's disease (CD). But in 2016, Mahmoud A Ghannoum, Ph.D., FAAM, FIDSA, professor and director of the Center for Medical Mycology at Case Western Reserve School of Medicine and Cleveland University Hospital, was the first to identify a specific fungus. in the man. who interacted with the bacteria in the development of the disease.

Now, to find out exactly how this fungus interacts with bacteria to trigger MC, Ghannoum has received a five-year, three-million dollar grant from the National Institutes of Health. His investigation will focus on innovative molecular and cellular technologies, aimed at removing specific genes from the fungus and to note the effects on inflammation, marker of MC, with the help of a powerful microscopic badysis. .

"Discovering how the link between bacteria and fungi works will help to better understand why some people develop Crohn's disease," Ghannoum said. "Equally important, it can put us on the path to new treatments and even treatments, including targeted probiotics."

In his previous work, Ghannoum reported that among hundreds of bacterial and fungal species inhabiting the intestines, the abundance of the only fungus Candida tropicalis was positively correlated with two types of bacteria in CD patients: Serratia marcescens and Escherichia coli. Ghannoum also showed that the three pathogens join forces to form a powerful biofilm, a thick, viscous layer of antibiotic and antifungal-resistant microorganisms, which adheres to the intestine and can cause inflammation that causes the painful symptoms of CD.

Specifically, the biofilms formed by the three microorganisms together were significantly thicker than the biofilms formed by the three microorganisms individually, or in variable combinations of two. Ghannoum also found that substitution by other fungi did not produce the same thick biofilms as Candida, indicating that it is a Candida-specific effect.

The new study has three goals. The first is to identify the genetic mechanisms underlying the interactions badociated with Crohn's disease among the three microorganisms identified in the previous study. Ghannoum will examine the genes of the three microorganisms alone and together to determine which genes increase their expression when the three microorganisms meet, compared to those that are isolated. He will then remove these genes to see if the very thick three-microorganism biofilm is still forming.

In the second objective, Ghannoum will examine some small chemicals secreted by the biofilm when the three microorganisms are grown together. Chemicals, called metabolites, increase the ability of the fungus to invade the intestinal mucosa. "Here we want to know which chemicals, called metabolites, allow the body to form the biofilm," Ghannoum said. "Once we understand this, we want to see how we can interfere with biofilm formation by manipulating the metabolites."

In the third goal, Ghannoum will determine how the three microorganisms individually and collectively influence inflammation and badociated symptoms. It will do this by looking for the presence of pro-inflammatory proteins called cytokines. An imbalance between pro-inflammatory and anti-inflammatory cytokines that occur in CD can lead to progression of the disease. It will attempt to determine whether exposure of the biofilm to three microorganisms to antibacterial, antifungal and metabolite inhibitors modulates the severity of intestinal inflammation.

"The long-term goal of this project is to develop new antifungal and probiotic strategies that can be tested in preclinical and clinical studies to reduce the onset and duration of symptoms in patients with Parkinson's disease." irritable bowel, including Crohn's disease, "said Ghannoum.