A recent study done on mice at Case Western Reserve University School of Medicine illuminated that a microscopic fungus by the name of Candida tropicalis is able to start gut inflammation and intensify symptoms of Crohn's disease. These findings were presented at Digestive Disease Week from May 5-9, 2017 at McCormick Place in Chicago, Illinois. It is possible that from this study, if replicated in humans, novel antifungal therapies may be able to treat severe symptoms of Crohn's disease.
Who conducted the study?
The senior author of the study was Fabio Cominelli, M.D., Ph.D. He is a Professor of Medicine and Pathology at Case Western Reserve University School of Medicine, the largest medical research institution in Ohio. He is also the Division Chief of Gastroenterology at University Hospitals Cleveland Medical Center. Not only was he the senior author, but he also authored five other studies that were presented at Digestive Disease Week from May 5-9, 2017. Lead author of the study was Luca Di Martino, Ph.D., who is a Postdoctoral Research Fellow in the Digestive Health Research Institute also at Case Western Reserve University School of Medicine. The study was funded and supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
Colitis, which is a word for colon inflammation, is an immensely painful symptom that those suffering from Crohn's disease often experience. An abnormal immune response causes colitis when the body attempts to combat an infection, but in this attempt, attacks the intestinal tract. This new study shows that the C. tropicalis infection is likely to intensify this preexisting malfunction. Lead author Di Martino investigated the ways in which C. tropicalis and other gut microorganisms have the potential to influence intestinal influence and explained, "the type of microorganisms that live in our intestine, our microbiome, has been shown to be a key element for triggering Crohn's disease. Recent studies have shown that the abundance of the fungus Candida tropicalis is significantly higher in the intestine of Crohn's disease patients compared to healthy people."
The researchers involved in the study added low levels of dextran sodium sulfate to the drinking water of mice in order to stimulate colitis symptoms. Dextran sodium sulfate causes acute intestinal injury, which is similar to the flare those with colitis experience. After they have added the chemical, they infected a subset of the mice with C. tropicalis fungi. They proceeded to examine the intestinal tracts and gut bacteria of the mice.
The results of the study
Upon examining the intestinal tracts and gut bacteria, the researchers found that the mice that had been infected with the C. tropicalis fungi experienced far more intensified Crohn's disease symptoms than the mice that were left uninfected. What this depicts to researchers is that anti-fungal medications have the potential to combat the debilitating symptoms of Crohn's disease by lowering gut levels of C. tropicalis.
Both Cominelli and Di Martino explained, "our data demonstrate that C. tropicalis may play a pro-inflammatory role in intestinal injury by exacerbating gut inflammation during the recovery phase of dextran sodium sulfate-induced colitis. We speculate that infection with the fungus C. tropicalis may play a role in triggering flares during Crohn's disease and that anti-fungal therapy may be beneficial in Crohn's disease patients." Di Martino went on to explain, "we found that high levels of C. Tropicalis increases the abundance of harmful proteobacteria in the intestine, such as E. coli, disrupting the normal balance of the gut bacteria and creating a dysbiosis, a key element that triggers intestinal inflammation."
Because the researchers presume that C. tropicalis fungus may be responsible for triggering gut inflammation by modulating other levels of bacteria, those with Crohn's disease may now be able to identify why some of their symptoms may be intensified. The research goes further to explain that infected mice displayed multiple signs of debilitating gut inflammation. The endoscopies performed on these mice shed light on that the colons of the infected mice had 4.5 times higher levels of certain inflammatory molecules that are associated with colitis, often referred to as IFN-γ. When the researchers examined this more closely, they found that infected intestinal tracts possessed more severe visual signs of swelling that the intestinal tracts in the mice that were not infected in the beginning of the study. Therefore, this may be a sign that C. tropicalis may, in fact, be the cause of the more severe symptoms among certain people suffering from Crohn's disease. However, finding this result in mice is not yet enough information to begin treatment in humans as well.
Potential roadblocks moving forward
Unfortunately, when studies are done on animals that are meant to address the effects certain diseases hold on humans, there are sometimes certain discrepancies. Therefore, the effects of human gut bacteria in mice may not actually be the same in human disease. Also, the researchers induced colitis in these mice acutely using dextran sodium sulfate. However, colitis can often be a chronic condition in humans. Because of these potential inconsistencies, although the study has definitely shed light on potential aspects of Crohn's disease and intestinal inflammation, it is possible that the effects this study will have on the immediate treatment of those with Crohn's disease will be very limited.
Lead author Di Martino explained, "We discovered that experimental mice infected with C. tropicalis were more susceptible to intestinal inflammation compared to uninfected mice. The most exciting discovery was that in the infected mice there was a significantly higher abundance of proteobacteria, the same type of deleterious bacteria found increased in Crohn's patients. This confirmed that the presence and the abundance of fungi in the intestine have the ability to modify the bacteria living in our intestine, leading to a dysbiosis which will eventually trigger an inflammatory syndrome. As a next step, we want to confirm the role of the fungi in the pathogenesis of Crohn's disease by treating infected mice with antifungal drugs to decrease symptoms of intestinal inflammation. If our hypothesis is right, that would open the door to novel antifungal therapies to treat Crohn's disease patients." If Di Martino and Cominelli's hypothesis is indeed correct, and novel antifungal therapies to treat Crohn's disease patients could become widely available, the suffering that Crohn's disease patients with C. tropicalis are currently experiencing could be drastically lessened.
As Di Martino explained, this study may prove to offer more than just an explanation as to why certain Crohn's disease patients suffer certain symptoms more severely than others, but offer potential future antifungal therapies that potentially possess the ability to treat Crohn's disease. In order to further assess this potential, researchers plan to continue their study regarding how Candida tropicalis affects Crohn's disease by treating the infected mice with anti-fungal medications. From this study, they will be able to analyze the effectiveness of anti-fungals in reducing inflammation and treating symptoms of Crohn's disease. If the treatment in mice is successful and the researchers can find a way to validate the impact this fungus has on humans as well, then new targeted therapies may soon be in the works to help treat patients with Crohn's disease.