Individual Candida albicans yeast strains in the human gut are as different from each other as the humans that carry them. Some C. albicans strains may damage the gut of patients with inflammatory bowel disease (IBD), according to a new study from researchers at Weill Cornell Medicine. The findings suggest a possible way to tailor treatments to individual patients in the future.
The researchers, who reported their results in the March 16, 2022, issue of Nature, used an array of techniques to study strains, or genetic variants, of Candida from the colons of people with and without ulcerative colitis. They found that certain strains, which they call “high-damaging,” produce a potent toxin called candidalysin that damages immune cells.
Dr. Iliyan Iliev with Dr. Xin Li
“Such strains retained their ‘high-damaging’ properties when they were removed from the patient’s gut and triggered pro-inflammatory immunity when colonized in mice, replicating certain disease hallmarks,” says senior author Iliyan D. Iliev, PhD, an Associate Professor of Immunology in Medicine in the Division of Gastroenterology and Hepatology and a scientist in the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.
IBD affects approximately 3.1 million people in the United States and can greatly impair patients’ quality of life. Only a handful of therapies are available, and treatments may not always be effective. The new study has suggested that one reason treatment with steroids may not work, finding that treating mice with the drug to suppress intestinal inflammation failed in the presence of high-damaging C. albicans strains.
“Our findings suggest that C. albicans strains do not cause spontaneous intestinal inflammation in a host with intact immunity,” says Dr. Iliev. “But they do expand in the intestines when inflammation is present and can be a factor that influences response to therapy in our experimental models and perhaps in patients.”
Most studies of the human microbiome in healthy individuals and those with IBD have focused on bacteria and viruses, but recent research by Dr. Iliev and others has illuminated the contributions of fungi to the effects of microbes on humans and mice. They have found that intestinal fungi play an important role in regulating immunity at surfaces exposed to the outside, such as the intestines and lungs, due to their potent immune-stimulating characteristics. While the collective community of fungi in the body – the mycobiota – has been linked to several diseases, including IBD, researchers previously had not understood the mechanisms by which the mycobiota contribute to inflammation in the gut.
In the new study, the Weill Cornell Medicine investigators initially found that Candida strains, while highly diverse in the intestines of both patients with and without colitis, were on average more abundant in the patients with IBD. But that did not explain disease outcomes in individual patients. So, the investigators set out to identify the characteristics of these strains that cause damage and how they relate to individual patients.
Neutrophils contribute to tissue damage and their accumulation is a hallmark of active IBD. The indication that these processes might in part be driven by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches.
— Dr. Ellen Scherl
The researchers observed that in the patients with ulcerative colitis, severe disease was associated with the presence of high-damaging Candida strains, which turned out to have a key factor in common: All produce the candidalysin toxin. The scientists showed that the toxin damages macrophages prompting a storm of the pro-inflammatory cytokine IL-1β.
To underscore this strain-specific effect, the researchers grew macrophages in the presence of Candida strains and found that the ability of the strains to induce IL-1β corresponded closely to the severity of colitis in the patients. “Our finding shows that a cell-damaging toxin candidalysin released by high-damaging C. albicans strains during the yeast-hyphae morphogenesis triggers pathogenic immunological responses in the gut,” says first author Xin Li, PhD, who was a Charles H. Revson Postdoctoral Fellow in the Iliev laboratory at the time of the study.
Opportunistic high-damaging Candida albicans strain in the colon mucosa of an IBD patient secretes the toxin candidalysin (red dots) during the transition from a benign commensal to a pathogenic state and aggravates intestinal inflammation.
Experiments in mice delineated that candidalysin-producing high-damaging strains induced the expansion of a population of Th17 T cells and other immune cells associated with inflammation, such as neutrophils.
Dr. Ellen Scherl
“Neutrophils contribute to tissue damage and their accumulation is a hallmark of active IBD,” says Ellen Scherl, MD, the Jill Roberts Professor of Inflammatory Bowel Disease at Weill Cornell Medicine and Founding Director of the Jill Roberts Center for IBD established at NewYork-Presbyterian/Weill Cornell Medical Center in 2006. “The indication that these processes might in part be driven by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches.”
Consistent with this finding, blocking IL-1β signaling had a dramatic effect in reducing colitis signs in mice that harbored these highly pro-inflammatory strains. The researchers noted that other recent studies have linked IBD to IL-1β in a general way, prompting ongoing investigations of drugs targeting related pathways as potential IBD therapies. “We do not know whether specific strains are acquired by specific patients during the course of disease or whether they have always been there and become a problem during episodes of active disease,” says Dr. Iliev. “Nevertheless, our findings highlight a mechanism by which commensal fungal strains can turn against their host and overdrive inflammation.”
The team is following up with studies of the mechanisms that drive the persistence of candidalysin-producing strains in the inflamed colon of specific IBD patients, as well as ways to choose patients for therapy targeting the mycobiome.