Researchers found that certain types of immune cells called CX3CR1+ mononuclear phagocytes play a key role in innate and adaptive immune responses to intestinal fungi in mice. They also found that a mutation in the gene encoding these same immune cells in patients with Crohn’s disease correlated with impaired immune response to intestinal fungi.
These findings, published in Science, led researchers to conclude that defects in CX3CR1+ mononuclear phagocytes (MNPs) may contribute to some cases of Crohn’s disease and other inflammatory bowel diseases, and could lead the way to new targeted therapies.
“After discovering that fungi might be involved in the pathology of IBD, one of the big questions in the field has been how to identify patients who would benefit from antifungal co-therapy, and our finding suggests a way to do that,” Iliyan D. Iliev, PhD, assistant professor of microbiology and immunology in medicine at Weill Cornell Medicine, and a scientist at the Jill Roberts Institute for Research in Inflammatory Bowel Disease, said in a press release.
While most gut microbiome research has focused on bacteria, Iliev and others have focused their work on intestinal fungi, known as the gut mycobiome, and the role it may play in IBD.
“Fungal DNA is hard to access and analyze using standard molecular biology techniques, but we have recently developed much better tools for doing so, and have now taken this further by visualizing fungal-host interactions in the gut,” Iliev said in the press release.
To better understand how the immune system regulates the gut mycobiome and prevents the expansion of harmful fungi, Iliev and colleagues first used a mouse model to identify CX3CR1+ MNPs as a key regulator of immune response to intestinal fungi.
“We were surprised how well-equipped those cells were for dealing with fungi,” Irina Leonardi, PhD, also of Weill Cornell and the Jill Roberts Institute, said in the press release.
While CX3CR1+ MNPs were previously known to drive immune response to bacteria and food-derived plant and animal cells in the gut, “our findings show that these CX3CR1+ cells are also essential for the initiation of immune responses to gut fungi, and regulate the composition of the gut mycobiome,” Iliev said in the release.
Further, Iliev and colleagues found that genetic ablation of CX3CR1+ MNPs in mice altered the composition of the gut mycobiome and induced severe colitis, which then resolved with antifungal treatment, suggesting that fungal overgrowth triggered intestinal disease.
Finally, the investigators evaluated 503 patients with Crohn’s disease, and found that those who carried a homozygous mutation in the CX3CR1 gene showed a reduced immune response to intestinal fungi similar to what they observed in the mouse model.
The investigators noted these findings may help explain why serum antibodies against a strain of fungi called Saccharomyces cerevisiae (ASCA) are often elevated in patients with Crohn’s disease and are therefore commonly used as a diagnostic marker. Notably, they found “a striking association” between a CX3CR1 polymorphism and ASCA (OR = 0.59), while IBD-associated antibodies against bacterial and host antigens were not affected by the mutation.
“Our study sheds light on the mechanisms leading to ASCA generation,” Leonardi said in the press release. “The team’s findings suggest that patients who have the CX3CR1 gene variant might be misdiagnosed since they are negative for ASCA. These individuals might additionally have impaired gut antifungal response that would allow fungal overgrowth and worsened colitis.”
Iliev added that the presence of this gene variant in addition to low ASCA titers “could be a good indicator that a Crohn’s disease patient might benefit from antifungal therapy.” – by Adam Leitenberger
Disclosures: The authors report no relevant financial disclosures.