External validation: Limon et al 2019
Updated: Apr 27, 2020
An article published this week in Cell Host & Microbe has provided the first strong external validation that Malassezia cause Crohn's disease. Limon and colleagues show that CARD9 mutations associated with Crohn's disease (and ulcerative colitis) affect disease risk by changing the immune response against Malassezia.
Their study provides conclusive evidence of Malassezia's central role in the subset of Crohn's patients who carry the CARD9 mutation S12N. This represents 25-50% of Americans suffering from Crohn's or ulcerative colitis. They also demonstrate that ASCAs are cross-reactive with Malassezia, as predicted by the Malassezia Project Crohn's video and by Laurence et al 2018.
Using mouse models, Limon and colleagues demonstrated that one of the main immunological pathways which causes Crohn's disease is recognition of Malassezia through Dectin-2 and CARD9.
Malassezia are abundantly present in the stools of ~80% of healthy adults (Nash et al 2017). About 50%-75% of Crohn's patients have antibodies against conserved fungal cell wall sugars (eg. ASCAs), a much higher rate than healthy controls (Dotan et al 2006). Therefore, it would be surprising if Malassezia were not involved in this large subset of patients—otherwise ASCAs would not be produced.
In the smaller ASCA-negative patient subset, it is likely that Malassezia are also involved but antibodies are not produced. This is plausible because Crohn's is a T cell-mediated disease (not a B cell-mediated disease*), so antibodies are not involved in the main immunological pathway, and are only a low sensitivity biomarker of T cell recognition of Malassezia (Laurence et al 2018).
Limon and colleagues concludes:
The findings suggest that a precision approach therapeutically targeting specific members of the fungal microbiota in certain individuals should be explored.
In plain English, which antifungal drugs can clear Malassezia from the gut? Do these drugs cure Crohn's disease? A preliminary study using the antifungal drug itraconazole suggests this might work (Samuel et al 2010).
* B cells produce antibodies, but T cells do not.