Fungal microbiome in inflammatory bowel disease: a critical assessment

Abstract

The gut microbiome is at the center of inflammatory bowel disease (IBD) pathogenesis and disease activity. While this has mainly been studied in the context of the bacterial microbiome, recent advances have provided tools for the study of host genetics and metagenomics of host-fungal interaction. Through these tools, strong evidence has emerged linking certain fungal taxa, such as Candida and Malassezia, with cellular and molecular pathways of IBD disease biology. Mouse models and human fecal microbial transplant also suggest that some disease-participatory bacteria and fungi may act not via the host directly, but via their fungal-bacterial ecologic interactions. We hope that these insights, and the study design and multi-omics strategies used to develop them, will facilitate the inclusion of the fungal community in basic and translational IBD research.

Figure 1. Diversity of IBD presentations and underlying causes.

Rather than being a single disease, or two diseases (CD and UC), IBD is increasingly being understood as a multifaceted disorder initiated and exacerbated by influences such as genetic susceptibility and alterations in the intestinal microbiota.

Figure 2. Innate antifungal receptors and key signaling pathways, including through CARD9.

Antifungal C-type lectin receptors such as Dectin-1/2 and Mincle have a single extracellular C-type lectin domain. Signaling is mediated either by a short intracellular signaling tail (Dectin-1) or through association in the membrane with the Fc receptor common γ chain (FcRγ) that mediates signaling. Proteins and processes linked to IBD through genetic studies are indicated with asterisks.

Figure 3. CARD9 polymorphisms and their effects.

The CARD9 gene comprises 13 exons. A common single-nucleotide polymorphism in exon 2 causes one allele to code for a serine in position 12 and the others to code for an arginine. A second polymorphism at the end of exon 11 results in production of a splice variant lacking exon 11 and production of a protein lacking function. While the N12 variant confers increased risk of developing CD, the truncation variant is protective. (Population distribution from Ensembl [ensembl.org].)