Review Article

Fungal Alterations in Inflammatory Bowel Diseases

Siu Lam; Tao Zuo; Martin Ho; Francis K. L. Chan; Paul K. S. Chan; Siew C. Ng


Aliment Pharmacol Ther. 2019;50(11):1159-1171. 

In This Article

Host Response to Fungal Alterations in IBD Animal Models

In a homeostatic state, fungal-host communications work harmoniously with other trans-kingdom microbes in the gut.[17] Dysbiosis of the mycobiota disrupts this communication and results in pro-inflammatory responses.[19,30,95] Several murine models of colitis have been used to interrogate the interplay between gut fungi and the host. Iliev et al showed that polymorphism of the gene CLEC7A encoding for Dectin-1 was significantly associated with UC severity in mice with predisposed susceptibility to intestinal colitis due to the disruption of fungal sensing.[22] The Dectin-1 signalling cascade was initiated by β-glucan recognition in fungal cell walls.[22,96,97] Ligand binding further signals Spleen tyrosine kinase (SYK) phosphorylation and CARD9 activation.[22,96,97] Activated CARD9 protein then activates Apoptosis-Associated Speck-Like Protein Containing CARD (ASC) adaptor molecules and caspase 1 which enzymatically cleaved pro-interleukin 18 (IL-18) into mature IL-18 in promoting epithelial cell proliferation and restitution.[22,96,97] Additionally, CARD9 activation was also coupled with binding of ubiquitin ligase—Tripartite Motif Containing 62 (TRIM62).[98] Mice with Trim62−/− that were challenged with Dextran Sodium Sulfate (DSS) -induced colitis had increased susceptibility to C albicans infection, suggesting that the absence of TRIM62 binding likely suppressed CARD9 ubiquitination, which consequently silenced the downstream CARD9 signalling.[98] In Illev's model, ITS1 sequencing data showed a similar pattern with Sokol et al,[22,30] whereby gut inflammation led to the expansion and reduction of Candida and Saccharomyces genus respectively.[22,30] Further administration of fluconazole successfully eliminated the over-presented C tropicalis and promoted colitis amelioration.[22] In contrast, Tang et al showed an opposite result whereby blockade of dectin-1 receptor ameliorated colitis progression.[82] The inactivated dectin-1 reduced dendritic cell signalling for antimicrobial peptide secretion, and eased the inhibitory burden on Lactobacillus murinus (L murinus).[82] The revived L murinus was able to signal dendritic cells to secrete Transforming growth factor beta (TGF-β) and IL-10 for stimulating Treg cells proliferation in mitigating gut inflammation.[82] Distinct results between those of Iliev et al and Tang et al studies might be due to the absence of commensal fungi in Tang's model under specific pathogen-free conditions, where the mice diet (a source of commensal fungi) was sterilised by gamma-ray radiation.[22,82] This was later confirmed by the author, who could not detect any live fungi in the murine faeces[82] (Figure 3).

Figure 3.

Mechanisms of fungal sensing in the host. A robust fractalkine receptor (CX3CR1+) recognises the attachment of normal microbial flora to intestinal epithelial cells (IECs) followed by secretion of interleukin 10 (IL-10), which further balances the T-helper cell 1 (Th1) and regulatory T cells (Treg) number in maintaining host-to-microbe homeostasis. Dextran Sodium Sulfate (DSS) treatment damages IECs and leads to encroachment of commensal fungi. β-glucan in fungal cell wall is recognised by dectin-1 receptor, which signals downstream spleen tyrosine kinase (SYK) - Caspase recruitment domain-containing protein 9 (CARD9) phosphorylation in promoting inflammasome formation and interleukin 18 (IL-18) maturation for IECs reconstitution. Mutant of dectin-1 receptor suppresses the signal for antimicrobial peptides (AMPs) secretion and reduces the inhibitory effect on L murinus. The revived L murinus stimulates host dendritic cells or macrophages to secrete TGF-β and IL-10, which positively regulate Treg cell proliferation and differentiation in suppressing gut inflammation. Fluconazole inhibits C albicans but stimulates drug-resistant filamentous fungi A amstelodami, E nigrum and W sebi, which are recognised by CX3CR1+

In addition to dectin-1 signalling, commensal fungi have been found to exacerbate colitis by stimulating host purine metabolism.[99,100] In a wild-type DSS-murine model with robust dectin-1 signalling, daily replenishment of S cerevisiae was found to increase intestinal epithelial barrier permeability as well as positively regulate host purine metabolism for uric acid production, which is positively correlated with the severity of colitis by NLRP3 (NALP3) inflammasome binding[99,100]