Nature｜Li Xin et al reveal the strain-specific effect of gut fungi on inflammatory bowel disease

Article｜617 Inflammatory bowel disease (IBD) is a chronic non-specific intestinal inflammatory disease of unknown etiology.
It is clinically divided into Crohn's disease (CD) and ulcerative colitis (UC).
The disease affects the world millions
.

Several studies in recent years have shown that intestinal fungi play an important role in IBD [1-7]
.

Candida is one of the most important intestinal fungi, and data from multiple cohorts have shown that the abundance of this genus is elevated in IBD patients [1,4,8]
.

However, little is known about the mechanisms by which Candida affects the development and progression of IBD
.

On March 16, 2022, the team of Iliyan D.
Iliev of Cornell University published an article entitled Immune regulation by fungal strain diversity in inflammatory bowel disease in the journal Nature.
Dr.
Xin Li is the first author of the article
.

The research aims to help people understand how human gut fungi initiate an inflammatory gut immune response and influence disease progression in the host
.

Using UC patients as a model, this study revealed that the intestinal tract of UC patients was revealed through fungal genome sequencing, fungal culture and genomics, CRISPR-Cas9-based clinical fungal strain editing technology, in vitro immune response monitoring, and mouse models.
Diversity and strain-specificity of the dominant fungus Candida albicans, and elucidated the mechanism of its regulation of host intestinal immunity
.

First, the authors used ITS sequencing technology and culture omics to detect the colonic mucosa of UC patients and healthy controls, and found that Candida albicans was significantly increased in the colonic mucosa of UC patients
.

Further, the authors explored the effect of Candida albicans on UC in a dextran sodium sulfate (DSS)-induced UC mouse model
.

The results suggest that C.
albicans negatively affects disease outcome under corticosteroid treatment (common therapy in UC)
.

Studies have shown that the specificity of fungal strains can affect the occurrence and development of infectious diseases [9-12].
Therefore, the authors further studied the Candida albicans strains isolated from the human gut and tested their effects on immune cells.
destructive ability
.

It was found that the isolated Candida albicans strains could be divided into two categories: one with strong destructive power (HD-Ca) to macrophages, the other with weaker destructive power (LD-Ca), and HD-Ca induces more robust pro-inflammatory responses in mouse colon, including neutrophil infiltration and TH17 responses
.

The above results suggest that the destructive power of C.
albicans in the human colon to immune cells and the ability to induce pro-inflammatory responses such as TH17 in the mouse gut are strain-specific
.

In addition, the evolutionary analysis of these strains showed that despite the close geographical location of the patients, C.
albicans varied among individuals, and even some patients contained multiple C.
albicans strains based on the same ancestor at the same time, indicating that human intestinal C.
albicans with high diversity
.

Further, the authors found that the destructive power on immune cells was associated with the formation of hyphae, and the destructive power was stronger in strains that responded to filamentous stimulation
.

Therefore, the authors deeply explored the Efg1 protein that is closely related to the process of hyphae formation
.

Based on CRISPR technology, the authors knocked out the EFG1 gene of the HD strain, and the results showed that the knockout strain had reduced destructive power to immune cells and reduced TH17 inducibility
.

Since morphologically similar strains of HD and LD can be observed in the intestinal mucosa, that is, the gut contains both oval (yeast) and hyphal forms of HD and LD Candida albicans, the authors believe that it is a specific fungal factor rather than a Pure hyphal morphology activates gut immunity
.

Studies have shown that after Candida albicans colonizes the gut, the expression of a gene called ECE1 is significantly up-regulated [13], which encodes candidalysin, a fungal hypha-related hole punching toxin, so the authors wondered whether this gene was involved in regulating the gut.
immune response
.

The authors first constructed an HD ece1 Δ/Δ mutant strain and found that although the mutant strain could still form hyphae normally, its destructive and pro-inflammatory abilities on immune cells were significantly reduced
.

After further knocking out the ECE1 gene of the HD strain, the authors found that its TH17 inducibility and pro-inflammatory ability were also significantly reduced, similar to those of the LD strain and HD ece1 Δ/Δ mutant
.

It can be seen that the toxin formation of Candida albicans in the intestinal tract of UC patients depends on the regulation of fungal transcription factor (Efg1), and the toxin candidalysin secreted during the generation of hyphae is a key factor in inducing mucosal immune responses and promoting intestinal inflammation, not bacteria.
The filament form itself
.

Taken together, these findings are the first to elucidate the mechanism by which C.
albicans induces an inflammatory response in the gut
.

HD Candida promotes intestinal inflammatory immune response through candidalysin Next, the authors further explored the pro-inflammatory factors associated with candidalysin
.

It was found that although C.
albicans could induce TNFα, IL-6, IL-1β and IL-10, only IL-1β was dependent on candidalysin, and its level correlated with the ability of the strain to destroy immune cells
.

Blocking the IL-1β receptor reduced disease severity in mice, suggesting that the IL-1 signaling pathway plays a key role in C.
albicans activating the gut immune response
.

In addition, the authors found that C.
albicans-induced immune cell damage and IL-1β expression levels, but not Candida abundance, were positively correlated with disease severity in UC patients
.


In conclusion, this study shows that the toxins produced during the morphological transition of highly virulent intestinal fungi are key factors in inducing tissue damage and initiating intestinal inflammatory responses, and the molecular mechanism is dependent on the cytokine IL-1β.

.

Therefore, this study not only provides new insights into the pathogenesis and treatment of IBD, but also reveals the importance of strain-specificity in host-gut-microbe interactions
.

Original link: https:// Publisher: Eleven References 1.
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11 .
Schonherr, FA et al.
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