Fungal commensal promotes intestinal repair via its secreted peptide in mice
Yiru Gao1, Tengyu Wang2, Nan Nan3
1College of Life and Health Sciences, Northeastern University, Shenyang, China.
Abstract:
The intestinal epithelium relies on continuous stem cell-driven renewal to maintain barrier function and recover from injury. While bacterial signals are known to influence intestinal stem cell behaviour, the regenerative capacity of the gut mycobiome has remained largely unexplored. Here we identify the commensal fungus Kazachstania pintolopesii (Kp) as a critical mediator of intestinal regeneration through its secreted protein Ygp1. We found that a 12-amino acid peptide fragment of Ygp1, CD12, was sufficient to promote intestinal organoid differentiation and accelerate intestinal healing in murine models of colitis and chemotherapy-induced injury. Transcriptomics, simulations and molecular interaction experiments revealed that CD12 binds mammalian α-enolase (ENO1), enhancing YAP1 (Yes-associated protein 1) protein levels and activating regenerative transcriptional programmes through the Hippo signalling pathway. Engineered probiotics expressing CD12 replicated its therapeutic benefits, offering a translatable delivery strategy. Our work expands the therapeutic potential of the mycobiome, positioning it as a source of biologics for inflammatory and iatrogenic gut disorders.
Insights
The gut mycobiome
Area of Science:
- Gastroenterology and Microbiology
- Stem Cell Biology
- Molecular Medicine
Background:
- Intestinal epithelium renewal is crucial for barrier function and injury repair.
- Bacterial signals influence intestinal stem cells, but the mycobiome's role is understudied.
- The gut mycobiome's regenerative capacity requires further investigation.
Purpose of the Study:
- To investigate the role of the gut mycobiome in intestinal regeneration.
- To identify specific fungal factors that promote gut healing.
- To explore therapeutic applications of mycobiome-derived molecules.
Main Methods:
- Identification of commensal fungi and their secreted proteins.
- In vitro studies using intestinal organoids.
- In vivo murine models of colitis and chemotherapy-induced injury.
- Transcriptomic analysis, molecular interaction assays, and computational simulations.
- Development of engineered probiotics for therapeutic delivery.
Main Results:
- Kazachstania pintolopesii (Kp) and its secreted protein Ygp1 are identified as critical for intestinal regeneration.
- A peptide fragment of Ygp1, CD12, promotes organoid differentiation and accelerates healing in injury models.
- CD12 binds mammalian α-enolase (ENO1), increasing YAP1 levels and activating the Hippo signaling pathway.
- Engineered probiotics expressing CD12 demonstrated therapeutic efficacy.
Conclusions:
- The commensal fungus Kp and its peptide CD12 are potent mediators of intestinal repair.
- CD12 functions by interacting with ENO1 and modulating the Hippo-YAP1 pathway.
- Engineered probiotics offer a viable strategy for delivering mycobiome-derived therapeutics.
- The mycobiome represents a promising source of biologics for gut disorders.
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