An orally administered peptide hydrogel disentangles immune-microbiota crosstalk for long-term ulcerative colitis therapy

Ulcerative colitis (UC), a worldwide health issue, stems from immune system mismanagement and gut bacteria imbalance.1 Existing treatments, hindered by limited effectiveness and systemic side effects when used long-term, are unable to heal the complex interplay between the immune system and microbes.2 In this study, researchers introduce an orally delivered self-assembled hydrogel, C2-(IIRR)2I-NH2 (CIR), made from host defense peptides, designed to break down the link between the immune system and microbiota.

The CIR hydrogel changes shape at inflamed areas rich in liposaccharide (LPS), a substance that triggers inflammation and is produced by harmful bacteria. When the beta-sheet nanofibers in the hydrogel change from a double-layered structure to a single-layered conformation, they transform into bioactive configurations that can target the affected area specifically, causing little to no harm to other parts of the body.

In experiments with mice with colitis, CIR improved the health of the lining of the intestine and reduced the severity of the disease better than the common drug 5-aminosalicylic acid (5-ASA). By examining the community of microbes in the gut, the researchers found that CIR can restore a healthy balance among the different types of bacteria, reducing the number of pathogenic bacteria like Prevotellaceae.

Additionally, CIR appears to deactivate a signaling pathway called TLR4, which plays a key role in immune system response. By simultaneously addressing issues with the immune system and the imbalance of gut bacteria, this self-assembled peptide hydrogel offers a novel approach to treating UC, potentially benefiting people with various gastrointestinal disorders.