Abstract
Mucosal healing plays a critical role in combatting the effects of inflammatory bowel disease, fistulae and ulcers. While most treatments for such diseases focus on systemically delivered anti-inflammatory drugs, often leading to detrimental side effects, mucosal healing agents that target the gut epithelium are underexplored. We genetically engineer Escherichia coli Nissle 1917 (EcN) to create fibrous matrices that promote gut epithelial integrity in situ. These matrices consist of curli nanofibers displaying trefoil factors (TFFs), known to promote intestinal barrier function and epithelial restitution. We confirm that engineered EcN can secrete the curli-fused TFFs in vitro and in vivo, and is non-pathogenic. We observe enhanced protective effects of engineered EcN against dextran sodium sulfate-induced colitis in mice, associated with mucosal healing and immunomodulation. This work lays a foundation for the development of a platform in which the in situ production of therapeutic protein matrices from beneficial bacteria can be exploited.
Highlights
Mucosal healing plays a critical role in combatting the effects of inflammatory bowel disease, fistulae and ulcers
We found that colon length did not differ significantly between the PBP8 CsgA-TFF3 group and the healthy control group, suggesting that in situ CsgA-TFF3 production attenuated colonic inflammation caused by dextran sodium sulfate (DSS)
We found that IL-6, IL-17A, and tumor necrosis factor (TNF)-α concentrations decreased in colonic tissues for the PBP8 CsgATFF3 group compared to the colitic group (Fig. 6k–l and Supplementary Fig. 7A)
Summary
Mucosal healing plays a critical role in combatting the effects of inflammatory bowel disease, fistulae and ulcers. Restitution can occur within hours after injury and relies on the migration of epithelial cells from the surrounding area into the wound site This process can restore mucosal continuity to the gut lining and protect it from bacteria and foreign antigens, and fluid and electrolyte losses, which prevent further inflammatory processes[7]. Engineered microbes have been explored, mostly as a means to secrete biologic drugs (e.g., interleukin (IL)-10, antitumor necrosis factor (TNF)) locally in the colon[13,14,15] Many such efforts have shown high efficacy in animal models but have yet to yield clinical successes, in part because of difficulties in achieving and maintaining sufficiently high concentrations of the therapeutic molecule at the site of disease. The promise of effective treatments that can be produced cheaply, delivered orally, and minimize systemic side effects has continued to fuel interest in microbes as therapeutics
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