Rewiring Tryptophan Metabolism <i>via</i> Programmable Probiotic Integrated by Dual-Layered Microcapsule Protects against Inflammatory Bowel Disease in Mice
Wen Li, Yichen Liu, Xiaoming Zheng, Jing Han, Anchen Shi, Chi Chun Wong, Ruochen Wang, Xunan Jing, Yan Li, Shu Fan, Cuiyu Zhang, Yinnan Chen, Gang Guo, Jun Yu, Junjun She
Abstract
Intestinal dysbiosis and the associated l -tryptophan metabolic disorder are pivotal in inflammatory bowel disease progression, leading to a compromised intestinal barrier integrity. Remedying the dysfunction in tryptophan metabolism has emerged as a promising therapeutic strategy. Herein, we reprogram the tryptophan metabolism in situ by EcN-TRP@A/G, encapsulating the engineered probiotic, EcN-TRP, with enhanced tryptophan synthesis capacity, for sustained modulation, thereby restoring intestinal barrier function and microbial homeostasis. The pH-responsive dual-layered EcN-TRP@A/G microcapsule developed via high-voltage electrospraying and liquid interface self-assembly, preserved probiotic viability in the harsh gastrointestinal milieu, and facilitated targeted colon release. Bioluminescent tracking in mice reveals a 22.84-fold increase in EcN-TRP@A/G viability and distribution compared to naked EcN-TRP. Targeted metabolomics highlights EcN-TRP@A/G’s modulation of the tryptophan–indole pathway. Oral administration of EcN-TRP@A/G sustained elevates indole metabolites, particularly indole-3-acetic acid and indole-3-propionic acid, in colon tissue for up to 7 days. In IBD mice, EcN-TRP@A/G improves intestinal permeability, reduces inflammation, and recovers the gut microbiome by enhancing beneficial bacteria abundance like Prevotellaceae_UCG-001 and Anaerostipes while suppressing pathogenic strains like Escherichia – Shigella . Our findings offer a cost-effective approach, harnessing the probiotic metabolic potential in situ through engineered modifications for effective IBD treatment.