Rewiring\nTryptophan Metabolism <i>via</i> Programmable Probiotic\nIntegrated by Dual-Layered Microcapsule Protects\nagainst Inflammatory Bowel Disease in Mice

Intestinal\ndysbiosis and the associated l-tryptophan metabolic\ndisorder are pivotal in inflammatory bowel disease progression, leading\nto a compromised intestinal barrier integrity. Remedying the dysfunction\nin tryptophan metabolism has emerged as a promising therapeutic strategy.\nHerein, we reprogram the tryptophan metabolism <i>in situ</i> by EcN-TRP@A/G, encapsulating the engineered probiotic, EcN-TRP,\nwith enhanced tryptophan synthesis capacity, for sustained modulation,\nthereby restoring intestinal barrier function and microbial homeostasis.\nThe pH-responsive dual-layered EcN-TRP@A/G microcapsule developed <i>via</i> high-voltage electrospraying and liquid interface self-assembly,\npreserved probiotic viability in the harsh gastrointestinal milieu,\nand facilitated targeted colon release. Bioluminescent tracking in\nmice reveals a 22.84-fold increase in EcN-TRP@A/G viability and distribution\ncompared to naked EcN-TRP. Targeted metabolomics highlights EcN-TRP@A/G’s\nmodulation of the tryptophan–indole pathway. Oral administration\nof EcN-TRP@A/G sustained elevates indole metabolites, particularly\nindole-3-acetic acid and indole-3-propionic acid, in colon tissue\nfor up to 7 days. In IBD mice, EcN-TRP@A/G improves intestinal permeability,\nreduces inflammation, and recovers the gut microbiome by enhancing\nbeneficial bacteria abundance like <i>Prevotellaceae_UCG-001</i> and <i>Anaerostipes</i> while suppressing pathogenic strains\nlike <i>Escherichia</i>–<i>Shigella</i>. Our findings offer a cost-effective approach, harnessing the probiotic\nmetabolic potential <i>in situ</i> through engineered modifications\nfor effective IBD treatment.