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Basic Gastroenterology
IDDF2024-ABS-0288 Engineered probiotic with high tryptophan synthesis capability protects against inflammatory bowel disease
  1. Yichen Liu1,
  2. Wen Li1,
  3. Jing Han1,
  4. Yinnan Chen1,
  5. Gang Guo1,
  6. Chi Chun Wong2,
  7. Jun Yu2,
  8. Junjun She3
  1. 1Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi’an Jiao Tong University, China
  2. 2Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
  3. 3Department of General Surgery, First Affiliated Hospital, Xi’an Jiaotong University, China

Abstract

Background Aberrant L-tryptophan metabolism has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Here, we engineered a probiotic, which in conjunction with microcapsule-aided delivery to the colon, rectifies colon tryptophan metabolism and alleviates IBD in mice.

Methods Probiotic EcN was genetically engineered to establish the EcN-TRP strain, with enhanced capacity to produce tryptophan. EcN-TRP was encapsulated in a dual-layered, pH-responsive microcapsule (EcN-TRP@A/G) through high-voltage electrospinning and liquid interface self-assembly. Murine IBD models were induced by DSS or TNBS, and they were orally administered with EcN-TRP@A/G.

Results EcN-TRP significantly increased the capacity for tryptophan synthesis, achieving a production level >370 times that of native EcN. EcN-TRP@A/G microcapsules largely preserved EcN-TRP viability under acidic conditions of the upper gastrointestinal tract and facilitated targeted release in the colon, with a 22.8-fold increase in delivery to the mouse colon compared to naked EcN-TRP by bioluminescent tracking. Metabolomic profiling validated that EcN-TRP@A/G significantly modulated tryptophan and indole metabolites indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) in the mouse colon for up to 7 days after a single dose. Concordantly, EcN-TRP@A/G administration significantly ameliorated DSS- or TNBS-induced IBD in mice and was effective in both preventive and treatment settings. Mechanistically, EcN-TRP@A/G restored gut barrier function, inhibited inflammation and reduced colon epithelial cell apoptosis in IBD mouse models. EcN-TRP@A/G also recovered gut microbial homeostasis by enriching beneficial bacteria such as Prevotellaceae_UCG-001 and Anaerostipes, together with the depletion of pathogenic strains like Escherichia-Shigella. Notably, some of the enriched probiotics are known to metabolize indole metabolites, suggesting the metabolic cross-feeding of EcN-TRP@A/G and other gut microbes to generate indole metabolites that confer synergistic effects against IBD.

Conclusions EcN-TRP@A/G formulation is a safe and cost-effective approach for the prevention and treatment of IBD.

https://doi.org/10.1136/gutjnl-2024-IDDF.117

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