Rebuilding the Barrier: How GLP-1-Engineered Probiotics Transform the Management of Fibre-Deficient Colitis

Abstract

Abstract

Fiber-deficient diets drive gut dysbiosis, erode the colonic mucus barrier, and exacerbate ulcerative colitis through disrupted short-chain fatty acid (SCFA) production and impaired GLP-1 signaling from L-cells. This review elucidates the fiber deficiency–microbiota–colitis axis, where SCFA shortage via GPR43 weakens tight junctions (ZO-1, occludin), unleashes NF-κB/MAPK-mediated inflammation, and amplifies neutrophil chemokines like CXCL2, priming severe dextran sulfate sodium (DSS)-induced phenotypes observed clinically.​

Beyond glucose regulation, GLP-1 exerts potent gut-protective effects by restoring barrier integrity, suppressing proinflammatory cytokines (TNF-α, IL-1β, IL-6), and modulating microbiota toward anti-inflammatory taxa. Synthetic biology addresses this via engineered probiotics (E. coli Nissle 1917 or Lactobacillus chassis) that colonize the colon and secrete GLP-1 peptides in situ, bypassing dietary fiber needs for sustained local delivery with minimal systemic exposure.​

Preclinical models demonstrate these probiotics normalize colon architecture, reduce myeloperoxidase/neutrophil infiltration, inhibit AKT/NF-κB pathways, and reverse fiber-deprived dysbiosis, weight loss, and bleeding—effects mirrored by GLP-1 agonists. Multiplexed strains incorporating IL-10, trefoil factors, or antioxidants enable synergistic therapy for heterogeneous colitis.​

Translation requires GMP production, genetic stability validation, phased trials against 5-ASA/biologics, and monitoring via fecal calprotectin/endoscopy in relapsing patients with poor fiber adherence. Future "sense-and-respond" biosensors promise precision, preventive deployment in at-risk cohorts, heralding microbiome-centric paradigms that harmonize diet, microbes, and immunity for transformative IBD management. Engineered probiotics,​