[1]Synergistic Efficacy of Inulin Gel Capsulated Metal-Phenolic Networks: Treating Colitis and Depression by Regulating AKK and Gut-Brain Axis

A single oral Lut-NPs/Gel system synergistically ameliorates both colitis and associated depression-like behaviors via the gut-brain axis. • Lut-NPs/Gel combats colitis via a synergistic combination of barrier repair, anti-inflammatory action, and beneficial microbiome remodeling. • Restoration of AKK abundance plays a critical regulatory role in gut microbiota remodeling. • Multi-omics analyses identified key modulated pathways, including TRP channels and neuroactive ligand-receptor interactions, functionally connecting gut repair to brain behavioral improvement. • Recovery of AKK in normal state is coordinated with upregulation of host repair genes (such as IGF1, Reg1), delineating a collaborative host-microbe network. Inflammatory bowel disease (IBD) is a chronic immune-mediated condition affecting the intestinal tract. Though conventional therapies aim to control symptoms and induce remission, their long-term use is hindered by systemic side effects and inadequate efficacy, highlighting the need for safer and more effective treatments. In this study, we developed luteolin-loaded nanoparticles (Lut-NPs) by encapsulating luteolin within metal-phenolic networks (MPNs) formed through coordination between epigallocatechin gallate (EGCG) and Ce 3 ⁺ ions. The resulting Lut-NPs showed excellent biocompatibility, strong antioxidant and anti-inflammatory activities, and remarkable stability under gastrointestinal conditions. To improve intestinal retention, the nanoparticles were incorporated into an inulin-based hydrogel, generating a Lut-NPs/Gel composite system. In a DSS-induced colitis model, oral administration of Lut-NPs/Gel demonstrated significant therapeutic efficacy, including restoration of the intestinal barrier, suppression of pro-inflammatory pathways, and reshaping the gut microbiome. The treatment also promoted macrophage polarization from the M1 to the M2 phenotype. AKK, usually considered beneficial but elevated during inflammation, was restored to normal levels after Lut-Nps/Gel treatment, suggesting its potential as a biomarker of intestinal recovery. Additionally, the treatment alleviated depression-like behaviors via the microbiota–gut–brain axis. Overall, this work provides a safe and promising multifunctional strategy for treating IBD and associated neuropsychiatric symptoms.