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bioRxiv · 10.64898/2026.03.10.710940

Multi-component functionalized Bifidobacterium longum hydrogel for multi-target integrated therapy of colitis-associated anxiety and depression

Zhang, S.·Zhang, Y.·He, J.·Li, S.·Ma, Q.·Li, Q.·Wang, Y.·Ma, S.·Jin, S.·Li, C.·Xie, X.·Zhang, H.·Deng, J.·Song, X.·Wu, D.·Ma, X.·Zhu, F.
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Abstract

Inflammatory bowel diseases (IBDs) are frequently accompanied by anxiety and depression, largely driven by perturbed gut-brain axis signaling. However, current oral therapies remain constrained by the spatial and functional separation between intestinal inflammation and central nervous system dysfunction. Here, we present a comprehensive gut-brain dual region integrated therapeutic strategy based on functionalized Bifidobacterium longum hydrogel (INPs@BL@Gel), in which baicalin and tyrosine are coordinated with Fe(III) to form infinite coordination polymers (ICPs), coated with inulin, assembled onto Bifidobacterium longum (BL), and subsequently encapsulated within a pH- and matrix metalloproteinase-responsive silk fibroin-gelatin hydrogel. INPs@BL@Gel exhibits high drug-loading, effective gastric protection, inflammation-triggered release, and long-term intestinal colonization. Within the inflamed intestine, BL and components synergistically suppress inflammatory responses, restore gut microbiota homeostasis, and promote intestinal barrier repair through multi-target integrated therapy. Importantly, BL combined with components markedly enhances the production of beneficial neuroactive metabolites such as homovanillic acid and short-chain fatty acids, which integrated regulate neuroinflammation, preserve synaptic function, and facilitate blood-brain barrier repair via the gut-brain axis. In vivo studies demonstrate that INPs@BL@Gel not only exert potent therapeutic efficacy against colitis and effectively alleviate associated depression, but also reshape the gut microbiota and restore barrier integrity, achieving an remarkable comprehensive therapeutic effect. O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/710940v1_fig1a.gif" ALT="Figure 11"> View larger version (59K): org.highwire.dtl.DTLVardef@1a831f3org.highwire.dtl.DTLVardef@1676617org.highwire.dtl.DTLVardef@15f99c1org.highwire.dtl.DTLVardef@1677cc4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOScheme 1.C_FLOATNO (a) Schematic diagram of the design and preparation of functionalized Bifidobacterium longum hydrogel. (b) Exploration of the mechanism of INPs@BL@Gel in treating colitis-associated anxiety and depression through a dual-site multi-target synergistic strategy. C_FIG

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Zhang, S., Zhang, Y., He, J., Li, S., Ma, Q., Li, Q., Wang, Y., Ma, S., Jin, S., Li, C., Xie, X., Zhang, H., Deng, J., Song, X., Wu, D., Ma, X., Zhu, F.. 2026-03-13. Multi-component functionalized Bifidobacterium longum hydrogel for multi-target integrated therapy of colitis-associated anxiety and depression. https://doi.org/10.64898/2026.03.10.710940

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