Colon‐Targeted Berberine Nanoparticles‐Embedded Yeast Microcapsules for Regulation of Gut Immunity of Sepsis

ABSTRACT Sepsis often progresses to multiorgan failure through intestinal barrier disruption and bacterial translocation. Berberine (BBR) has anti‐inflammatory and intestinal protective activity, but its oral use is limited by poor solubility and low bioavailability (< 1%). Here, we designed BGNP@YM, an oral colon‐targeted system in which BBR‐loaded gelatin nanoparticles (BGNP) are encapsulated within yeast microcapsules (YM), and tested it in a lipopolysaccharide (LPS)‐induced sepsis mouse model. BGNP@YM was stable in simulated gastric and intestinal fluids and released its payload in simulated colonic fluid, confirming colon‐specific delivery. In vivo, BGNP@YM outperformed free BBR, BGNP, or YM alone, improving survival, attenuating weight loss and splenomegaly, and lowering TNF‐α, IL‐6, and IL‐1β in colonic and renal tissues. Histology showed restored intestinal barrier integrity and reduced injury in multiple organs, with no detectable hepatic or renal toxicity. 16S rRNA sequencing further revealed partial reversal of sepsis‐induced dysbiosis, with increased microbial diversity, a restored Firmicutes / Bacteroidetes ratio, and enrichment of short‐chain fatty acid (SCFA)‐producing taxa such as Odoribacter . The associated renal protection is consistent with a gut‐kidney axis effect. These findings support BGNP@YM as a promising oral candidate for the treatment of sepsis‐induced intestinal injury.