Modulatory Effects of <i>Bifidobacterium longum</i> Subsp. <i>Longum</i> BL21 on Intestinal Barrier Impairment and Metabolic Dysregulation in a Low‐Dose Dextran Sulfate Sodium‐Induced Chronic Inflammation Model

Abstract Chronic low‐grade intestinal inflammation is closely linked to gut barrier dysfunction and metabolic disturbance. This study established a low‐dose dextran sulfate sodium (DSS)‐induced chronic inflammation model and evaluated the protective effects of Bifidobacterium longum subsp. longum BL21 on gut barrier function, inflammatory cytokines, gut microbiota, and metabolic regulation. Male C57BL/6 J mice ( n = 30) were randomly assigned to three groups ( n = 10/per group): control (CTL), model (MC, 0.2% DSS), and probiotic intervention (BL21, 0.2% DSS + 1 × 10 9 CFU/mouse/day BL21). Chronic histopathology; gut‐barrier markers (occludin, zonula occludens‐1 [ZO‐1]); urolithin A; intestinal alkaline phosphatase (IAP) activity; and cytokines (tumor necrosis factor‐ α [TNF‐ α ], interleukin‐4 [IL‐4], interleukin‐10 [IL‐10], and C‐X‐C motif chemokine ligand 1 [CXCL1]) were quantified by ELISA, and gut microbiota composition was analyzed by 16S rRNA sequencing. Low‐dose DSS induced mild colonic inflammation and pancreatic islet damage without significantly affecting body weight or fasting glucose. BL21 alleviated colonic inflammation, restored islet structure, reduced TNF‐α and CXCL1, increased IL‐4 and IL‐10 ( p &lt; 0.05), and improved gut barrier integrity by enhancing Occludin, ZO‐1, and Urolithin A ( p &lt; 0.05) while reducing IAP activity ( p &lt; 0.05). BL21 also enriched beneficial genera ( Lactobacillus , Bifidobacterium , Akkermansia ) and reduced pro‐inflammatory genera ( Odoribacter , Desulfovibrio ). Low‐dose DSS effectively models chronic inflammation. BL21 shows significant potential in restoring gut barrier integrity, balancing inflammation, and modulating gut microbiota, supporting its clinical application in managing chronic inflammation and related metabolic disorders.