{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:32:24Z","timestamp":1792524744474,"version":"4.5.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ulcerative colitis (UC) is driven by a self-perpetuating cycle of intestinal barrier disruption and chronic inflammation. Current therapeutic options are limited, underscoring the need for safer and more effective agents. Earthworm extract (EE, derived from Dilong used in traditional Chinese medicine) has a documented history of use in inflammatory and reparative contexts. In this study, we evaluated the therapeutic potential and mechanism of EE using a murine model of colitis and Caco-2 intestinal epithelial cells model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A murine model of ulcerative colitis was established with 3% DSS. Serum cytokines were measured by ELISA, and intestinal permeability was assessed via the FITC-dextran assay.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , LPS and TNF-\n                      <jats:italic>\u03b1<\/jats:italic>\n                      \/IFN-\n                      <jats:italic>\u03b3<\/jats:italic>\n                      -stimulated Caco-2 monolayers were used to monitor transepithelial electrical resistance. Gene and protein expression were analyzed by qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence. Mechanisms were investigated through network pharmacology and validated by pharmacological intervention. The bioactive components in EE were characterized by heat inactivation, protease sensitivity, and dialysis-based molecular weight fractionation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Earthworm extract administration significantly alleviated DSS-induced disease severity, including weight loss, colon shortening, and histological damage. At the molecular level, EE suppressed pro-inflammatory cytokines (TNF-\u03b1, IL-1\u03b2, and IL-6) by inhibiting the NF-\u03baB pathway and enhanced intestinal barrier function by upregulating tight junction proteins (ZO-1 and Occludin)\n                      <jats:italic>in vivo<\/jats:italic>\n                      . These protective effects were corroborated\n                      <jats:italic>in vitro<\/jats:italic>\n                      , where EE restored epithelial monolayer integrity and reversed inflammatory cytokine release and tight junctional protein loss induced by LPS or TNF-\u03b1\/IFN-\u03b3. Through an integrative network pharmacology analysis, the PI3K\/AKT pathway was identified as a key signaling hub mediating the effects of EE against UC. Subsequent experimental validation confirmed that EE significantly inhibits PI3K\/AKT activation. Notably, EE alone exhibited no detectable short-term toxicity or adverse effects. Characterization studies confirmed that the bioactive components in EE are proteinaceous, heat-labile, non-dialyzable macromolecules.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that EE ameliorates experimental colitis primarily through inhibition of the PI3K\/AKT signaling pathway, thereby attenuating inflammation and restoring intestinal barrier integrity, while maintaining a favorable safety profile. This work provides a scientific rationale for developing EE as a promising natural agent for inflammatory bowel disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1787022","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:48:34Z","timestamp":1780030114000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Earthworm extract ameliorates colitis via modulation of the PI3K\/AKT pathway: attenuation of inflammation and restoration of intestinal barrier integrity"],"prefix":"10.3389","volume":"13","author":[{"given":"Shaoru","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Clinical Nutrition, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical 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