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The intestinal barrier is a multilayered system maintained by four key components: the physical, chemical, microbiological, and immunological barriers. Each layer plays a unique role in preventing the translocation of harmful entities from the intestinal lumen into the body. Disruption of this integrated barrier increases intestinal permeability, a condition commonly referred to as \u201cleaky gut,\u201d in which harmful substances and pathogens can enter the systemic circulation. We also highlight that barrier dysfunction differs between the small and large intestines, reflecting regional differences in epithelial structure, mucus architecture, and microbial load. Growing evidence indicates that such barrier disruption triggers cascades of inflammatory responses in various organs, including the liver, brain, muscles, and kidneys, leading to impaired physiological functions. This review delineates the four layers of the intestinal barrier and explores the systemic consequences of its disruption. In addition, it summarizes current approaches for assessing intestinal barrier function and discusses the strengths and limitations of widely used experimental models. The review also outlines current therapeutic strategies for barrier restoration, including dietary interventions, microbiota\u2010directed approaches, postbiotics, bile acid modulators, anti\u2010inflammatory and immunomodulatory therapies, and lifestyle modification. A deeper understanding of this multilayered gatekeeper is essential for developing novel preventive and therapeutic strategies aimed at restoring barrier integrity and strengthening the defense against a wide range of systemic diseases.<\/jats:p>","DOI":"10.1155\/ijm\/2828137","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:26:38Z","timestamp":1781072798000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Intestinal Barrier: A Multilayered Gatekeeper Against Systemic Disease"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0823-5562","authenticated-orcid":false,"given":"Jun","family":"Wakabayashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7106-2650","authenticated-orcid":false,"given":"Katsunori","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8650-4474","authenticated-orcid":false,"given":"Takeshi","family":"Kawauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-022-00514-x"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/21688370.2021.1879719"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2653"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.011"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00794-x"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms6040107"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-325428"},{"key":"e_1_2_12_8_2","first-page":"264","article-title":"Leaky Gut Syndrome: Myths and Management","volume":"20","author":"Lacy B. 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