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Emerging evidence indicates that obesity-induced gut microbial dysbiosis and intestinal barrier disruption may serve as a biologically plausible mechanism connecting these processes via the gut\u2013brain axis although direct clinical causality remains to be firmly established. In obesity, alterations in gut microbiota composition characterized by depletion of barrier-protective taxa and enrichment of pro-inflammatory and genotoxic pathobionts compromise epithelial tight-junction integrity and promote metabolic endotoxemia. The translocation of microbial products, including lipopolysaccharide, sustains chronic systemic inflammation, accelerates CRC progression, and remodels the tumor microenvironment. Notably, these peripheral inflammatory signals extend beyond the intestine and tumor, disrupting blood\u2013brain barrier integrity, activating microglia and astrocytes, and impairing synaptic plasticity within hippocampal and frontal networks. Clinically, these processes manifest as cancer-related cognitive impairment (CRCI), with predominant deficits in attention, processing speed, and working memory, which are often detectable around the time of diagnosis and independent of chemotherapy exposure. This review synthesizes in vivo, in vitro, and human evidence into a proposed theoretical \u201ctwo-barrier failure\u201d model of obesity-associated CRC and cognitive dysfunction. In addition to mechanistic synthesis, we discuss barrier-centered therapeutic strategies, including targeted probiotics, postbiotics, SCFA supplementation, obesity management through dietary and weight-loss interventions, and potential pharmacological approaches to epithelial and neurovascular barrier protection. We also outline testable clinical trial designs for evaluating these interventions in obesity-associated CRC.<\/jats:p>","DOI":"10.3390\/nu18121909","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:01:27Z","timestamp":1781492487000},"page":"1909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Leaky Gut to a Vulnerable Brain: Obesity-Associated Gut Barrier Failure in Colorectal Cancer and Cognitive Dysfunction"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9200-7933","authenticated-orcid":false,"given":"Soo Young","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Surgery, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7995-7862","authenticated-orcid":false,"given":"Sang Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Hemato-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital and Chonnam National University, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9165-8507","authenticated-orcid":false,"given":"Juhyun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ye, P., Xi, Y., Huang, Z., and Xu, P. 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