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From Leaky Gut to a Vulnerable Brain: Obesity-Associated Gut Barrier Failure in Colorectal Cancer and Cognitive Dysfunction

Lee, Soo Young, Cho, Sang Hee, Song, Juhyun·2026·Nutrients
DOI 10.3390/nu18121909
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Abstract

Obesity is a major risk factor for colorectal cancer (CRC) and is increasingly recognized as a contributor to cancer-related cognitive impairment; however, the mechanistic pathways linking metabolic dysfunction, tumor progression, and brain dysfunction remain incompletely defined. 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–brain 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–brain 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 “two-barrier failure” 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.

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Metadata

Authors
Lee, S. Y., Cho, S. H., & Song, J.
Venue
Nutrients
Publisher
MDPI AG
Published
2026-06-12
Volume
18
Issue
12
Pages
1909
ISSN
2072-6643
DOI
10.3390/nu18121909
Cited by
0
References
6
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Research Foundation of Korea (RS-2025-02213506, RS-2025-19612989)
  • Korea Health Industry Development Institute (RS-2025-19252970)
  • Chonnam National University Hwasun Hospital Institute for Biomedical Science (HCRI26026)

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Lee, S. Y., Cho, S. H., & Song, J. (2026). From Leaky Gut to a Vulnerable Brain: Obesity-Associated Gut Barrier Failure in Colorectal Cancer and Cognitive Dysfunction. Nutrients. https://doi.org/10.3390/nu18121909

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