Sonmez G., Akkus M. S., Oyken A., Ozturk S. C., Aktas C. C., Muftuoglu S. F., ...More
PHYSIOLOGY, vol.41, no.S1, pp.1, 2026 (SCI-Expanded, Scopus)
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Publication Type:
Article / Abstract
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Volume:
41
Issue:
S1
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Publication Date:
2026
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Doi Number:
10.1152/physiol.2026.41.s1.2298901
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Journal Name:
PHYSIOLOGY
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Journal Indexes:
SportDiscus, Academic Search Ultimate (EBSCO), Scopus, Science Citation Index Expanded (SCI-EXPANDED), BIOSIS, EMBASE, MEDLINE
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Page Numbers:
pp.1
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Hacettepe University Affiliated:
Yes
Abstract
Background: The aryl hydrocarbon receptor (AhR) maintains intestinal immune balance and barrier integrity through downstream targets such as CYP1A1, and impaired AhR signaling contributes to IBD. Although chlorogenic acid (CGA), a dietary polyphenol, is not a direct AhR agonist, evidence suggests it may influence AhR activity via microbiome-dependent pathways. AhR is also expressed in the brain, yet its role in gut–brain communication during intestinal inflammation is unclear. Because colitis can disrupt the gut barrier and induce neuroinflammation, we hypothesize that DSS-induced colitis systemically impairs AhR signaling and drives sex-dependent neuroinflammatory responses. We further propose that CGA can counteract these effects by indirectly supporting AhR signaling and barrier integrity. Methods: Male and female C57BL/6 mice were randomly assigned to three groups: Control, DSS, and DSS+CGA (n = 8/sex/group). Acute colitis was induced using 3% dextran sulfate sodium (DSS) for 7 days. CGA (150 mg/kg) was administered daily via oral gavage. Body weight, disease activity index (DAI), colon length, and histological scoring were used to assess colitis severity. Levels of inflammatory markers (TNF-α and IL-6) were measured in the colon, prefrontal cortex (PFC), and hippocampus. AhR and CYP1A1 expression in the colon, PFC, and hippocampus was quantified by qRT-PCR, immunofluorescence, and ELISA. Tight junction proteins (ZO-1 and occludin) were evaluated to determine epithelial barrier integrity. Results: DSS induced significant colitis in both sexes, characterized by weight loss, shortened colon length (p=0.004), and elevated DAI scores. This was accompanied by marked increases in colonic TNF-α (p< 0.0001) and IL-6 levels (p< 0.0001), alongside significant downregulation of AhR (p=0.0017) and CYP1A1 expression (p=0.0024). CGA treatment attenuated disease severity (p< 0.05) and partially restored colonic AhR levels (p=0.0103). In the brain, neuroinflammatory responses exhibited marked sexual dimorphism. In the PFC, DSS triggered a significant surge in IL-6 (p=0.044) and TNF-α levels (p=0.0367) exclusively in males, while females showed negligible alterations (p=0.4509). Importantly, CGA administration effectively reversed this neuroinflammatory spike in the male PFC (p=0.024). In contrast, the hippocampus showed the opposite pattern: DSS-treated females exhibited higher hippocampal cytokine levels compared to controls (p=0.026), indicating region-specific vulnerability. While global hippocampal AhR mRNA and protein levels remained unchanged, region-specific immunofluorescence revealed a significant reduction in AhR staining in the CA2 region in both sexes. Notably, CGA restored the CA2 AhR signal in males (p=0.012) but failed to do so in females (p=0.340). Conclusion: DSS-induced colitis suppresses intestinal AhR signaling and compromises barrier integrity, triggering neuroinflammation with distinct sex-specific spatial patterns. Specifically, females exhibit heightened vulnerability in the hippocampus, whereas the PFC is more susceptible to inflammation in males. While CGA effectively ameliorates intestinal pathology and restores colonic AhR expression in both sexes, its neuroprotective capacity is sex-dependent; notably, CGA failed to restore AhR expression in the female hippocampal CA2 region. These findings suggest that while CGA ameliorates gut dysfunction, targeting the gut–brain axis requires sex-stratified approaches to address psychiatric comorbidities.
This study is supported by Hacettepe University Scientific Research Projects (Grant No: TSA-2024-21414).
This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.