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bioRxiv · 10.64898/2025.12.15.694447

Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate

Salian, V. S.·Veerareddy, V.·Tang, X.·Xiao, Y.·Kalari, K. R.·Kashyap, P.·Kandimalla, K. K.
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Abstract

Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimers disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (A{beta}) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by A{beta} and TNF-. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates A{beta} and TNF--induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced A{beta}42 and TNF- mediated upregulation of VCAM-1. Furthermore, we have shown STAT3/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrates protective role and highlight its potential to mitigate A{beta} and TNF--induced cerebrovascular inflammation in AD.

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Salian, V. S., Veerareddy, V., Tang, X., Xiao, Y., Kalari, K. R., Kashyap, P., Kandimalla, K. K.. 2025-12-17. Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate. https://doi.org/10.64898/2025.12.15.694447

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