2. Academic Validation
  3. Trimethylamine N-oxide induced cognitive impairment through disruption of blood-brain barrier by inhibiting TGF-β pathway

Trimethylamine N-oxide induced cognitive impairment through disruption of blood-brain barrier by inhibiting TGF-β pathway

  • Chem Biol Interact. 2026 Jan 25:424:111862. doi: 10.1016/j.cbi.2025.111862.
Yue Liu 1,  Hua-Yue Zhang 2,  Xi-Yan Hong 3,  Yi-Xiao Wu 4,  Ming-Jie Li 5,  Hua-Jun Zheng 6
Affiliations

Affiliations

  • 1 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 2 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 3 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 4 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 5 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 6 Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 41354139 DOI: 10.1016/j.cbi.2025.111862
Abstract

Growing evidence suggests that trimethylamine N-oxide (TMAO) is closely associated with cognitive impairment. However, the mechanisms by which TMAO causes cognitive impairment remain unclear. TMAO has been reported to regulate blood-brain barrier (BBB) integrity and suppress the expression of tight junction proteins (TJs) in the microvasculature. This study aims to investigate whether disruption of the BBB contributes to TMAO-induced cognitive impairment and to elucidate the underlying molecular mechanisms. Mice recieved an intraperitoneal injection (1.1 mg/kg) of TMAO and underwent the Y-maze test, novel object recognition test, and passive avoidance test 72 h post-treatment. To assess BBB integrity, Evans blue staining, immunofluorescence, western blotting, and qRT-PCR analysis were carried out. Our findings indicated that TMAO treatment induced cognitive impairment and disrupted the BBB integrity in mice. In the hippocampus, TMAO reduced the expression of ZO-1, occludin, claudin1, and CD31 and caused significant ultrastructural changes in the microvasculature. To explore the underlying molecular mechanisms, human cerebral microvascular endothelial cells (hCMEC/D3) were cultured with TMAO. TMAO treatment suppressed TJs and increased monolayer permeability in hCMEC/D3 cells. Transcriptomic analysis revealed that TMAO activated multiple inflammation-related pathways while inhibiting the TGF-β pathway. Moreover, TGF-β1 intervention rescued the down-regulation of TJs and reduced permeability in TMAO-treated hCMEC/D3 cells. Our research demonstrates that TMAO-induced cognitive impairment occurs through the disruption of the BBB by inhibiting the TGF-β pathway in endothelial cells. The current investigation provides new insights into the mechanisms of TMAO neurotoxicity and suggests that increasing TGF-β1 level represents an effective strategy to counteract TMAO-induced cognitive impairment.

Keywords

Blood-brain barrier; Cognitive impairment; TGF-β1; Tight junction; Trimethylamine N-Oxide.

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