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Background <p>The present study aimed to investigate the alterations in wake-promoting neurotransmitters (histamine and orexin-A) and markers of blood-brain barrier and intestinal mucosal barrier including zonula occludens-1 (ZO-1), claudin-5, zonulin, and S100 calcium-binding protein B (S100β) in insomnia disorder (ID). Additionally, we examined the correlations between these neurotransmitters and barrier markers, and explored their combined associations with sleep parameters.</p> Methods <p>This study enrolled 54 ID patients and 45 healthy controls. The demographic and clinical characteristics of all participants were investigated, and participants underwent overnight polysomnography. Serum levels of wake-promoting neurotransmitters and barrier markers were measured using enzyme-linked immunosorbent assay (ELISA). Spearman’s correlation analysis was conducted to explore the associations between these serum biomarkers and sleep parameters, as well as between the neurotransmitters and barrier markers. Furthermore, mediation analysis was performed to examine whether barrier markers mediated the relationship between wake-promoting neurotransmitters and sleep parameters.</p> Results <p>Levels of peripheral wake-promoting neurotransmitters (histamine and orexin-A) and barrier markers (zonulin, S100β, ZO-1, and claudin-5) were elevated in the ID group (all <i>p</i> &lt; 0.001). Additionally, sleep efficiency was positively correlated with histamine levels (<i>r</i> = 0.57), negatively correlated with orexin-A levels (<i>r</i> = -0.62), and positively correlated with ZO-1 levels (<i>r</i> = 0.56) in ID patients. Moreover, histamine levels showed positive correlations with claudin-5 (<i>r</i> = 0.37) and ZO-1 (<i>r</i> = 0.31), and a negative correlation with S100β (<i>r</i> = -0.33). Additionally, orexin-A was negatively correlated with claudin-5 levels (<i>r</i> = -0.46). Furthermore, ZO-1 showed a statistical mediation effect in the associations between histamine and sleep efficiency (<i>p</i> = 0.006) as well as between orexin-A and sleep efficiency (<i>p</i> = 0.012), consistent with a potential indirect pathway.</p> Conclusions <p>This study observed dysregulation of peripheral wake-promoting neurotransmitters along with markers of blood-brain barrier and intestinal mucosal barrier in ID patients. Notably, ZO-1 showed a statistical mediation effect in the associations between these neurotransmitters and sleep efficiency, though causality cannot be inferred from the cross-sectional design. These clinical findings provide preliminary insights into the molecular features associated with ID and may inform directions for future mechanistic research. Further studies are needed to fully elucidate the underlying mechanisms.</p>

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Markers of blood-brain barrier and intestinal mucosal barrier in insomnia disorder: an observational study linking wake-promoting neurotransmitters to sleep efficiency

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Jingjing Lin,
  • Yixian Cai,
  • Xiaoqin Yang,
  • Yaxi Liu,
  • Xian Shi,
  • Yong Xu,
  • Jiyang Pan

摘要

Background

The present study aimed to investigate the alterations in wake-promoting neurotransmitters (histamine and orexin-A) and markers of blood-brain barrier and intestinal mucosal barrier including zonula occludens-1 (ZO-1), claudin-5, zonulin, and S100 calcium-binding protein B (S100β) in insomnia disorder (ID). Additionally, we examined the correlations between these neurotransmitters and barrier markers, and explored their combined associations with sleep parameters.

Methods

This study enrolled 54 ID patients and 45 healthy controls. The demographic and clinical characteristics of all participants were investigated, and participants underwent overnight polysomnography. Serum levels of wake-promoting neurotransmitters and barrier markers were measured using enzyme-linked immunosorbent assay (ELISA). Spearman’s correlation analysis was conducted to explore the associations between these serum biomarkers and sleep parameters, as well as between the neurotransmitters and barrier markers. Furthermore, mediation analysis was performed to examine whether barrier markers mediated the relationship between wake-promoting neurotransmitters and sleep parameters.

Results

Levels of peripheral wake-promoting neurotransmitters (histamine and orexin-A) and barrier markers (zonulin, S100β, ZO-1, and claudin-5) were elevated in the ID group (all p < 0.001). Additionally, sleep efficiency was positively correlated with histamine levels (r = 0.57), negatively correlated with orexin-A levels (r = -0.62), and positively correlated with ZO-1 levels (r = 0.56) in ID patients. Moreover, histamine levels showed positive correlations with claudin-5 (r = 0.37) and ZO-1 (r = 0.31), and a negative correlation with S100β (r = -0.33). Additionally, orexin-A was negatively correlated with claudin-5 levels (r = -0.46). Furthermore, ZO-1 showed a statistical mediation effect in the associations between histamine and sleep efficiency (p = 0.006) as well as between orexin-A and sleep efficiency (p = 0.012), consistent with a potential indirect pathway.

Conclusions

This study observed dysregulation of peripheral wake-promoting neurotransmitters along with markers of blood-brain barrier and intestinal mucosal barrier in ID patients. Notably, ZO-1 showed a statistical mediation effect in the associations between these neurotransmitters and sleep efficiency, though causality cannot be inferred from the cross-sectional design. These clinical findings provide preliminary insights into the molecular features associated with ID and may inform directions for future mechanistic research. Further studies are needed to fully elucidate the underlying mechanisms.