What question did this study set out to answer?

The research aimed to explore quercetin as a treatment for insomnia associated with IBS-D and its underlying mechanisms.

March 19, 2026Open Access

Quercetin Ameliorates Comorbid Insomnia in Diarrhea-Predominant Irritable Bowel Syndrome via the PI3K/AKT/NF-κB Signaling Pathway

Key Points

The research aimed to explore quercetin as a treatment for insomnia associated with IBS-D and its underlying mechanisms.
Targets related to CID and IBS-D were identified from public databases.
Bioinformatics and network pharmacology were used to screen candidate compounds.
Molecular docking was performed to validate candidate interactions.
C57BL/6J mice were divided into control, CID+IBS-D model, quercetin-treated, and quercetin-plus-Recilisib-treated groups.
Sleep behavior, intestinal function, and inflammatory markers were assessed.
Quercetin emerged as a core candidate influencing both sleep and intestinal health.
Bioinformatics revealed 43 targets shared between CID, IBS-D, and quercetin, notably in PI3K/AKT signaling.
Quercetin improved sleep and intestinal dysfunction while reducing inflammatory responses.
Significant reductions in phosphorylation of PI3K, AKT, IκB, and NF-κB p65 were observed in the hypothalamus.

Abstract

Background: Chronic insomnia disorder (CID) frequently coexists with diarrhea-predominant irritable bowel syndrome (IBS-D), a comorbidity characterized by gut–brain axis dysfunction and persistent inflammatory activation. However, the molecular mechanisms underlying this overlap remain incompletely understood, and effective multitarget interventions are lacking. Objectives: This study aimed to identify quercetin as a potential bioactive compound for IBS-D-associated insomnia and to investigate whether its protective effects are associated with modulation of the PI3K/AKT/NF-κB signaling pathway. Methods: CID- and IBS-D-related targets were collected from public databases. Candidate compounds were screened using bioinformatics and network pharmacology analyses, followed by molecular docking. Experimental validation was conducted in 36 male C57BL/6J mice assigned to control, CID+IBS-D model, quercetin-treated, and quercetin-plus-Recilisib-treated groups. Sleep-related behavior, EEG/EMG-derived sleep architecture, intestinal function, inflammatory markers, and pathway-related proteins were assessed. Results: Quercetin was identified as a core candidate compound. Network pharmacology revealed 43 shared targets among CID, IBS-D, and quercetin, with significant enrichment in PI3K/AKT-related signaling. In vivo, quercetin improved sleep-associated phenotypes and intestinal dysfunction; reduced visceral hypersensitivity; restored ZO-1 and Occludin expression; suppressed hypothalamic and colonic inflammatory responses; and was accompanied by reduced phosphorylation of PI3K, AKT, IκB, and NF-κB p65 in the hypothalamus. Quercetin also increased hypothalamic 5-HT1A and GABAA Rα5 expression. These effects were partially reversed by Recilisib, supporting the involvement of PI3K/AKT-associated signaling in quercetin-mediated protection. Conclusions: Quercetin alleviated key sleep-related and IBS-D-like phenotypes in a composite murine model of gut–sleep comorbidity. The protective effects were associated with reduced inflammatory activation and modulation of PI3K/AKT/NF-κB-related signaling. These findings support quercetin as a promising candidate for gut–brain axis-related comorbid disorders, while further studies are needed to define pathway specificity, tissue exposure, and translational applicability.

Quercetin Ameliorates Comorbid Insomnia in Diarrhea-Predominant Irritable Bowel Syndrome via the PI3K/AKT/NF-κB Signaling Pathway

Key Points

Abstract

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