Cedrol ameliorates ulcerative colitis via myeloid differentiation factor 2-mediated inflammation suppression, with barrier restoration and microbiota modulation.

Cedrol significantly alleviated colitis symptoms and mitigated histopathological damage in a dextran sulfate sodium (DSS)-induced murine colitis model.

• The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a DSS-induced murine colitis model.
• CE significantly alleviated colitis symptoms and suppressed inflammation as measured by standard colitis parameters.
• Histopathological damage was mitigated upon CE treatment.

Cedrol restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins.

• CE upregulated tight junction proteins including zonula occludens 1 (ZO-1), occludin, and claudin-1.
• CE enhanced mucus secretion as part of its barrier-restorative effects.
• These findings indicate CE promotes mucosal barrier reconstitution in the context of UC.

Cedrol stably bound to myeloid differentiation factor 2 (MD2) within the TLR4/MD2 complex, as confirmed by molecular docking and dynamics simulations.

• Network pharmacology was employed to predict potential targets and pathways prior to molecular binding studies.
• Molecular docking and dynamics simulations confirmed a stable interaction between CE and the TLR4/MD2 complex.
• CE's binding target was identified specifically as MD2 rather than TLR4 directly.

Cedrol inhibited lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells, suppressing downstream MAPK and NF-κB pathways.

• In vitro assays in RAW264.7 cells confirmed CE inhibited LPS-induced TLR4 signaling.
• Downstream suppression of both the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways was observed.
• This led to downregulated expression of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6).

Cedrol reversed DSS-induced gut microbiota dysbiosis with significant enrichment of the butyrogenic bacterium Christensenella minuta.

• Gut microbiota composition was analyzed via 16S rRNA gene sequencing.
• CE treatment reversed DSS-induced dysbiosis in the gut microbiota.
• Significant enrichment of butyrogenic Christensenella minuta was specifically noted following CE treatment.