Dihydroartemisinin Alleviates Diclofenac Sodium-Induced Small Intestinal Mucosal Injury by Regulating the MAPK/NF-κB Signaling Pathway and Gut Microbiota Homeostasis

Background

Dihydroartemisinin (DHA), a well-established antimalarial agent has been increasingly recognized for its antiviral and antitumor effects across multiple diseases. However, the potential effects of DHA on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)-induced intestinal mucosal injury remain largely unexplored. The current work was designed to characterize the therapeutic actions and the underlying molecular mechanisms governing DHA against histopathological damage and gut microbiota dysbiosis in a rat model of Diclofenac Sodium (DS)-induced Small Intestinal Mucosal Injury (SIMI).

Materials and Methods

A rat model of DS-induced SIMI was established, and the animals were treated with varying doses of DHA. Histological injury scores were evaluated by Hematoxylin and eosin (H&E) staining. Protein expression levels were determined using immunofluorescence, immunohistochemistry and Western blot analysis. 16S rRNA-based sequencing was applied to assess compositional variations of the gut microbiota.

Results

Our findings demonstrated that DHA treatment increased ileal length, while reducing the pathological inflammation scores and the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and CD68-positive macrophage infiltration. Furthermore, DHA attenuated intestinal epithelial cell apoptosis, promoted cell proliferation, and preserved intestinal mucosal barrier integrity, accompanied by downregulated expression of CHGA, LYZ and MYC, as well as inactivation of MAPK/NF-κB signaling pathway. Moreover, DHA elevated the relative abundances of Lachnospiraceae_ NK4A136, Lactobacillus, Intestinimonas and Bacterodetes, while decreasing the abundance of Desulfovibrionaceae in SIMI models.

Conclusion

DHA mitigates NSAID-induced SIMI by inhibiting the MAPK/NF-κB signaling pathway and modulating gut microbiota homeostasis.