<i>Zanthoxylum Nitidum</i> Ameliorates Intestinal Barrier Dysfunction and Inflammation in <scp>TNBS</scp> ‐Induced Colitis Rats and <scp>LPS</scp> ‐Stimulated Caco‐2 Cells

Ulcerative colitis (UC) is a chronic, untreatable inflammatory bowel disease that severely impairs patients' work capacity and quality of life. It is characterized by bacterial infection and intestinal barrier disruption. Zanthoxylum nitidum (Roxb.) DC (Z. nitidum) is a famous Chinese herbal medicine traditionally used to promote wound healing and treat gastrointestinal disorders. However, the effect of Z. nitidum on intestinal barrier function and its related mechanisms remains unclear. The present study aims to investigate the protective effects and molecular mechanisms of Z. nitidum ethanol extract (ZNE) against UC using in vivo and in vitro models. The therapeutic potential was evaluated in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced UC rat models, while the effects on lipopolysaccharide (LPS)-stimulated human Caco-2 cells were examined in vitro. Results indicated that ZNE significantly improved weight loss, DAI scores, colon shortening, and tissue damage in TNBS-induced UC rats, with superior efficacy to 5-ASA at equivalent doses. Meanwhile, ZNE dose-dependently reduced pro-inflammatory mediators (NO, TNF-α, IL-6, IL-1β, and IL-8) in colonic mucosa, exerting anti-inflammatory effects by activating the PPARγ/SIRT1 pathway and suppressing NF-κB signaling. In vitro, ZNE markedly upgraded trans-epithelial electric resistance (TEER) values, lowered FITC-glucan flux penetrability in enteric epithelia, and increased the expression and distribution of ZO-1, occludin, and claudin-1 in LPS-evoked Caco-2 cells. Moreover, ZNE strongly repressed LPS-elicited cellular apoptosis and inflammatory response via lowering the degrees of inflammatory mediators, such as NO, PGE₂, TNF-α, and IL-1β. Meanwhile, ZNE observably mitigated LPS-evoked oxidant stress via elevating the degrees of antioxidant enzymes superoxide dismutase (SOD) and glutathione (GSH), and lowering the degrees of malondialdehyde (MDA) and reactive oxygen species (ROS). Besides, ZNE administration markedly boosted the mRNA and protein degree of PPARγ and inhibited the activation of NF-κB signaling. Importantly, GW9662, a PPARγ antagonist, observably abrogated the protective function of ZNE. ZNE has a prominent inhibiting property toward epithelial injury, which is related to the regulation of PPARγ/SIRT1/NF-κB signaling pathway to inhibit apoptosis, inflammatory response, and oxidative stress. Hence, ZNE could be a latent medication for the remedy of sick persons with UC.