Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China; Department of Rheumatology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, 226001, China.
Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
J Pharmacol Sci. 2024 Nov;156(3):149-160. doi: 10.1016/j.jphs.2024.08.003. Epub 2024 Aug 11.
Oxymatrine (OMT) as a quinazine alkaloid extracted from matrine has been shown to exhibit anti-inflammatory and anti-tumour effects. However, the protective mechanism of OMT on NSAID-associated small bowel mucosal injury remains unreported. We found that OMT could improve the clinical symptoms and pathological inflammation scoring, reduce the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α and cell apoptosis, promote cell proliferation and protect intestinal mucosal barrier as compared with the Diclofenac Sodium (DS) group. Further RNA-seq and KEGG analysis uncovered that the differentially expressed genes between DS and control groups were mainly enriched in immune regulation, of which MIP-1γ and its receptor CCR1 expression were validated to be repressed by OMTH. MAPK/NF-κB as the MIP-1 upstream signalling was also inactivated by OMT treatment. In this study, OMT regulated gut microbiota. Venn diagrams visualized and identified 1163 shared OTUs between DS group and OMTH group. The results showed that the α diversity index in the DS group was lower than that in the OMTH group, indicating that the complexity of the flora was reduced in the intestinal inflammatory state. β diversity mainly includes Principal Component Analysis (PCA) and Principal Co-ordinates Analysis (PCoA). The differences between groups can be observed through PCA. The more similar the composition of the flora, the closer the samples are. We found that the difference was smaller in the DS group than in the OMTH group. The results of PcoA showed that the sample similarity between OMTH groups was the highest. Moreover, gut microbiota analysis unveiled that the abundances of Ruminococcus 1, Oscillibacter and Prevotellaceae at the genus level as well as Lactobacillus SP-L-Yj at the species level were increased in OMTH group as compared with the DS group but the abundance of Allobaculum, Ruminococceos-UCG-005, Ruminococceos-NK4A214 and Clostridium associated with DS-induced small bowel mucosal injury could be decreased by OMTH. MIP-1α and CCR1 were upregulated in human small bowel injury samples as compared with the normal ileal mucosa tissues. In conclusion, our findings demonstrated that OMT could alleviate NSAID-associated small bowel mucosal injury by inhibiting MIP-1γ/CCR1 signalling and regulating gut microbiota.
氧化苦参碱 (OMT) 作为一种从苦参中提取的喹嗪生物碱，已被证明具有抗炎和抗肿瘤作用。然而，OMT 对 NSAID 相关小肠黏膜损伤的保护机制尚未报道。我们发现，与双氯芬酸钠 (DS) 组相比，OMT 可改善临床症状和病理炎症评分，减少促炎细胞因子 IL-1β、IL-6 和 TNF-α 的分泌和细胞凋亡，促进细胞增殖，保护肠黏膜屏障。进一步的 RNA-seq 和 KEGG 分析发现，DS 组和对照组之间的差异表达基因主要富集在免疫调节中，其中 MIP-1γ及其受体 CCR1 的表达被证实受到 OMTH 的抑制。MAPK/NF-κB 作为 MIP-1 的上游信号也被 OMT 治疗失活。在这项研究中，OMT 调节了肠道微生物群。Venn 图可视化并鉴定了 DS 组和 OMTH 组之间的 1163 个共有 OTUs。结果表明，DS 组的 α多样性指数低于 OMTH 组，表明在肠道炎症状态下，菌群的复杂性降低。β多样性主要包括主成分分析 (PCA) 和主坐标分析 (PCoA)。通过 PCA 可以观察到组间的差异。菌群组成越相似，样本越接近。我们发现 DS 组的差异比 OMTH 组小。PcoA 的结果表明，OMTH 组之间的样本相似性最高。此外，肠道微生物群分析表明，与 DS 组相比，OMTH 组中属水平的 Ruminococcus 1、Oscillibacter 和 Prevotellaceae 以及种水平的 Lactobacillus SP-L-Yj 的丰度增加，而与 DS 诱导的小肠黏膜损伤相关的 Allobaculum、Ruminococceos-UCG-005、Ruminococceos-NK4A214 和 Clostridium 的丰度可被 OMTH 降低。与正常回肠黏膜组织相比，人类小肠损伤样本中 MIP-1α 和 CCR1 上调。总之，我们的研究结果表明，OMT 通过抑制 MIP-1γ/CCR1 信号和调节肠道微生物群来减轻 NSAID 相关的小肠黏膜损伤。
