Multi-omics integrated analysis to explore the molecular mechanisms of Xinkai Kujiang formula in treating gastric intestinal metaplasia in rats

Abstract

Background Gastric intestinal metaplasia (GIM) is a typical precancerous lesion of gastric cancer (PLGC). Previous studies have demonstrated that Xinkai Kujiang formula can effectively alleviate GIM, but its underlying mechanism remains largely unclear. Methods The GIM rat model was established using 2% sodium salicylate and 20 mmol/L sodium deoxycholate, and then the rats were treated with Banxia Xiexin Decoction (BXD) and Xinkai Kujiang Decoction (XKD) for 4 weeks. Multi-omics analyses including 16 S ribosomal RNA gene sequencing, transcriptomics, single-cell RNA sequencing, network pharmacology, and component identification were performed to explore the therapeutic mechanisms of Xinkai Kujiang formula on GIM. Results In the model rats, severe gastric mucosal atrophy was observed, characterized by disordered glands and goblet cells. Following intervention with BXD and XKD, gastric mucosal thickness was restored, glandular structures became regularly arranged, and the number of metaplastic goblet cells markedly decreased. Microbiota profiling of gastric mucosa revealed significant enrichment of Lactobacillus and Enterococcus in the model group. These abundances were reduced in the BXD group, and short-chain fatty acid-producing bacteria such as Alistipes and Lachnospira were enriched. In the intestine, opportunistic pathogens like Streptococcus and Enterococcus were enriched in the model group, whereas Corynebacterium and Bifidobacterium were enriched in the XKD group. Transcriptomic analysis presented that BXD upregulated innate immune-related genes in the gastric mucosa, and single-cell RNA sequencing (scRNA-Seq) showed that XKD alleviated GIM by inhibiting the VEGF and HIF-1α pathways, reducing angiogenesis, suppressing inflammatory infiltration, and regulating energy metabolism. Conclusion BXD and XKD improve gastrointestinal microbiota disorders and metabolic disorders, enhance gastric mucosal immunity, and inhibit the VEGF and HIF-1α pathway. Collectively, these multi-omics data provide novel insights into the therapeutic mechanisms of Xinkai Kujiang formula for GIM.