Water extract of Hericium erinaceus alleviates chronic atrophic gastritis with intestinal metaplasia

Background: Hericium erinaceus (Bull.) Pers., a well-known medicinal and edible fungus that has been used in folk medicine for centuries, exhibits prominent therapeutic potential against various gastric disorders; however, its precise therapeutic effects on chronic atrophic gastritis (CAG) and the corresponding molecular mechanisms have not been fully elucidated. Objective: This study aimed to characterize the therapeutic effects of the aqueous extract of H. erinaceus (WEHE) on CAG and elucidate its underlying molecular mechanisms. Methods: A multifactorial composite CAG rat model was established via combined interventions: free access to 0.1% ammonia water, intermittent fasting, and alternate intragastric administration of 2% sodium salicylate in 30% ethanol and 20 mmol/L sodium deoxycholate. Hematoxylin and eosin (H&E) staining was performed to evaluate gastric histopathological lesions, and transmission electron microscopy (TEM) was used to observe ultrastructural changes in the gastric antrum. Masson’s trichrome, Sirius red, and Alcian blue-periodic acid-Schiff (AB-PAS) staining were applied to assess intestinal metaplasia and collagen deposition. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of gastrin, pepsinogen I/II (PG I/II), and motilin. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to quantify the mRNA expression of inflammatory mediators including interleukin-1 beta ( IL-1β ), tumor necrosis factor-alpha ( TNF-α ), interleukin-6 ( IL-6 ), interferon-gamma ( IFN-γ ), and interleukin-10 ( IL-10 ) in gastric tissues. Transcriptome sequencing was carried out to screen differentially expressed genes and enriched signaling pathways. Immunohistochemistry, immunofluorescence staining, and Western blotting were further employed to detect the expression of core proteins involved in VEGF signaling and intercellular adhesion junctions. Results: WEHE significantly restored the secretory function of atrophic gastric glands and alleviated epithelial ultrastructural damage. WEHE inhibited the transcription of pro-inflammatory cytokines IL-1β and TNF-α , and decreased the protein abundance of Toll-like receptor 4 (TLR4), p65, and phosphorylated p65. Meanwhile, WEHE downregulated hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor A (VEGF-A), and vascular endothelial growth factor receptor 2 (VEGFR2), and reduced the CD31-positive area to suppress pathological vascular remodeling. Furthermore, WEHE increased the levels of adhesion junction proteins epithelial cadherin (E-cadherin), claudin 18 isoform 2 (claudin18.2), and zonula occludens-1 (ZO-1), while decreasing vimentin and alpha-smooth muscle actin (α-SMA) to inhibit endothelial-mesenchymal transition (EndMT). Conclusion: WEHE ameliorates CAG lesions, alleviates intestinal metaplasia, and preserves the physiological barrier function of gastric mucosa. These beneficial effects are closely associated with three core regulatory mechanisms: modulation of VEGF signaling, suppression of EndMT progression, and reconstruction of intact intercellular adhesion junctions.