Background : Peptic ulcer disease ( PUD ) is mainly caused by Helicobacter pylori infection and the use of non-steroidal anti-inflammatory drugs ( NSAIDs ). Studies have shown that the morbidity of NSAID-related gastric ulcers continues to rise. As the second largest prescription drug in the world, NSAIDs are taken by more than 30 million people every day, but they increase the risk of gastric ulcers by 40 times compared with the general population. Currently, proton pump inhibitors ( PPIs ) are clinically used to prevent NSAIDs-induced gastric injury, but long-term use will change gastric pH, aggravate flora imbalance, and may aggravate gastric injury. Our research team isolated and screened a strain of Lactobacillus fermentum LAF-09 from the gastric mucosa of healthy individuals, which has excellent gastric acid tolerance and gastric mucosal adhesion potential, and has the potential to prevent gastric diseases. Therefore, the purpose of this study was to investigate the protective effect and potential mechanism of LAF-09 on NSAIDs-Induced gastric ulcer and acute gastric hemorrhage.

Methods : Twenty 6-8-week-old male C57BL/6 mice were randomly divided into 4 groups (Control group, Indomethacin group, LAF-09 group, ATCC group). Mice were given PBS, LAF-09 ( 1 × 109CFU ) suspension or the model strain ATCC14931 ( 1 × 109CFU ) suspension by forced feeding. After seven consecutive days of gavage, a single gavage of Indomethacin (IND) suspension (80mg/kg) was given to induce acute gastric injury. Mice were sacrificed six hours after administration, and gastric tissues were collected. Morphological observations were performed using H&E staining. Western blot was used to detect the expression of gastric mucosal barrier proteins (ZO-1, Occludin). ELISA was used to detect the expression levels of COX-1, COX-2, PGE2, SOD, GSH, CAT, and MDA. Quantitative Real-Time PCR was used to detect changes in inflammatory factors (IL-1β, IL-6, TNF-α) and the composition of gastric microbiota in mice. In addition, indicators related to anemia and blood loss were evaluated.

Results : Macroscopic morphological observation showed that the gastric mucosa of mice in the indomethacin group was red and swollen, with dark brown ulcer surfaces accompanied by many punctate and striped bleeding points, showing obvious gastric bleeding. LAF-09 pretreatment significantly alleviated indomethacin-induced gastric injury in mice and reduced the number of bleeding points. Routine blood tests showed that hemoglobin and red blood cell counts decreased in the IND group, while the LAF-09 group significantly improved these indicators and effectively alleviated gastric bleeding. H&E staining results showed that the indomethacin group caused severe gastric mucosal defects, local necrosis and inflammatory cell infiltration, and the LAF-09 group was significantly better than the indomethacin group and the ATCC group. Compared with the indomethacin group, LAF-09 pretreatment significantly enhanced the antioxidant defense capacity of gastric mucosa, which was manifested by a significant increase in the levels of SOD, GSH and CAT, and a significant decrease in the level of MDA.In addition, LAF-09 effectively inhibited the inflammatory response of gastric mucosa and significantly reduced the levels of pro-inflammatory cytokines IL-1β, TNF-α and IL-6. LAF-09 pretreatment partially restored the prostaglandin synthesis pathway inhibited by indomethacin, as evidenced by the significantly higher expressions of COX-1, COX-2 and their key product PGE2 compared with the IND group. Compared with the indomethacin group and the ATCC group, LAF-09 improved the reduction of barrier proteins (ZO-1 and Occludin) caused by indomethacin and maintained the integrity of the gastric mucosal barrier. Analysis of gastric flora composition by quantitative PCR showed that compared with the indomethacin group, the LAF-09 pretreatment group significantly enriched Lactobacillus and significantly reduced Gram-negative bacteria.

Conclusion: Limosilactobacillus Fermentum LAF - 09 of human gastric origin can effectively prevent NSAIDs - induced gastric ulcer and acute gastric hemorrhage by enhancing the antioxidant defense ability of gastric mucosa, protecting the integrity of tight junction barrier and positively regulating the gastric flora.

(Acknowledgements:This study was supported by National Natural Science Foundation of China. Grant No32370139 to Hongying Fan)

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2025
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