Dose-dependent antiulcerogenic effect of bacterial levans on indomethacin-induced gastric lesions through modulation of NF-κB/TNF-α expression and apoptotic pathways.

Despite the availability of antiulcer agents, non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers remain prevalent owing to poor tolerability and associated side effects. This study investigated the protective efficacy of bacterial levans against NSAID-induced gastric damage, evaluating their dose-dependent and molecular effects, and assessing possible synergy between LevAE and its probiotic-like producing isolate, Pseudomonas aeruginosa HI1. Levans were purified from different honey bacterial isolates and tested in Wistar rats receiving 100 mg/kg indomethacin for 10 days. All the treatments reduced the number and severity of ulcers in a dose-dependent manner. Notably, LevAE-Low showed superior gastroprotective effects, surpassing Ranitidine in reducing the ulcer burden, normalizing gastric inflammatory cytokines, alleviating oxidative stress, and preserving the mucosal structure. This superior effect was associated with NF-κB and BAX suppression; increased expression of COX-1, PGES, and Bcl-2; and restoration of the baseline BAX/Bcl-2 ratio. Interestingly, lower doses of LevAE and LevZ were more effective than higher doses, indicating a hormetic response, whereas LevP demonstrated a classical dose-response pattern. Although P. aeruginosa HI1 alone achieved comparable or superior cytokine and redox modulation, its combination with LevAE-Low showed weaker effects at some endpoints. These findings highlight the treatment- and dose-specific benefits of bacterial levans and probiotics in NSAID-induced gastric injury, emphasizing careful dose optimization to avoid undesirable outcomes.