Paraprobiotics Derived From Bifidobacterium animalis Subsp. LactisBB-12 Attenuates Indomethacin-Induced Gastric Ulcer by Inhibiting the PANoptosis Pathway

Gastric ulcer pathogenesis involves inflammation and cell death. Paraprobiotics are emerging as safer therapeutic alternatives. This study aimed to investigate the gastroprotective effect of paraprobiotics derived from Bifidobacterium animalis subsp. lactis BB-12 and its role in modulating PANoptosis in the experimental ulcer model. Gastric ulcers were induced in Balb/c mice using indomethacin. Mice were pre-treated by oral gavage with live B. animalis subsp. lactis BB-12 probiotic (1 × 109 CFU/mL, 200 μL), its heat-inactivated paraprobiotic (1 × 109 CFU/mL, 200 μL), or lansoprazole (30 mg/kg), each administered 5 min before ulcer induction with indomethacin (25 mg/kg). Gastric damage was assessed macroscopically and histologically. Oxidative stress markers (superoxide dismutase [SOD], catalase [CAT], reduced glutathione [GSH], malondialdehyde [MDA]), myeloperoxidase (MPO) activity, and serum cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], IL-10) were measured. Key proteins of the PANoptosis pathway were analyzed by Western blot. Both probiotic and paraprobiotic treatments significantly reduced the ulcer area (from 52.54% in the ulcer group to 21.57% and 17.34%, respectively) and the total histological damage index (from 3.95 to 1.27 and 0.95, respectively) (p < 0.001). Both treatments reversed the depletion of antioxidant enzymes and the increase in MDA and MPO levels. Additionally, they restored IL-10 to control levels while suppressing TNF-α and IL-6 (p < 0.001). Paraprobiotics also strongly inhibited key regulatory proteins in three cell death pathways, including NLRP3, c-Caspase-1/3/8, ZBP1, and p-RIPK3/MLKL. Paraprobiotics derived from B. lactis subsp. lactis BB-12 exhibit a potent gastric protective effect against gastric ulcers. As they were administered before ulcer induction, paraprobiotics represent a promising prophylactic strategy for the prevention of inflammatory gastrointestinal disorders, identifying PANoptosis as an important therapeutic target.