Oral Administration of Heat-Killed Multi-Strain Probiotics Confers Durable Protection Against Antibiotic-Resistant Primary and Recurrent Urinary Tract Infections in a Murine Model.

Unlabelled: Background/Objectives Alternative therapies for urinary tract infections (UTIs) have been explored, but their efficacy remains inconsistent. With rising antibiotic resistance, this study aimed to evaluate simplified postbiotic formulations derived from heat-killed probiotics for long-term protection against primary and recurrent UTIs in a murine model.

Methods: We compared a multi-strain (seven-strain) versus a single-strain postbiotic in preventing -induced UTIs and recurrent polymicrobial UTIs, assessed protection persistence after treatment discontinuation, and established a novel sustained UTI model via intravesical co-inoculation of three uropathogens. Mice were allocated to three experimental groups: a placebo group (PBS), Postbiotic I group (a seven-strain heat-killed probiotic formulation), and Postbiotic II group (a single-strain heat-killed probiotic). After two weeks of treatment, mice were challenged with uropathogenic (UPEC) and treated for seven days. Following a 14-day washout and bacterial clearance, they were rechallenged with multidrug-resistant UPEC, , and .

Results: Both postbiotics significantly accelerated bacterial clearance in primary UTIs ( < 0.05). In recurrent UTIs, placebo-treated mice exhibited persistent bacteriuria, while Postbiotic I maintained a significantly higher sterile urine rate (50-80%, < 0.01) post-treatment. Histopathological analysis confirmed reduced bladder and kidney inflammation ( < 0.05) with Postbiotic I.

Conclusions: These findings demonstrate the superior efficacy of Postbiotic I in mitigating UTIs, with sustained protection post-treatment, supporting its potential as a long-term, non-antibiotic strategy. Additionally, our reproducible chronic UTI model, achieved through the co-inoculation of three uropathogens, provides a valuable tool for future research on chronic UTI pathogenesis and treatment.