Probiotics combined with antidiabetic drugs overcome the “drug black hole,” achieving enhanced efficacy and reduced toxicity

Glibenclamide is a widely used therapeutic agent for the treatment of type 2 diabetes mellitus; however, its long-term administration is frequently associated with adverse effects, including weight gain and hepatotoxicity. In recent years, accumulating evidence has highlighted the crucial role of the gut microbiota in modulating drug metabolism and therapeutic efficacy, making the combined use of probiotics and pharmaceuticals an emerging strategy for adjunctive therapy. Nevertheless, this approach faces the challenge of the “microbial drug black hole,” whereby certain microbial strains can degrade drugs and thereby reduce their bioavailability. To address this issue, the research team employed high-performance liquid chromatography to screen 71 Bifidobacterium strains and identified Bifidobacterium animalis subsp. lactis B960 as a standout candidate. This strain exhibited a glibenclamide degradation rate of only 0.8%, and its metabolites were found to synergistically enhance the glucose-lowering efficacy of glibenclamide in cellular models.

In a mouse model of type 2 diabetes, the combination of B960 and glibenclamide demonstrated pronounced synergistic effects. Compared with monotherapy, the combined treatment more effectively reduced fasting blood glucose levels, controlled body weight gain, and improved pancreatic islet structure and function. Importantly, the combination therapy markedly alleviated glibenclamide-induced hepatotoxicity and systemic inflammatory responses .

Mechanistic investigations revealed that B960 markedly improves insulin sensitivity by activating the IRS1/PI3K/AKT insulin signaling pathway. Integrated metabolomic and whole-genome analyses further demonstrated that B960 is capable of synthesizing a key triterpenoid metabolite, Calenduloside E, both in vitro and in vivo, through a dedicated biosynthetic pathway comprising nine enzymes, including IolS and EpsJ. Notably, direct supplementation with Calenduloside E was sufficient to recapitulate the synergistic effects observed with B960 treatment.

Another major highlight of this study is the successful application of a state-of-the-art human-derived gut–liver organ-on-a-chip platform to recapitulate key aspects of the human physiological microenvironment in vitro. Using this system, the metabolic regulatory functions of Calenduloside E were independently validated, providing a robust experimental foundation for the potential clinical translation of these findings.

This study systematically elucidates the mechanisms by which B960 and its active metabolite, Calenduloside E, enhance therapeutic efficacy while reducing adverse effects. By addressing the “microbial drug black hole,” it proposes a new microbe–drug synergistic therapeutic strategy and advances the development of precision nutrition-based interventions for type 2 diabetes mellitus.

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