A novel daidzein-betaine cocrystal alleviates obesity by improving lipid metabolism, modulating inflammation, and reshaping gut microbiota

Daidzein (DAI) and betaine (BTN) exhibit outstanding therapeutic effects on the treatment of obesity and lipid-related diseases. However, the low solubility and oral bioavailability of DAI, along with the poor stability of BTN, limit the clinical application of both compounds. Here, a novel 1:2 drug-drug cocrystal of daidzein and betaine (DAI-BTN) was successfully prepared using crystal engineering technology. Dynamic vapor sorption analysis showed that the mass change of DAI-BTN was reduced by 58% in a relatively humidity range of 0% to 95% compared to BTN. As compared to pure DAI, the intrinsic dissolution rate and the bioavailability of DAI-BTN were enhanced by 4.34-fold and 3.73-fold, respectively. Furthermore, the effect and mechanisms of DAI-BTN in a mouse model of diet-induced obesity were explored. The results showed that the DAI-BTN can reduce body weight and adipocyte area, which were negatively correlated with the levels of TG, TC, LDL-C, AST, ALT, TNF-α, IL-1β and IL-6. Particularly, DAI-BTN was associated with improving the diversity, structure, and composition of the gut microbiome, promoted the growth of beneficial bacteria (e.g., Proteobacteria and Akkermansia ) and inhibited the proliferation of harmful bacteria (e.g., Desulfovibrio and Flexispira ). Therefore, DAI-BTN hold great promise to be developed as an effective drug combination agent for the alleviation of obesity.