The carotenoid torularhodin alleviates NAFLD by promoting Akkermanisa muniniphila-mediated adenosylcobalamin metabolism
Chang Liu, Xiaojiao Zheng, Jian Ji, Xuan Zhu, Xiaoning Liu, Liu He, Lichun Guo, Kun Ye, Shuang Zhang, Yong‐Jiang Xu, Xiulan Sun, Weibiao Zhou, Hoi Leong Xavier Wong, Yaoqi Tian, He Qian
Abstract
Torularhodin, a unique carotenoid, confers beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism underlying its therapeutic effects remains unknown. Here, we report that torularhodin alleviates NAFLD in male mice by modulating the gut microbiota. Additionally, transplanting fecal microbiota from torularhodin-treated mice to germ-free mice also improves NAFLD. Mechanistically, torularhodin specifically enriches the abundance of Akkermansia muciniphila, which alleviates NAFLD by promoting the synthesis of adenosylcobalamin. Utilizing a human gastrointestinal system and a colonic organoid model, we further demonstrate that adenosylcobalamin confers protective effects against NAFLD through reducing ceramides, a well-known liver damaging compound, and this effect is mediated by inhibition of the hypoxia-inducible factor 2α pathway. Notably, we construct electrospun microsphere-encapsulated torularhodin, which facilitates the slow release of torularhodin in the colon. Together, our findings indicate the therapeutic potential of microbial utilization of carotenoids, such as torularhodin, for treating NAFLD. Nonalcoholic fatty liver disease (NAFLD) has limited dietary treatment options. Here, the authors show that torularhodin, a microbial carotenoid, alleviates NAFLD by enriching Akkermansia muciniphila and promoting adenosylcobalamin synthesis, which reduces ceramides via HIF-2α inhibition.