Blueberry Extract Improves Obesity through Regulation of the Gut Microbiota and Bile Acids via Pathways Involving FXR and TGR5

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe antimetabolic disease function of plant polyphenols (PPs) has long been noted by researchers studying the “health secrets” of people following Mediterranean diet, which contains abundant PPs (). Numerous animal and human studies have demonstrated that, although controversial, PPs from fruits, vegetables, and wines can improve diet-induced obesity and its related metabolic syndromes, including inflammation and insulin resistance (IR) (, ). Certain mechanisms underlying these phenotypes have been studied, such as the inhibition of α-glucosidase, enhancement of pancreatic β-cell function, and regulation of liver function (). However, the reasons for these effects are unclear, as most natural PPs cannot be absorbed directly by mammals, and the plasma concentration of natural PPs or their metabolites is low, making it difficult to fulfill their physiological function ().Recently, the regulation of the gut microbiota (GM) by PPs has received more attention for its potential to improve metabolism. The GM of mammals has fundamental impacts on the host's health in many aspects, such as immunity, psychology, behavior and, especially, energy metabolism (, ). The GM plays a significant role in regulating the body weight (BW) of hosts (). Metabolites of the GM are important in regulating the host's metabolism, and, among others, bile acids (BAs) play a key role (). BAs are synthesized from cholesterol and conjugated to taurine (mouse) or glycine (human) in the liver before being released into the intestine, where they meet microbes. The GM can convert conjugated primary BAs to free BAs via bile salt hydrolase (BSH) and then further to secondary BAs through dehydroxylation and dehydrogenation (). BAs can modulate energy homeostasis through G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) and farnesoid X receptor (FXR, also known as BAR). Supplementation with cholic acid (CA) prevented diet-induced obesity and its related metabolic syndromes in mice via the activation of TGR5 ().Blueberries (Vaccinium spp.) are rich in PPs (mainly anthocyanins) and known for their antioxidant and cardiovascular protective function (). It has been shown that blueberries (or their phenolic extract) were able to ameliorate high-fat diet (HFD)-induced obesity and related metabolic syndromes such as hyperglycemia and IR and to regulate the GM composition (, ). However, although a correlation between the regulation of the GM and an improvement in metabolism has been observed, neither has the causal link of this relationship nor has the mechanism of this connection been studied yet (). To investigate the correlation between blueberry PPs, the GM, and metabolism, we performed four independent experiments (three mouse studies and one in vitro study, more details seen in href="#mmc1" rid="mmc1" class=" supplementary-material">Transparent Methods-Animals and Cell Separation and Culture) employing both mouse and mouse primary cells. The results of this study have implications for understanding the mechanism(s) of the effects of dietary PPs on health and the relationship between the GM and host metabolism.