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Summary We demonstrated the metabolic benefits of Parabacteroides distasonis (PD) on decreasing weight gain, hyperglycemia, and hepatic steatosis in ob/ob and high-fat diet (HFD)-fed mice. Treatment with live P. distasonis (LPD) dramatically altered the bile acid profile with elevated lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) and increased the level of succinate in the gut. In vitro cultivation of PD demonstrated its capacity to transform bile acids and production of succinate. Succinate supplementation in the diet decreased hyperglycemia in ob/ob mice via the activation of intestinal gluconeogenesis (IGN). Gavage with a mixture of LCA and UDCA reduced hyperlipidemia by activating the FXR pathway and repairing gut barrier integrity. Co-treatment with succinate and LCA/UDCA mirrored the benefits of LPD. The binding target of succinate was identified as fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN. The succinate and secondary bile acids produced by P. distasonis played key roles in the modulation of host metabolism.

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.

We demonstrated the metabolic benefits of Parabacteroides distasonis (PD) in decreasing the weight gain, hyperglycemia, and hepatic steatosis in ob/ob mice. Treatment with PD dramatically altered the bile acids profile with the elevated lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) and increased the level of succinate. In vitro culture of PD confirmed its capacity in transforming bile acids and generating succinate. Succinate supplemented in diet decreased the hyperglycemia in ob/ob mice via the activation of intestinal gluconeogenesis (IGN). Gavage with the mixture of LCA and UDCA reduced hyperlipidemia through activating the FXR pathway and repairing the gut barrier integrity. Co-treatment with both succinate and LCA/UDCA mirrored the benefits of LPD. Importantly, the binding target of succinate was identified to be the fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN. The succinate and secondary bile acids from P. distasonis synergistically modulate host metabolism to alleviate metabolic dysfunctions.