Succinate and Secondary Bile Acids Produced by Parabacteroides Distasonis Synergistically Modulate Host Metabolism to Alleviate Obesity and Metabolic Dysfunctions

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.