Parabacteroides distasonis Alleviates Obesity and Metabolic Dysfunctions via Production of Succinate and Secondary Bile Acids

TLDR

Obesity and related metabolic disorders are influenced by gut microbial metabolites, notably succinate and secondary bile acids, which modulate intestinal gluconeogenesis and FXR signaling pathways. This study tests whether Parabacteroides distasonis can mitigate obesity, hyperglycemia, and hepatic steatosis in ob/ob and high‑fat‑diet mice through its production of succinate and secondary bile acids.

Abstract

Highlights•Parabacteroides distasonis alleviates obesity and obesity-related dysfunctions in mice.•P. distasonis generates succinate and secondary bile acids in the gut.•P. distasonis activates intestinal gluconeogenesis (IGN) and FXR pathways in the gut.•Succinate is a ligand of fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN.SummaryWe 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.Graphical abstract