Christensenella tenuis alleviates endotoxemia and metabolic disorders via inhibition of intestinal lipopolysaccharide translocation.

Lipopolysaccharide (LPS)-induced endotoxemia is a key pathogenic factor in metabolic diseases. Probiotics reduce LPS levels and alleviate related disorders, but the underlying mechanism remains unclear. Here, we demonstrated that Christensenella tenuis alleviated endotoxemia and metabolic disorders in Diet-Induced Obese (DIO) mice by inhibiting the LPS-TLR4 signaling pathway and modulating downstream metabolism. Omics analysis revealed increased levels of gut free bile acids (BAs) after C. tenuis treatment, while in vitro experiments confirmed that C. tenuis hydrolyzed conjugated BAs into free BAs via bile salt hydrolase (BSH) activity. Further molecular dynamics simulations showed that free BAs formed non-membrane-permeable complexes with LPS, preventing the transmembrane translocation of intestinal LPS. Experimental evidence from isothermal titration calorimetry confirmed that free bile acids bound directly with LPS in an enthalpy-driven manner, which is consistent with in silico simulations and validates specific molecular interactions. Oral administration of free BAs also reduced plasma LPS levels in DIO mice. These findings uncover a novel mechanism by which BSH-positive gut microbes and probiotics benefit host metabolism and lay the groundwork for gut-targeted biotherapies for endotoxemia and metabolic diseases.