Allo-lithocholic acid, a microbiome derived secondary bile acid, attenuates liver fibrosis

: Secondary bile acids, lithocholic acid and deoxycholic acid (LCA and DCA), are dehydroxylated derivatives of primary bile acids. However, in addition to LCA and DCA the intestinal microbiota produced a variety of poorly characterized metabolites. Allo-LCA, a LCA metabolite, acts as a dual GPBAR1 agonist and RORγt inverse agonist and modulates intestinal immunity, although is not yet known whether allo-LCA exerts regulatory functions outside the intestine. In the present study we have therefore investigated whether administration of allo-LCA, 10 mg/kg/day, to mice administered a high fat/high fructose diet (HFD-F) and carbon tetrachloride (Ccl4), a model for metabolic dysfunction-associated steatohepatitis (MASH), protects from development of liver damage. In vitro allo-LCA functions as GPBAR1 agonist and RORγt inverse agonist and prevents macrophages M1 polarization and Th17 polarization of CD4 cells. In vivo studies, while exposure to a HFD-F/Ccl4 promoted insulin resistance and development of a pro-atherogenic lipid profile and liver steatosis and fibrosis, allo-LCA reversed this pattern by improving insulin sensitivity and liver lipid accumulation. The liver transcriptomic profile demonstrated that allo-LCA reversed the dysregulation of multiple pathways associated with immunological, inflammatory and metabolic signaling. Allo-LCA also restored bile acid homeostasis, reversing HFD/Ccl4-induced shifts in bile acid pool composition and restored adipose tissue histopathology and function by reducing the expression of leptin and resistin, two pro-inflammatory adipokines, and restored a healthier composition of the intestinal microbiota. In conclusion, present results expand on the characterization of entero-hepatic signaling and suggest that allo-LCA, a microbial metabolite, might have therapeutic potential in liver diseases.