β-Klotho deficiency shifts the gut-liver bile acid axis and induces hepatic alterations in mice.

β-Klotho (encoded by Klb) is an obligate coreceptor, mediating both fibroblast growth factor (FGF)15 and FGF21 signaling. Klb ^-/- mice are refractory to metabolic FGF15 and FGF21 action and exhibit derepressed (increased) bile acid (BA) synthesis. Here, we deeply phenotyped male Klb ^-/- mice on a pure C57BL/6J genetic background, fed a chow diet focusing on metabolic aspects. This aims to better understand the physiological consequences of concomitant FGF15 and FGF21 signaling deficiency, in particular on the gut-liver axis. Klb ^-/- mice present permanent growth restriction independent of adiposity and energy balance. Klb ^-/- mice also exhibit few changes in carbohydrate metabolism, combining normal gluco-tolerance, insulin sensitivity, and fasting response with increased gluconeogenic capacity and decreased glycogen mobilization. Livers of Klb ^-/- mice reveal pathologic features, including a proinflammatory status and initiation of fibrosis. These defects are associated to a massive shift in BA composition in the enterohepatic system and blood circulation featured by a large excess of microbiota-derived deoxycholic acid, classically known for its genotoxicity in the gastrointestinal tract. In conclusion, β-Klotho is a gatekeeper of hepatic integrity through direct action (mediating FGF21 anti-inflammatory signaling) and indirect mechanisms (mediating FGF15 signaling that maintains BA level and composition).