Dysbiosis in the Gut‐Liver Axis Is Associated With Low Bone Mass During Murine Cholestasis

The gut-liver axis is the bidirectional relationship between the gut microbiota and the liver. Dysbiosis in the gut-liver axis and disrupted bile acid homeostasis contribute to cholestatic liver disease pathogenesis. Patients afflicted with cholestasis have accelerated bone loss, a higher incidence of fractures, and are at risk of developing osteoporosis. However, the mechanisms underlying bone loss are largely unknown. The study purpose was to investigate the role of the gut-liver axis and bile acid signaling on skeletal homeostasis during cholestasis. Male C57BL/6J specific-pathogen-free mice were administered 3,5-diethoxycarbonyl-1,4-dihydrocollidine from age 11 to 15 weeks to induce cholestasis. 16s rDNA sequencing was performed on colonic contents. Livers were processed for qRT-pCR. Trabecular and cortical bone were analyzed by micro-CT. Osteoclast/osteoblast outcomes were determined by histomorphometry. Bile acid concentrations in serum and bone marrow were assessed by mass spectrometry. MC3T3-E1 and RAW 264.7 cells were stimulated with bile acids at concentrations found in the bone marrow to determine their effects on osteoblasts and osteoclasts. Cholestatic mice had less bone mass than controls, attributed to increases in osteoclasts and decreases in osteoblasts. Following cholestatic injury, mice show dysbiotic shifts in their colonic bacteriome, increased expression of hepatic bile acid efflux transporters, and elevated bone marrow bile acids. In vitro, bile acids from the bone marrow of cholestatic mice suppressed osteoblastogenesis and promoted osteoclastogenesis, which was rescued by stimulating cells with a farnesoid X receptor agonist. This study introduces the gut-liver axis as a novel regulator of skeletal homeostasis during cholestatic liver disease through dysregulated bile acid signaling.