Berberine ameliorates estrogen deficiency-associated bone loss via inducing tuft cell expansion

Estrogen deficiency not only induces osteoporosis in long bone but also promotes inflammatory alveolar bone resorption. Increasing evidence indicated the role of the gut-bone axis in estrogen deficiency-aggravated bone loss. Berberine is a Traditional Chinese Medicine with known gut microbiota modulating activity and exhibits potential in the prevention and treatment of bone resorption.

The present study aimed to investigate the protective effects of berberine on bone loss under estrogen deficiency, and further explored its underlying mechanisms with a particular focus on intestinal tuft cells.

The ovariectomy rodent models were established and gavage-fed with berberine to investigate its effects on bone resorption under estrogen deficiency. The underlying link between gut homeostasis and osteoimmune response was investigated with histological analyses, serum examination, flow cytometry, 16S rRNA sequencing and transcriptomic analysis, with a particular focus on intestinal barrier and tuft cells. Trpm5^-/- mice and intestinal organoids were further employed to verify the underlying mechanisms by which berberine induces tuft cell expansion and thus promoted gut barrier function.

We demonstrated that berberine benefited gut/bone homeostasis via inducing tuft cell expansion under estrogen deficiency. Berberine elevated intestinal butyrate production, which induced tuft cell expansion via GPR41. Tuft cell expansion promoted intestinal remodeling and restored gut barrier, thus ameliorating bone resorption under estrogen deficiency via rescuing the skewed Th17/Treg balance.

Our data demonstrated the critical role of gut-bone axis under estrogen deficiency. As a bioactive phytochemical, berberine represents a promising combined strategy for managing postmenopausal osteoporosis and inflammatory alveolar bone resorption.