Spermine Regulates Bone Homeostasis Through The Gut-Bone Axis

This study aims to explore the specific mechanism by which spermine, a metabolite highly expressed in the saliva of patients with MRONJ, regulates bone homeostasis through the gut-bone axis. The 7-week-old female mice were given continuous administration of spermine (SPM, 0.6 umol/g/d) for 3 weeks (n=5), and the control group was given equal dose of saline. After the experiment, the changes of bone phenotype were evaluated by Micro-CT and H&E staining, and the colon barrier function were detected by RT-qPCR and immunohistochemical staining. The composition and function of gut microbiota in feces were also detected by metgenomic sequencing. Exogenous administration of spermine could increase bone mineral density, enhance bone mass and make the microstructure of femur more compact in mice, while the beneficial regulatory effect of spermine on skeletal system disappeared after antibiotic cocktail cleaning. Mice received spermine gavage showed improved mechanical barrier function of colon epithelium, and spermine could promote mucin 2 secretion, deepen intestinal crypt depth as well as increasing goblet cell number. Moreover, metagenomic analysis found that the kind of species within the gut microbiota of mice after spermine administration increased and its composition changed obviously, among which Akkermansia muciniphila was up-regulated nearly twice, which was a characteristic microbe in SPM group. Spermine plays a regulatory role in bone homeostasis through improving the function of colon epithelial barrier, reprogramming gut microbiota, and promoting the expression of beneficial bacteria Akkermansia muciniphila.