Dietary Tart Cherry and Fructooligosaccharides Promote Bone Health via the Gut Microbiota and Increased Bone Formation

<b>Background/Objectives:</b> Fructooligosaccharides (FOS) and dried tart cherry (TC) are examples of simple and complex (i.e., within a food matrix) prebiotics that have demonstrated promising osteoprotective activity. In this study, we examined how dietary supplementation with TC or FOS shapes the gut-bone axis to promote bone accrual in young adult mice, and the role of the gut microbiota in mediating these responses. <b>Methods:</b> Studies were performed using 10-wk-old female C57BL/6 mice (n = 10-12/group) fed a control diet or control diet supplemented with 10% TC or FOS for 10 wks alone or in combination with an antibiotic/anti-fungal cocktail to suppress the gut microbiota. The bone phenotype was characterized by dual-energy X-ray absorptiometry, micro-computed tomography and static and dynamic bone histomorphometry. The gut-microbiota was profiled and short chain fatty acids (SCFA) were assessed based on 16S rRNA profiling and gas chromatographic techniques, respectively. <b>Results:</b> FOS and TC enhanced bone structure, with FOS yielding more pronounced benefits across cortical and trabecular compartments. These skeletal improvements with FOS occurred in the absence of systemic changes in bone turnover markers but were accompanied by increases in local bone formation, osteoblast and osteocyte numbers, and bone mineralization in the femur. Both diets altered gut microbiota composition and increased fecal concentrations of the most abundant SCFAs (i.e., acetate, propionate and butyrate), but the response was greater with FOS. Suppression of the gut microbiota and fecal SCFAs with the antibiotic/anti-fungal cocktail inhibited the effects of FOS and TC on cortical bone, but induced unexpected improvements in the trabecular bone. <b>Conclusions:</b> These findings demonstrate differential effects of simple and complex prebiotics on the gut-bone axis in young adult female mice and support a role for SCFA in the cortical bone response, but not in the trabecular bone response with this model of gut microbiota suppression.