Microbiome-induced Increases and Decreases in Bone Matrix Strength can be Initiated After Skeletal Maturity.

Recent studies in mice have indicated that the gut microbiome can regulate bone tissue strength. However, prior work involved modifications to the gut microbiome in growing animals and it is unclear if the same changes in the microbiome, applied later in life, would change matrix strength. Here we changed the composition of the gut microbiome before and/or after skeletal maturity (16 weeks of age) using oral antibiotics (ampicillin + neomycin). Male and female mice (n = 143 total, n = 12-17/group/sex) were allocated into five study groups:1) Unaltered, 2) Continuous (dosing 4-24 weeks of age), 3) Delayed (dosing only 16-24 weeks of age), 4) Initial (dosing 4-16 weeks of age, suspended at 16 weeks), and 5) Reconstituted (dosing from 4-16 weeks following by fecal microbiota transplant from Unaltered donors). Animals were euthanized at 24 weeks of age. In males, bone matrix strength in the femur was 25-35% less than expected by geometry in mice from the Continuous (P=.001), Delayed (P=.005), and Initial (P=.040) groups as compared to Unaltered. Reconstitution of the gut microbiota led to a bone matrix strength similar to Unaltered animals (P=.929). In females, microbiome-induced changes in bone matrix strength followed the same trend as males but were not significantly different, demonstrating a sex-dependent response of bone matrix to the gut microbiota. Minor differences in chemical composition of bone matrix were observed with Raman spectroscopy. Our findings indicate that microbiome-induced impairment of bone matrix in males can be initiated and/or reversed after skeletal maturity. The portion of the femoral cortical bone formed after skeletal maturity (16 weeks) was small; suggesting that microbiome-induced changes in bone matrix occurred without osteoblast/osteoclast turnover through a yet unidentified mechanism. These findings provide evidence that the mechanical properties of bone matrix can be altered in the adult skeleton. This study looked at how changes in the gut microbiome affect bone strength in adult mice. The gut microbiome of male and female mice was altered either before or after skeletal maturity. In male mice, those with altered microbiomes had weaker bones (a 25-35% reduction). Alterations to the gut microbiome after skeletal maturity had the same effect as lifelong changes, and restoration of an altered gut microbiome after skeletal maturity reversed the effect. Female mice showed a similar trend, but the changes were not statistically significant. The study concluded that changes in the gut microbiome can weaken bone strength in adult male mice in as short as two months, but this effect can be reversed by restoring the microbiome. These changes seem to occur without removal and replacement of bone tissue using the common bone remodeling processes, suggesting an unknown mechanism. This research provides new evidence that gut bacteria can affect bone strength suggesting the possibility that the microbiome can influence bone fragility.

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