Osteoporosis is a disease characterized by low bone mass and increased fracture risk. It is currently estimated that over 300 million people are impacted by osteoporosis. This thesis will primarily focus on secondary osteoporosis, which is due to consequences of diseases or treatments for disease. With current treatments having several adverse side effects, there is an increased need to develop novel therapies for osteoporosis. One area of research that has gained attention recently involves the influence of the gut microbiota on bone health. My thesis work investigated the role of the gut microbiota in two different models of bone loss. First, I investigated how 2 weeks of broad-spectrum antibiotics and subsequent intestinal microbiome repopulation (dysbiosis) affected bone density. Intestinal microbiome repopulation, 4-weeks post-antibiotic treatment, resulted in an increase in dysbiosis, increased intestinal permeability and notably reduced femoral trabecular bone volume (~30%). Treatment with a mucus supplement (MDY) prevented the post-antibiotic induced barrier break as well as bone loss, indicating a mechanistic link between increased intestinal permeability and bone loss. A link between the microbiome composition and bone density was demonstrated by supplementing the mice with probiotic bacteria. Specifically, Lactobacillus reuteri, reduced the post-antibiotic elevation of the Firmicutes:Bacteroidetes ratio and prevented femoral and vertebral trabecular bone loss. Consistent with causing bone loss, post-antibiotic induced dysbiosis decreased osteoblast and increased osteoclast activities, changes that were prevented by both Lactobacillus reuteri and MDY. These data underscore the importance of microbial dysbiosis in the regulation of intestinal permeability and bone health as well as identify Lactobacillus reuteri and MDY as novel therapies for preventing these adverse effects.In the second part of this thesis, I present an in vivo murine model to study the role of the gut microbiota in glucocorticoid-induced osteoporosis (GIO). Glucocorticoids (GCs) directly induce osteoblast and osteocyte apoptosis but can affect other organs including the intestine. Our lab and others identified that the microbiota contributes to the regulation of bone density; however, the role of the gut in mediating GIO has never been examined. We report that GC treatment alters the microbiota composition. To determine the contribution of the microbiota to GIO pathogenesis, we treated adult male mice for 8-weeks with GC (prednisolone) in the presence or absence of broad-spectrum antibiotic treatment (ABX) to deplete the microbiota. Strikingly, depletion of the microbiota prevented GC-induced bone loss, establishing the requirement of the microbiota in the pathogenesis GIO. We next supplemented GC treated mice with an oral probiotic (Lactobacillus reuteri, LR; 108 CFU/day) for the duration of GC treatment. LR treatment prevented bone loss, suggesting a role for beneficial bacteria in modulating GIO. Interestingly, we found that GC treatment causes intestinal barrier leaks and raises serum endotoxin levels, a response that was prevented by both LR and ABX treatments. Accordingly, enhancement of barrier function, with a mucus supplement, prevented both GC-induced barrier dysfunction and GIO, establishing a mechanistic link between intestinal barrier function and GIO. Taken together, these data highlight the previously unappreciated role of the gut microbiota and intestinal barrier function in GIO pathogenesis and identify the gut as a novel therapeutic target for preventing GIO
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