Probiotic Lactobacillus reuteri Prevents Postantibiotic Bone Loss by Reducing Intestinal Dysbiosis and Preventing Barrier Disruption

Abstract

Antibiotic treatment, commonly prescribed for bacterial infections, depletes and subsequently causes long‐term alterations in intestinal microbiota composition. Knowing the importance of the microbiome in the regulation of bone density, we investigated the effect of postantibiotic treatment on gut and bone health. Intestinal microbiome repopulation at 4‐weeks postantibiotic treatment resulted in an increase in the Firmicutes:Bacteroidetes ratio, increased intestinal permeability, and notably reduced femoral trabecular bone volume (approximately 30%, p < 0.01). Treatment with a mucus supplement (a high‐molecular‐weight polymer, MDY‐1001 [MDY]) prevented the postantibiotic‐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, but not Lactobacillus rhamnosus GG or nonpathogenic Escherichia coli, reduced the postantibiotic elevation of the Firmicutes:Bacteroidetes ratio and prevented femoral and vertebral trabecular bone loss. Consistent with causing bone loss, postantibiotic‐induced dysbiosis decreased osteoblast and increased osteoclast activities, changes that were prevented by both L. reuteri and MDY. These data underscore the importance of microbial dysbiosis in the regulation of intestinal permeability and bone health, as well as identify L. reuteri and MDY as novel therapies for preventing these adverse effects. © 2018 American Society for Bone and Mineral Research.

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

“…As we note here, we did not observe any direct effect of chronic ABX treatment on bone density (control versus ABX) similar to Guss and colleagues . This is distinct from our recent observation that short‐term ABX treatment followed by natural microbiota repopulation for 4 weeks is associated with significant dysbiosis, elevated serum endotoxin levels, and bone loss . Interestingly, in the post‐ABX model as well as in other bone models (including H. hepaticus , L. reuteri , etc.…”

“…Previous studies show GCs as well as gut microbiota to be important regulators of bone health . However, whether gut microbiota is necessary for the GC effects on bone is not known.…”

“…Intestinal barrier disruption and endotoxin leakage into the blood stream are now recognized as important pathogenic events in a number of chronic diseases . Importantly, we recently identified intestinal barrier dysfunction as a key mediator of dysbiosis‐induced bone loss . Because our results so far indicate that gut microbiota is altered and necessary for GIO, we tested whether GC‐Tx affects barrier function and if strengthening the intestinal barrier can protect mice from GIO.…”

“…One week prior to the start of GC treatment, the ABX mouse groups were treated with broad‐spectrum antibiotics ampicillin (1.0 g/L; Sigma‐Aldrich, St. Louis, MO, USA) and neomycin (0.5 g/L; Sigma‐Aldrich) at a dose of 160 and 80 mg/kg/day, respectively . These antibiotics are poorly absorbed by the intestine (or unabsorbed in the case of neomycin) to allow the successful targeting and depletion of intestinal commensal microbes . Water intake was measured to account for any increase in consumption due to GC treatment and antibiotic dose was altered to keep dose the same among antibiotic treatment groups.…”

“…It is now clear that changes in the gut microbiota can impact bone density and health . For example, intestinal infection with pathogenic bacteria can induce bone loss in male mice .…”