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Unintended side effects

 

Antibiotic disruption of the gut microbiome dysregulates skeletal health

By Matthew Greseth

Researchers at MUSC have examined the impact of disrupting the healthy gut microbiome with antibiotics on post-pubertal skeletal development. Their results, published in the February 2019 issue of American Journal of Pathology, showed that antibiotic disruption of the gut microbiota dysregulates communication between immune cells and bone cells.

“This report introduces antibiotics as a critical exogenous modulator of gut microbiota osteoimmune responses during post-pubertal skeletal development,” says Chad M. Novince, D.D.S., Ph.D., an assistant professor in both the Colleges of Medicine and Dental Medicine who studies the impact of the microbiome on osteoimmunology and skeletal development. “Antibiotics are known to perturb the microbiota, but this is the first known study evaluating how that has downstream effects on immune cells that regulate bone cells and the overall skeletal phenotype.”

Working with team members at MUSC, Novince’s lab treated mice with a cocktail of three antibiotics. In collaboration with microbiome scientist Alexander V. Alekseyenko, Ph.D., associate professor in the Biomedical Informatics Center and founding director of the MUSC Program for Human Microbiome Research, they were able to show that antibiotic treatment altered the gut microbiota by inducing specific changes to large groups of bacteria. 

Image showing myeloid-derived suppressor cells the bone marrow of control treated animals.
Image showing myeloid-derived suppressor cells in the bone marrow of control treated animals.
Image showing an increase of myeloid-derived suppressor cells the bone marrow of mice that have been treated with antibiotics.
Image showing an increase of myeloid-derived suppressor cells (in red) in the bone marrow of mice that have been treated with antibiotics.

Following antibiotic disruption of the microbiota, the Novince lab examined the integrity of the skeletal system. Antibiotic-induced changes in the microbiota significantly impacted trabecular bone, the type of bone that undergoes high rates of metabolism, which is controlled through actions of bone-resorbing (osteoclast) and bone-building (osteoblast) cells. Focusing on the cellular details, they saw no changes to osteoblasts, while osteoclast cell number, size and activity were increased.

To determine what enhanced osteoclast outcomes, the Novince lab assessed the levels of osteoclast signaling molecules. They found that pro-osteoclastic signaling molecules were increased in the circulation of antibiotic-treated animals, suggesting that increased osteoclast activity is the result of a specific immune response to a change in the microbiota.

“Our study is able to dive into specific adaptive and innate immune cell mechanisms within the bone marrow to show that there is an effect on the bone cells,” says Jessica D. Hathaway-Schrader, Ph.D., post-doctoral scholar and first author on this study.

Examination of immune cell populations in the bone marrow surprisingly revealed a significant increase in myeloid-derived suppressor cells (MDSCs) of antibiotic-treated animals. MDSCs are known to regulate the immune response during various diseases but have not been extensively studied in health.

Future studies are focused on incorporating an antibiotic regimen that better translates to human treatments. These studies could lead to clinical trials aimed at defining the impact of specific antibiotics on the gut microbiome. This research would support developing non-invasive interventions in the microbiome intended to prevent and treat skeletal deterioration.