Sex hormones play a major role in physiologic changes that occur during adolescence. The onset of acne, a skin disorder brought on by the clogging of hair follicles with oil and dead skin cells, is one of the most common, and occasionally distressing, adolescent experiences. Systemic antibiotics are sometimes used to help with symptom relief and skin clearing in those whose acne is resistant to topical treatments.
It frequently takes a long time, perhaps up to two years, to treat acne with systemic antibiotics like minocycline, but it is uncertain what effects such a lengthy time of antibiotic therapy will have.
Researchers at the Medical University of South Carolina (MUSC) show in work published online on Nov. 22 in the Journal of Clinical Investigation (JCI) Insight that there is a strong link between the makeup of the gut microbiome a community of microorganisms that live together in the gut and healthy skeletal maturation. A systemic antibiotic used over an extended period of time, like minocycline, may have unexpected effects during the crucial period of adolescent bone formation.
“There are sustained changes to the gut microbiome following long-term systemic minocycline therapy that lead to reduced bone maturation,” said Matthew Carson, first author on this study and graduate student studying the effects of the gut microbiome on skeletal development in the Novince lab.
“From a clinical perspective, not only is minocycline treatment causing changes to the maturing skeleton, the microbiome, and the skeleton aren’t able to recover fully after antibiotic therapy,” added Chad Novince, D.D.S., Ph.D., principal investigator and associate professor in the Department of Oral Health Sciences in the College of Dental Medicine.
This research expands on earlier work from the Novince group that shown a proinflammatory immune response was triggered by a high-dose antibiotic cocktail, increasing the activity of bone-eating osteoclasts and impairing bone formation. The Novince team wondered whether there were any clinical circumstances in which systemic antibiotics would have an impact on the growing skeleton in light of the study’s findings.
They discovered that minocycline is a systemic antibiotic that doctors use to treat teen acne. The antibiotic class known as the tetracycline family, which also contains tetracycline, doxycycline, and sarecycline, includes minocycline. These antibiotics function by halting the growth and spread of bacteria; in the case of acne, they eradicate the bacteria that invade pores and lessen some of the naturally occurring greasy compounds that are responsible for acne.
Carson and Novince gave mice receiving pubertal/postpubertal growth the same age of adolescence in humans a therapeutically relevant dose of minocycline to see if it would have comparable effects on the skeleton to earlier antibiotic treatments. They discovered that, contrary to what they had previously suspected, minocycline therapy does not have any cytotoxic effects and does not provoke a pro-inflammatory response. However, there were changes in the gut microbiome’s composition, which led to reduced bone mass accumulation and impaired skeletal maturation.
Bile acids had not previously been considered as important communication molecules between the gut and the skeleton. By changing the gut microbiome, the makeup of the bile acids is altered, which influences host physiology, including skeletal maturation.
Chad Novince
In and of themselves, these data highlight an important but underappreciated, consequence of long-term systemic antibiotic use during adolescence. But they also went on to show that long-term minocycline therapy prevented the ability of the gut microbiome and skeleton to recover to a stable state even after the therapy was stopped.
Early research suggested that our gut microbiome develops into a mature state in the first few years of life, but this idea has recently been called into question, with recent investigations showing that the gut microbiome continues to develop into a stable, mature state during adolescence.
“What’s really interesting is if you cause changes to the microbiome during this adolescent phase when your microbiota is still progressing toward a stable adult state, you’re going to have profound effects on the maturing skeleton,” explained Carson.
In puberty, we accrue up to 40% of our peak bone mass, which correlates with the maturation of our microbiome. If we disrupt the system during this critical window of growth and reduce our peak bone mass, we may no longer be able to weather the storm of natural bone loss as a consequence of aging. Therefore, disruption of the microbiome during puberty can have a long-lasting impact on skeletal health and fracture risk.
The Novince team further analyzed how the microbiome could communicate with and change the structure of the skeleton. Surprisingly, altering the gut microbiome with minocycline disrupted the normal communication between the liver and the small intestine. This communication centers around small molecules called bile acids.
Normally, bile acids travel from the liver to the small intestine to aid in digestion and help to break down fats, but this view of bile acids is expanding.
“Bile acids had not previously been considered as important communication molecules between the gut and the skeleton,” said Novince. “By changing the gut microbiome, the makeup of the bile acids is altered, which influences host physiology, including skeletal maturation.”
The gut microbiome continuously modifies the pool of bile acids in the small intestine. The bile acids then act as messenger molecules and communicate with host cells in the intestine and at distant anatomic sites. For example, bile acids can stimulate bone formation when they talk to osteoblasts.
Interestingly, the altered gut microbiome resulting from minocycline treatment generated a different pool of bile acids. This different profile of bile acids failed to activate bone-forming osteoblasts and caused a significant decrease of more than 30% in bone formation and mineralization.
This work exemplifies the benefits of a cross-disciplinary approach to science.
“This was truly collaborative science, which is where I think we’re at today,” said Novince. “To drive high-impact science, you need to bring in experts from different professions and disciplines. We were fortunate to have a really strong team. It was fun the whole thing was exciting!”
In summary, this work strengthens the importance of the gut-liver-bone communication network. It reveals that systemic minocycline therapy has unintended, profound, and life-long effects on the skeleton.
“Treatment of adolescent mice with minocycline caused a change in the gut microbiome and altered bile acid metabolism,” summarized Carson. “We found that the change of these bile acids inhibited osteoblast function and impaired skeletal maturation.”
