Study Finds That Single Course of Antibiotics Raises T1D Risk in Mice

For a number of years, researchers have observed an association between taking antibiotics early in life and developing Type 1 diabetes. The urgency of understanding this relationship has increased along with children’s exposure to antibiotics in recent decades — with children in the United States receiving an average of nearly three courses of antibiotics during the first two years of life, according to a press release from NYU Langone Health.

So a recent study from the NYU School of Medicine on the effects of antibiotics on diabetes development in mice may be of interest to clinicians and researchers alike. Published in July 2018 in the journal eLife, the study documents changes in diabetes development, gut bacterial balance, levels of metabolites and intestinal wall gene expression resulting from a single course of antibiotics.

One antibiotic course, wide-ranging effects

The latest study builds on the researchers’ previous work, which showed that multiple courses of antibiotics accelerated the development of diabetes in NOD mice (bred to be highly prone to developing Type 1 diabetes).

NOD mice were given either a single course, three courses or none of a macrolide antibiotic. Since diabetes development across the groups was similar in female mice (and higher than in male mice), the researchers focused on results in male mice — in which both the single course and the triple course of antibiotics resulted in higher rates of diabetes development over 20 weeks compared with the control group.

The balance of gut bacteria was also significantly different in the single-course group compared with the control group. Four different bacterial species groups (Enterococcus, Blautia, Enterobacteriaceae and Akkermansia) were more common in these mice, of which two groups (Blautia and Akkermansia) have been shown in studies of human children to increase the risk of Type 1 diabetes when unusually abundant in gut bacteria.

Four other groups of bacteria (S24-7, Clostridiales, Oscillospira and Ruminococcus) were shown to be less common in the single-course group compared with the control group.

The researchers also found that mice in the single-course group had an altered gut metagenome, with different patterns of gene expression seen collectively in gut bacteria. This parallels differences seen in short-chain fatty acids (SCFAs) produced by gut bacteria: Significantly reduced levels of butyric and propionic acid were seen in cecal samples of these mice compared with the control group.

What’s more, different levels of several metabolites (citric acid, isoleucine, uracil and valine) were seen in blood and liver samples of single-course mice compared with control mice. There was also different expression of genes in their intestinal wall, showing a potentially clear pathway to immune system dysfunction.

Potential implications for clinicians and patients

Martin Blaser, MD
Martin Blaser, MD (photo by Troi Santos)

Naturally, a study of mice cannot lead to any direct recommendations for humans, notes Martin J. Blaser, MD, the study’s senior investigator and director of the Human Microbiome Program at the NYU School of Medicine.

But the results, Blaser says, “are a model of the pervasive effects that antibiotic courses may have on children, causing immune systems to develop abnormally on the way to serious illness.”

Lead author Xuesong Zhang, PhD, an assistant professor of medicine at the NYU School of Medicine, emphasizes that the findings “confirm earlier work showing that antibiotics can increase the risk for Type 1 diabetes.”

“Even a single early-life course,” says Zhang, “may perturb the intestinal microbiome in ways that lead to long-term consequences in the intestinal wall, including immune cell changes and damage to the pancreas.”

Xue Song Zhang
Xuesong Zhang, PhD

Blaser notes that the potential for a physiological disruptions in early life to have profound and lasting consequences has long been established. “What is new,” he says, “is that we now see the microbiome as an important participant in the development of healthy immunity, metabolism, and cognition.”

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