Prenatal exposure to opioids has been associated with a range of adverse outcomes for infants, including poor fetal growth, low birth weight, potential birth defects, and a higher risk of neonatal intensive care unit admission. However, less is known about how developmental opioid exposure shapes the infant microbiome and how this influence, in turn, may cause neurological or behavioral effects later in life.
For a mouse study published this week in the mSystems, the open access journal of the American Society for Microbiology, researchers at the University of Missouri, Columbia, found significant changes in the gut microbiome of infants associated with maternal exposure to oxycodone, a commonly used and abused opioid. These bacterial changes are associated with changes in metabolic pathways, a link that suggests maternal opioid use affects infant metabolism.
“Doctors are prescribing oxycodone, but they don’t have all the data on fetal and long-term health effects,” said microbiologist Cheryl Rosenfeld, Ph.D., who led the study with bioinformatics scientist Trupti Joshi, Ph.D. .D. “What happens in utero can have long-term health consequences.”
Rosenfeld and Joshi hypothesized that developmental exposure to oxycodone may cause gut dysbiosis—a disruption of the natural balance of bacteria in the gut—and that these bacterial changes may be related to other changes previously reported in adult offspring. To find out, the researchers administered oxycodone to female mice in the experimental group starting two weeks before breeding and continuing until the offspring were born. The amount of oxycodone, 5 mg per kilogram of body weight, was calculated to mimic the level reported in people with opioid use disorder.
The researchers collected feces from the offspring of mice at the age of 120 days and isolated bacterial DNA from the samples. They used 16s rRNA sequencing to identify the bacterial population in each sample and bioinformatics tools to identify sex-related differences in bacterial abundance, as well as differences between experimental and control groups. Consistent use of these tools, Joshi said, has allowed researchers to discover connections between biological systems.
“Bioinformatics really allows you to go deeper and create more understanding and connect data to biology,” she said.
Notably, males and females did not respond similarly when their mothers were exposed to oxycodone. Men exposed to oxycodone showed higher numbers of Coriobacteriaceae, Roseburia spp., Satterella spp., and Clostridia than those not exposed to the drug. Females showed a higher number Butyricimonas spp., Bacteroidetes, Anaeroplasma spp., TM7, Enterococcus spp., and Clostridia. For both sexes, the detected bacterial changes were associated with changes in metabolic pathways that ultimately affect human metabolism.
Rosenfeld cautioned that the new study identifies important links between opioid exposure and changes in the microbiome, but it does not demonstrate causality or elucidate the underlying mechanisms. In future research, she and Joshi plan to continue using an informatics approach to better understand the role of the microbiome in linking drug exposure to long-term consequences. She also said she would like to see research that explores whether this link exists in mice in humans — and what that means for the health of babies prenatally exposed to the drugs.
“We can’t just think about newborns,” she said. “We need long-term studies of these children.”