Mouse study: Proteins do the damage in fetal abdominal inflammation

Inflammation of the abdominal cavity in human fetuses resulting from a perforation of their intestine is likely to be caused by proteins contained in the fetal stool. This is the result of a Kobe University study that establishes a new mouse model allowing research and drug development for a condition that is otherwise difficult to approach.

The fetus’s stool, called the “meconium,” is sterile but nevertheless causes inflammation of the abdominal cavity when it leaks out of the intestine after a perforation. Called “meconium peritonitis,” this is a life-threatening condition for the baby with a mortality rate of 10%-15% in humans, and neither a cause nor a treatment have been established.

The Kobe University pediatrician FUJIOKA Kazumichi and his team therefore decided to replicate the condition in mice. Since the intestinal development of mice and humans is different, the intestine of a newborn mouse pup is equivalent to that of a human fetus after the 12th week of pregnancy, but even so, the mouse pup is too small and fragile to induce the condition through an operation. The research team therefore created a slurry of meconium, which they took from human newborns, and injected it into the abdominal cavity of the pups. They then characterized the resulting condition and compared the pups’ mortality rates in response to different treatments.

Their results, published in the journal Pediatric Research, show that mortality was not influenced by antibiotic treatment, ruling out a bacterial cause. However, when they heat-treated the meconium slurry before injection, which disrupts the natural shapes of proteins, they found a significant reduction in mortality. This indicates that proteins contained in the meconium are responsible for the inflammation and in particular the researchers assume digestive enzymes that are abundant in the meconium to be the culprits.

The Kobe University development has more general implications, too. In a different set of experiments, Fujioka and his team characterized the condition of the mice pups after the meconium slurry administration by analyzing the mice’s biochemical and gene expression profiles. Comparing that to the results of a previously established mouse model, where the pups were injected an extract of intestinal contents of adult mice, they could show that their model results in different symptoms. Believing that their model is thus likely to be specific to meconium-caused inflammation, the researchers argue that it is an apt platform to conduct more research on the condition.

Fujioka and his team hope that their work will enable the search for an effective treatment of the condition, which occurs in about one out of every 35,000 live births. They conclude their paper saying, “As our mouse model is simple and highly reproducible, it can be used in research to elucidate the pathophysiology of meconium peritonitis.”

This research was funded by the Japan Society for the Promotion of Science (grants 18K15710 and 20K08229), the Morinaga Hoshi-kai Foundation, the Kawano Masanori Memorial Public Interest Incorporated Foundation for the Promotion of Pediatrics and the Japan Foundation for Pediatric Research.

Kobe University is a national university with roots dating back to the Kobe Commercial School founded in 1902. It is now one of Japan’s leading comprehensive research universities with nearly 16,000 students and nearly 1,700 faculty in 10 faculties and schools and 15 graduate schools. Combining the social and natural sciences to cultivate leaders with an interdisciplinary perspective, Kobe University creates knowledge and fosters innovation to address society’s challenges.