Study uncovers relationship between stem cell development and gut microbes in newborn health

Researchers at The Hospital for Sick Children (SickKids) have demystified the relationship between microbes and stem cell development in the intestines in early life, with significant implications for both developmental biology and the care of premature infants with necrotizing enterocolitis.

Necrotizing enterocolitis (NEC), a disease which causes the death of cells in the intestinal wall, causes poor feeding, swollen belly and bloody stools in infants. NEC affects between five and 10 per cent of preterm babies in North America and is one of the most common and fatal diseases in premature infants. Previous studies have shown that antibiotics and reduced numbers of Paneth cells, specialized cells that defend against microbes in the small intestine, are both associated with NEC, but the reasons why have remained unclear.

In the study published today in Immunity, researchers led by Dr. Tae-Hee Kim, a Senior Scientist in the Developmental & Stem Cell Biology program, showed that antibiotic treatment early in life impaired stem cell development in the intestines. The findings indicate that exposure to antibiotics as a newborn may leave stem cells less able to properly differentiate into Paneth cells. They may also impair both macrophages, a specialized white blood cell that is essential to your immune system, and mesenchymal cells, a class of cells that give rise to connective tissues. 

“When newborns are given antibiotics, cells in the gut may be unable to properly develop,” says Kim. “Our cells do not exist in isolation, and this has a domino effect on the surrounding environment leading to the impairment of essential biological processes.”

Creating the right microbiome environment

While some external factors contribute to NEC, the researchers also identified several factors which may reduce the severity of NEC symptoms and improve survival rates for newborns.

Together with first author Dr. Ji-Eun Kim, a Postdoctoral Fellow in the Developmental & Stem Cell Biology program, the team determined that a subset of macrophages, known as CD206+ macrophages, may be an essential part of maintaining the right environment for the development of Paneth cells.

By transferring these specialized macrophages to the gut in a mouse model, the researchers discovered that stem cells were better able to differentiate. This also partially improved the cellular changes associated with NEC.

Further research demonstrated that some NEC-like displays in cells could be reduced by administering the bacterial strain Lactobacillus, a probiotic commonly found in over-the-counter supplements.

“The early period of life is critical for cell development,” says Kim. “Whether it’s a probiotic or a cell transplant, these wider cellular and environmental interactions may prove essential for improving survival rates for NEC and other conditions of the gut such as Crohn’s disease and gastrointestinal cancer.”

This is the latest research to come out of the Kim Lab at SickKids, which investigates the mechanisms of gut stem cell niches with the goal to uncover new therapeutic targets for digestive tract cancers and regenerative medicine. The lab also collaborated with other SickKids scientists, Dr. Agostino Pierro, Senior Associate Scientist at the Pierro Lab in the Translational Medicine program, and Dr. Phil Sherman, a paediatric gastroenterologist and Senior Scientist Emeritus in the Cell Biology program.

This study was supported by the SickKids Foundation, March of Dimes Basil O’Connor Starter Scholar Research Award, University of Toronto’s Medicine by Design Initiative, Canadian Institutes of Health Research (CIHR) and Natural Science Research Council of Canada (NSERC).