Researchers at the University of Toronto have discovered that bacteria can drive stem cell regeneration to repair the intestinal lining after injury - uncovering an unexpected way in which the gut microbiome contributes to human health.
Previous research has shown that the community of gut microbes does not influence intestinal stem cell function during normal healthy conditions.
But PhD student Shawn Goyal and his supervisor Stephen Girardin, a professor of immunology and laboratory medicine and pathobiology in the Temerty Faculty of Medicine, sought to investigate if the microbiome could support stem-cell function during intestinal injury and repair.
Their study, published in Cell Stem Cell , holds implications for both colorectal cancer and inflammatory bowel disease development.
Stem cells are remarkable for their ability to produce more of themselves and to become different types of cells. During early development, embryonic stem cells differentiate into all the cell types needed to form the body's organs and tissues, but the role of stem cells doesn't stop there.
"Our bodies are constantly required to regenerate tissues because of daily wear and tear and constant insults," says Goyal. "As adults, we have stem cells across our entire body including in the intestine, where intestinal stem cells are responsible for replacing the intestinal lining every few days."
The layer of intestinal stem cells acts as a barrier separating partially digesting food in the intestinal space from the tissues underneath - keeping microbes, toxins and other potentially harmful substances out while selectively allowing nutrients in.
These cells reside in a part of the intestinal lining that is sterile under healthy conditions. Exposure of these cells to microbial byproducts signals that potentially harmful microbes and substances have breached the barrier.
"Bacteria are going to get into areas where they shouldn't be, so we need to engage a defense program to protect the stem cells because these are the cells you need to maintain your intestinal barrier," says Girardin.
For their study, conducted in mouse and cell models, the researchers found that a unique bacteria-made sugar called ADP-heptose triggered a signalling pathway that caused intestinal stem cells to self-destruct.
The loss of these stem cells directly impacted intestinal development. When intestinal organoids - miniature 3D tissue models grown in the lab - were exposed to ADP-heptose, the organoids were smaller and lacked the complex architecture seen in healthy tissues.
ADP-heptose also turned on a regenerative stem-cell program that prompted Paneth cells - a type of intestinal cells - to revert to a stem-cell state. These so-called revival stem cells were key to replenishing the lost stem cells and restoring the integrity of the intestinal barrier.
The researchers hypothesize that this protective pathway proactively gets rid of intestinal stem cells that could be damaged by toxins or microbes and replaces them with healthy stem cells to restore the intestinal lining.
Girardin notes that bacteria can cause DNA damage which, when accumulated, can lead to cancer, inflammatory bowel disease and other conditions, an area that he is keen to follow up with future work.
"Is it possible that we've uncovered a mechanism by which stem cells that have been exposed to microbes are replaced because there is a big risk that those cells might be mutated? And by doing so, would that be protective against colorectal cancer?" he asks.
His lab is also exploring whether antiviral defenses play a similar role in maintaining the intestinal lining.
Girardin credits the germ-free facility at Temerty Medicine's division of comparative medicine for enabling this and other research from his group looking at the role of gut microbes.
"Germ-free facilities are always expensive and difficult to maintain, but at the end of the day, we would not be able to do these studies without it," he says.
This study was funded by the Canadian Institutes of Health Research and Crohn's and Colitis Canada.
