The location of intestinal stem cells and their proliferation inhibitors were recently identified in a study “The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites,” published in Cell.
The findings could help better understand and better develop therapeutic approaches for intestinal diseases such as inflammatory bowel disease (IBD).
IBD is a group of chronic inflammatory conditions of the colon and small intestine, with Crohn’s disease and ulcerative colitis as its most common disease types. Several therapeutic approaches have been developed for treating IBD. Now, stem cell therapy is currently being explored as a possible treatment for the disease.
Stem cells found in various tissues of the body, including the intestinal tract, are fast dividing cells that replace damaged cells, but little is still known about stem cells — particularly those living in the intestinal gut.
In this study, the researchers found that a metabolite called butyrate strongly influences the proliferation of intestinal stem cells by inhibiting reproduction. They showed that the intestinal stem cells live in protected sacs called crypts of Leiberkuhn, designed to prevent their contact with intestinal metabolites, including butyrate. However, intestinal injury due to IBD exposes the stem cells to butyrate, inhibiting reproduction.
“Scientists have known about these crypts for more than 250 years but never really understood why they existed,” said the study’s senior author Dr. Thaddeus Stappenbeck, a professor of pathology, immunology, and developmental biology, in a press release “Based on our findings, we suspect that crypts evolved to protect stem cells so that the intestine could have a way of constantly regenerating its inner lining.”
On the other hand, the findings may explain why butyrate explored for treatment of IBD in the 1990s did not work efficiently, despite showing anti-inflammatory properties.
“When there’s damage to the lining of the intestine — whether from acute injury or disease — stem cells have to divide to repair that damage,” Stappenbeck said. “Inhibiting stem cell proliferation could be an unfortunate side effect of butyrate treatment.”
To determine if some metabolites present in the intestinal gut could boost the stem cell proliferation, the researchers isolated over 100 abundant metabolites released in a mouse gut, then tested them on cultured intestinal stem cells. They identified no particular metabolite boosting stem cell proliferation. The treatment of mice with doses of butyrate illustrated no further decline in the stem cells’ proliferation rates.
“In the mice, stem cells congregate at the very bottom of crypts, whereas in the lab, the stem cells are directly exposed to butyrate,” said Stacy Ryu, a co-first author on the study. “We began to wonder whether the crypt structure was protecting the stem cells from butyrate.”
To answer the question, the researchers then measured butyrate levels at two intestinal locations: near the butyrate-producing bacteria and at the crypts, and found very low levels at the crypts. Other data suggested that treatment of young zebrafish with butyrate reduced stem cells proliferation due to the absence of gut microbes in that fish.
“We think these butyrate-producing bacteria are one of the driving forces in the evolution of crypts, but we need to do a systematic survey to find out whether there is a correlation between the animals that have intestinal crypts and the animals that carry butyrate-producing bacteria,” Stappenbeck said. “A lot more work needs to be done before we can draw any definitive conclusions.”