Mini guts stand in for little guts

To do the research, the team studied a strain of E. coli related to ones commonly found in newborn babies’ stool. The researchers couldn’t do their research in actual newborns’ intestines, of course. Instead, they used stem cells to grow miniature versions of the gut lining, called human intestinal organoids.

SEE ALSO: Gut Bacteria May Protect Newborns Against Infections, New Mice Study Shows

Each HIO, as they’re called, is made up of thousands of cells that the scientists coax to grow, divide and organize into structures that resemble the actual gut. At each HIO’s center is a hollow area called a lumen, which mimics the hollow inner portion of the tube-like human intestine.

“We have previously shown that HIOs closely resemble the immature human intestine,” says lead author David Hill, Ph.D., a postdoctoral fellow in gastroenterology at Michigan Medicine, U-M’s academic medical center. “In this study, we wanted to discover the effects of colonization on the intestine with a nonharmful strain of E. coli, a type of bacteria that is commonly found in the guts of newborn babies.”

During growth, they kept these HIOs germ-free, just like the gut of a fetus in the womb. Then, they introduced the helpful E. coli into the hollow center of the organoids. They tracked what happened inside the cells whose surfaces face the center and in the spaces between the cells. They looked at how the cells were altering gene activity over time in response to the introduction of E. coli.

The results were clear. After the scientists introduced the E. coli, the cells facing the lumen began to mature, form tighter connections with one another and produce mucus to coat their surface.

Genes involved in cell-to-cell communication, and the physical structures cells use to link with their neighbors, activated. So did genes involved in making antimicrobial substances and mucus and transporting them to the cell surface, and in adaptation to low oxygen, which is caused by bacterial metabolism and is a hallmark of the mature adult intestine.

This activity led the HIOs to develop better resistance to inflammation-causing stimuli, which meant less damage to the cells lining the lumen.

“Our results show that colonization of the immature intestinal tract with E. coli results in intestinal tissue that is more robust to challenge by potentially damaging pathogens or inflammatory substances,” says senior author Jason Spence, Ph.D., an associate professor of internal medicine and of cell and developmental biology at U-M.

Co-senior author Vincent Young, M.D., Ph.D., adds, “We have developed a system that faithfully reproduces the physiology of the immature human intestine, and will now make it possible to study a range of host-microbe interactions in the intestine to understand their functional role in health and disease.”

Young is a professor of internal medicine who specializes in infectious diseases and is also a professor of microbiology and immunology at Michigan Medicine and a leader of U-M’s Host Microbiome Initiative.