The gut is protected by a single cell layer and immune cells, including macrophages that help repair tissue, control inflammation, and manage bacteria. Now, researchers found that sensing a specific bacterial protein by stem-like cells in the gut helps to coordinate immune protection by recruiting protective macrophages.

The findings, published in Science Immunology, suggest that these intestinal cells, rather than immune cells, are the key sensors of beneficial microbes, helping maintain gut health and prevent inflammation.

Scientists have known that macrophages depend on signals from gut microbes to develop properly, and when this process fails, chronic diseases such as inflammatory bowel disease can occur. Although sensors called Toll-like receptors on the surface of immune cells help detect microbes, what guides macrophage recruitment is unclear.

So, researchers led by Ming-Ting Tsai at Baylor College of Medicine in Houston, Texas, set out to investigate how epithelial cells in the gut communicate with the immune system.

Activating immunity

The researchers found that colonizing mice with a specific strain of the commensal bacterium Escherichia coli, called 541-15, restored macrophages after antibiotic treatment. Mice with E. coli 541-15 were also protected against chemically induced colitis, showing less inflammation, longer colons, and lower disease markers than mice without the bacterium. 

E. coli 541-15, through its flagellin protein—which makes up the tail-like flagellum that the bacteria use to move, is sensed by a specific Toll-like receptor called TLR5 on epithelial cells that act like stem cells in the gut. These cells secrete molecules that attract immune cells, including macrophages. 

Using lab-grown “mini-colons” that mimic human intestinal tissue, the team discovered that mature colon cells did not respond to the bacteria, while the stem-like cells strongly activated genes involved in immune recruitment without causing inflammation. 

Microbial sensing 

Further experiments showed that E. coli 541-15 helps the colon recruit key immune cells that can develop into macrophages, leading to more mature, protective macrophages and fewer immature ones. 

This effect depended on a chemical signal called CCL2. When CCL2 was blocked or genetically removed from epithelial cells, mice were no longer protected against colitis, and fewer immune cells were recruited to the gut lining. E. coli strains with active flagellin activated TLR5 on epithelial cells, while strains without active flagellin didn’t.

It’s still unclear how these findings apply to humans, and whether other microbial signals help recruit immune cells to the gut, the authors say. However, they add, “our study demonstrates a role for intestinal epithelial stem cells in microbial sensing, which promotes intestinal macrophage replenishment and maturation and supports intestinal barrier function.”