What is already known on this topic
Several studies have shown that many foodborne pathogens, including some strains of Salmonella, can induce programmed cell death, and people with inflammatory bowel disease display increased levels of cell death in their gut. However, much is unknown about the relationship between programmed cell death and bacterial infections, and whether signaling molecules released from dying cells could provide fuel for bacterial growth.

What this research adds
Working in cell and tissue explants from mice, researchers found that specific molecules produced and shed by dying gut cells can be sensed and used by intestinal bacteria such as Salmonella and Escherichia coli. The researchers also showed that intestinal epithelial cell death fuels bacterial growth in living mice. However, reducing the release of specific molecules from dying cells — without blocking programmed cell death — protects the animals from infection.

Conclusions
The findings can have implications for easing the symptoms of gut inflammation and chemotherapy-induced gastrointestinal toxicity.

Scientists have known that chemotherapy treatment, intestinal diseases and other conditions can alter the highly regulated process of programmed cell death. Now, researchers have found that gut bacteria can use nutrients released from dying cells as fuel to grow and infect the gastrointestinal tract.

The findings, published in Nature, can have implications for easing the symptoms of gut inflammation and chemotherapy-induced gastrointestinal toxicity.

Several studies have shown that many foodborne pathogens, including some strains of Salmonella, can induce programmed cell death, and people with inflammatory bowel disease display increased levels of cell death in their gut. However, much is unknown about the relationship between programmed cell death and bacterial infections, and whether signaling molecules released from dying cells could provide fuel for bacterial growth.

“We have known for a few decades that the cell death process itself can indirectly influence bacterial infections by changing the body’s immune response. At the same time, we have also been studying how dying cells can communicate with their neighbors,” says study senior author Kodi Ravichandran at Ghent University. “If these dying cells are secreting factors that can be recognized and sensed by healthy neighboring cells, what is to stop other organisms like intestinal bacteria from recognizing these same molecules?”

To address this question, Ravichandran and his colleagues set out to examine cell and tissue samples from the mouse gut.

Enhancing growth

First, the researchers grew cells from gut explants and induced cell death through treatment with a drug. Cultured cells underwent programmed cell death and released molecules that increased the growth of Salmonella bacteria, the team found. 

Inducing programmed cell death in gut epithelial cell lines with UV radiation or drug treatment also led to the production of molecules that increased the growth of Salmonella and other bacteria, including the pathogen Klebsiella pneumoniae and E. coli bacteria obtained from people with Crohn’s disease, colorectal cancer, and urinary tract infection.

Forced death did not increase bacterial growth, which indicates the requirement of regulated cell death — a well-known phenomenon called apoptosis. The researchers found that the molecules released by apoptotic cells are small metabolites acting as nutrients that increase the growth of Enterobacteriaceae. The team called this process ‘death-induced nutrient release’ — or DINNR.

Advancing therapies

Death-induced nutrient release increased bacterial growth by inducing the expression of specific microbial genes that promote colonization, the team found. Further experiments showed that intestinal epithelial cell apoptosis fueled Salmonella growth in living mice, too. However, reducing the release of specific molecules from dying cells — without blocking programmed cell death — protected the animals from infection

This finding was particular interesting to the researchers. “Unlike foodborne infections or flare-ups of inflammatory bowel disease or Crohn’s disease, where a patient does not know when he or she will be ‘under attack,’ physicians know exactly when they are administering chemotherapeutic drugs to cancer patients,” says study lead author Christopher Anderson. “This means we have a therapeutic window where we can try to develop some sort of combination therapy to limit some of this fuel for bacteria.”

The results could also help to develop new therapeutic approaches for certain bowel conditions. “What was exciting to us was that we do not need to cheat death itself to still see some protection. We do not need to go searching for the Holy Grail. If we can change or restrict some of these nutrients that are released during death, we can try to improve patient care,” Anderson says. “As with any piece of fundamental research, there is more work to be done, but the opportunity is there for future therapies.”