A new study in fruit flies describes how an animal's gut reacts differently to beneficial microbes versus harmful pathogens.
A pathway known for repairing damaged genetic material, called the ATM-gH2av pathway, gets repurposed and activated when pathogens destroy cells in the lining of the gut, in the absence of any DNA damage.
When pathogens invade the gut, the pathway helps remove impaired and dying cells in the gut's lining, while also prompting stem cells to rebuild the tissues. When the researchers fed beneficial bacteria to fruit flies, the pathway remained inactive.
The discovery, reported Sept. 17 in Cell Reports, is important because the molecules involved are shared across many species, including humans, so the findings could reshape how scientists think about gut health and immunity.
"Identifying a pathway that responds only to pathogens and not to normal gut microbes is intriguing," said Nicolas Buchon, associate professor in the Department of Entomology in the College of Agriculture and Life Sciences and the paper's senior author. "Because innate immunity is shared from flies to mammals, studying how these mechanisms work in fruit flies can teach us about our own immune system."
In the study, Buchon and co-author Peter Nagy, a research associate in Buchon's lab, fed fruit flies a variety of human and fly pathogens. They also fed another set of fruit flies several beneficial microbes. They used RNA sequencing to track which genes were activated. They found that genes linked to the DNA-repair pathway lit up only in response to pathogens.
Pathogens wreak havoc on the flies' intestines. "When we feed the flies pathogens, their guts lose nearly half of their cells," Buchon said. "Imagine losing half the cells in one of your organs?"
The researchers showed that for reasons not yet fully understood, the ATM-gH2av pathway is involved in two processes when activated by pathogens. First, it participates in the elimination of some of the damaged cells. And second, it helps to signal and prompt stem cells to replace those damaged cells.
Buchon and Nagy checked to see if any DNA damage occurred during these infections, which might help explain why the ATM-gH2av pathway was co-opted during gut infections. "We didn't see any damage," Buchon said. "This suggests that the pathway is not reacting to DNA breaks but is instead being repurposed during infection and regulated in a different way."
The research was supported by the National Institutes of Health and the National Science Foundation.
