When someone gets food poisoning, it might be a while before they want to eat the thing that made them sick again, and the same is true for fruit flies (Drosophila melanogaster). In a study published today (July 21) in Nature, researchers determined that after a bacterial infection in the gut, glial cells and neurons in the fly brain communicate in a way that tamps down olfaction and protects the animals from eating the pathogen again.
These authors “unraveled a mechanism that on the genetic, neuronal, and organismic level connects bacteria in the gut all the way to behavior,” says Ilona Grunwald Kadow, a neuroscientist at the Technical University of Munich who did not participate in the study. “It may be one of the fundamental ways that good or bad microorganisms in our gut impact our brains.”
Genentech’s Heinrich Jasper knew from previous work that aging flies experience a big uptick in inflammation. In the gut, for instance, there’s an accumulation of epithelial damage caused by bacterial dysbiosis—a perturbation of the commensal microbiota as it changes with age—that leads to the release of inflammatory cytokines and could be connected to neurodegeneration, he explains. A 2018 study from Grunwald Kadow’s group, showing, among other things, that fruit flies lose their sense of smell with age, seemed like a good system for Jasper’s group to use to test whether or not age-related inflammation in the intestine affects the brain. Plus, previous work had shown that the loss of smelling ability can be an early sign of neurodegeneration in people.
Jasper and colleagues started by reproducing the published findings and confirmed that olfactory perception in the fly declines with age. Then, they asked whether perturbing inflammatory processes in the intestinal epithelium would be sufficient to induce that change in young flies.
In the young animals, this is a protective mechanism . . . that allows them to basically avoid the food that is laced with these bacteria.—Heinrich Jasper, Genetech
The researchers gave young flies a choice between regular food and food containing a nonlethal intestinal pathogen (Erwinia carotovora carotovora 15). The animals chose the bacteria-laced food, unless they’d been previously infected with the microbe, in which case they showed a strong preference for the normal food. They determined that after infection, the flies were less adept at detecting both attractive and aversive odors, indicating that the change in preference for the bacteria-laced food was due to a transient decrease in olfaction.
“We realized pretty quickly that this decline or this change in olfactory perception must also be an adaptive process in young animals, where intestinal inflammation occurs naturally after ingestion of enteropathogens,” Jasper says.
Once the team figured out which cytokines were released by the infected guts, they could guess which pathways might be influenced. One prime candidate was the JAK-STAT signaling pathway, known for transmitting signals between cells, such as those from cytokines, to control downstream gene expression in a variety of contexts, including cell proliferation and inflammation. Many aspects of the pathway are functionally conserved between Drosophila and mammals. When they looked, the researchers found that the shift in olfaction is facilitated by increased JAK-STAT signaling triggered by inflammatory cytokines from the gut after bacterial infection.
In this case, glial cells in the olfactory bulb, but not neurons, activated STAT, causing a shift in the expression of genes involved in lactate metabolism, the authors showed. The glia typically serve as metabolic support for neurons, ensuring that neurons have the molecules they need to function. There is “a transient shutdown of the lactate shuttle and an accumulation of lipids in the glia,” thereby impeding olfaction, but that gets restored once the inflammation recedes, Jasper explains.
“Olfactory research is very welcome because it reveals a little bit more of how we construct our reality and how, in many cases, pathological conditions distort that reality,” Edgar Soria-Gómez, a neuroscientist at the University of the Basque Country in Spain who was not involved in the work, writes in an email to The Scientist. Another next step would be to explore whether similar pathways are activated during viral infections or infections with other species of bacteria, he adds. “In any case, these results beautifully highlight the intense interconnection between different body systems.”
Parallel pathways in aging
Jasper’s team found that age-related inflammation in the intestine also sets off the same JAK-STAT pathway from gut to glia, leading to permanent changes in olfaction in aging flies.
“In the young animals, this is a protective mechanism . . . that allows them to basically avoid the food that is laced with these bacteria,” says Jasper. But in aging, as microbial dysbiosis sets in, there is “a chronic inflammatory response of the epithelium in old flies, which then leads to chronic release of these inflammatory cytokines, [and] chronic activation of JAK-STAT signaling in the glia,” he explains.
One of the open questions, according to Grunwald Kadow, is how conserved the pathway is in other animals and how inflammation connects to neurodegeneration—one of Jasper’s original questions. “If it’s true in the fly that having [a certain] microbiome triggers similar mechanisms as aging,” she says, “would that be also maybe an explanation why some people come down with neurodegenerative diseases earlier than others?”
Correction (July 22): The story has been updated to state that the lactate shuttle is upregulated, not shutdown as originally written. The Scientist regrets the error.