Bacterial infections interfere with the sense of smell of flies
WWhen someone has food poisoning, it may take a while before they want to eat again which made them sick, and the same is true for fruit flies.Drosophila melanogaster). In a study published today (July 21) in Nature, the researchers determined that after a bacterial infection in the gut, glial cells and neurons in the fly’s brain communicate in a way that inhibits smell and protects the animals from eating the pathogen again.
These authors “discovered a mechanism which, at the genetic, neuronal and organism level, links the bacteria in the gut to behavior”, explains Ilona Grunwald Kadow, neuroscientist at the Technical University of Munich who did not participate in the study. “This may be one of the fundamental ways in which the good or bad microorganisms in our gut impact our brains.”
Heinrich Jasper of Genentech knew from previous work that aging flies experience a sharp increase in inflammation. In the gut, for example, there is an accumulation of epithelial damage caused by bacterial dysbiosis – a disruption of the commensal microbiota that changes with age – which leads to the release of inflammatory cytokines and could be linked to neurodegeneration, he explains. A 2018 study by Grunwald Kadow’s group, showing, among other things, that fruit flies lose their sense of smell with age, appeared to be a good system for Jasper’s group to use to test whether inflammation related to age in the gut affects the brain. In addition, previous work had shown that the loss of olfactory capacity can be an early sign of neurodegeneration in humans.
Jasper and his colleagues began by reproducing the published results and confirmed that olfactory perception in flies decreases with age. Then they asked if the disruption of inflammatory processes in the intestinal epithelium would be sufficient to induce this change in young flies.
In young animals, this is a protective mechanism. . . this allows them to essentially avoid foods containing these bacteria.
—Heinrich Jasper, Génétech
The researchers gave the young flies the choice between regular food and food containing a non-lethal intestinal pathogen (Erwinia carotovora carotovora 15). The animals chose food containing bacteria, unless they had previously been infected with the microbe, in which case they showed a strong preference for normal food. They determined that after infection, the flies were less able to detect attractive and aversive odors, indicating that the change in preference for food containing bacteria was due to a transient decrease in smell.
“We realized quite quickly that this decline or change in olfactory perception must also be an adaptive process in young animals, where intestinal inflammation occurs naturally after ingestion of enteropathogens,” explains Jasper.
Once the team determined which cytokines were released from the infected intestines, they were able to guess which pathways might be influenced. One of the main candidates was the JAK-STAT signaling pathway, known to transmit signals between cells, such as cytokines, to control the expression of downstream genes in a variety of settings, including cell proliferation and l ‘inflammation. Many aspects of the track are functionally conserved between Drosophila and mammals. When they looked, the researchers found that the change in olfaction is facilitated by the increase in JAK-STAT signaling triggered by inflammatory cytokines in the gut after bacterial infection.
In this case, the glial cells of the olfactory bulb, but not the neurons, activated STAT, causing a change in the expression of genes involved in lactate metabolism, the authors showed. Glia generally serves as a metabolic support for neurons, ensuring that neurons have the molecules they need to function. There is “a transient shutdown of the lactate shuttle and a build-up of lipids in the glia,” thus hampering smell, but this recovers once the inflammation subsides, Jasper explains.
“Olfactory research is welcome because it reveals a little more how we construct our reality and how, in many cases, pathological conditions distort this reality”, Edgar Soria-Gómez, neuroscientist at the University of the Basque Country in Spain who was not involved in the work, wrote 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 the different bodily systems.”
Parallel paths to aging
Jasper’s team found that age-related inflammation in the gut also triggers the same JAK-STAT pathway from the gut to the glia, leading to permanent changes in smell in aging flies.
“In young animals, this is a protective mechanism. . . this essentially allows them to avoid foods containing these bacteria, ”explains Jasper. But as we age, as microbial dysbiosis sets in, there is “a chronic inflammatory response from the epithelium in older flies, which then leads to a 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 well the pathway is conserved in other animals and how inflammation connects to neurodegeneration – one of Jasper’s original questions. “If it is true on the fly that having [a certain] the microbiome triggers mechanisms similar to those of aging, ”she says,“ would that also explain why some people get neurodegenerative diseases earlier than others?