Gut microbes in larvae steer adult food choices in flies

A fleeting encounter with bacteria during youth can echo decades later in an animal’s behavior, and scientists are now closer to understanding how. A new study in PLOS Biology, examined in a Primer by Kyu-Chan Cho and Won-Jae Lee of Seoul National University, traces a complete pathway in fruit flies that links a microbial signal encountered during the juvenile stage to a specific feeding avoidance that emerges in adulthood. The work identifies uracil, a molecule released by certain gut bacteria, as the trigger that sets off a chain of host responses running from the larval gut to a defined sensory neuron, ultimately leaving adult flies reluctant to eat food contaminated with bacterial components.

The research builds on earlier findings from the same group showing that larvae fed certain gut microbes, particularly Levilactobacillus brevis, become primed as adults to avoid food containing peptidoglycan, a common component of bacterial cell walls. That earlier work also established that the effect requires larval gustatory neurons expressing Gustatory receptor 66a, known as Gr66a+ neurons, which are best known for detecting bitter and aversive compounds. Those findings raised two central questions that the new study set out to answer: what microbial signal actually triggers priming, and how is that signal detected by the larval Gr66a+ neurons?

Milleville and colleagues, the authors of the new PLOS Biology study, first tackled the identity of the microbial signal. When larvae were fed live L. brevis, they grew into adults that avoided peptidoglycan-containing food. Larvae fed heat-killed bacteria or bacterial supernatant, however, did not develop this avoidance, suggesting that priming requires an actively produced microbial signal rather than a static molecular signature. Notably, L. brevis, unlike another common Drosophila gut bacterium, Lactiplantibacillus plantarum, can undergo a commensal-to-pathogen transition, behaving as a pathobiont—a normally harmless member of the microbiota that can shift to a pathogenic state under certain conditions. That transition has been linked to bacterial uracil release through nucleoside catabolism, pointing to uracil as a candidate priming signal.

To test this idea, the researchers turned to Erwinia carotovora strain Ecc15, also known as Pectobacterium carotovorum, a well-characterized Drosophila pathobiont for which strains differing in uracil release were available. Larvae fed Ecc15 strains capable of releasing uracil developed adult peptidoglycan avoidance, while those fed strains defective in uracil release did not. Feeding larvae uracil alone was sufficient to prime adult peptidoglycan avoidance, whereas the related pyrimidine bases cytosine and thymine were ineffective. Uracil thus emerges as the specific bacterial cue that initiates developmental priming, a finding that narrows a broad microbial exposure down to a single identifiable molecule.

The next question was whether larval Gr66a+ neurons sense uracil directly or indirectly through a host-derived signal. Bacterial uracil is known to activate intestinal Dual oxidase, or Duox, leading to the production of reactive oxygen species. In the new study, uracil induced a transient increase in intestinal ROS, with hydrogen peroxide implicated as an important component. Genetic or pharmacological suppression of this redox response prevented priming. The Gr66a+ neurons therefore appear to respond not to uracil itself but to a host-generated redox signal induced by it, meaning the gut’s own defensive chemistry acts as the messenger between microbe and nervous system.

How is this host signal detected at the neuronal level? Transient receptor potential ankyrin 1, or TrpA1, a sensory ion channel in larval Gr66a+ neurons, had previously been shown to be required for priming. Among the different TrpA1 isoforms, the authors identified TrpA1-B as the specific isoform required in Gr66a+ neurons for this response. Silencing this neuronal population prevented adult peptidoglycan avoidance, while restoring TrpA1-B in Gr66a+ cells rescued priming in TrpA1-null animals. Calcium imaging further showed that hydrogen peroxide activates this neuron in a TrpA1-dependent manner. Together, these results demonstrate that a bacterial signal triggers a host-derived signal, which in turn activates a specific sensory neuron to initiate developmental priming.

Perhaps the most intriguing part of the story remains unresolved. Activation of Gr66a+ neurons during the larval stage is required to establish priming, yet these neurons are not required for peptidoglycan avoidance in adults. Instead, adult peptidoglycan avoidance depends on a distinct population of ppk23+ sensory neurons, which are best known as contact chemosensory neurons involved in pheromone detection and courtship behavior. How, then, is information detected by larval Gr66a+ neurons transmitted across development to influence the adult ppk23+ neuron-dependent response? This question is particularly compelling because metamorphosis extensively remodels the Drosophila nervous system, yet the consequence of larval sensory experience persists into adulthood.

Two broad possibilities could explain this persistence. One is that larval Gr66a+ neuronal activation induces persistent changes in neural circuits that survive metamorphosis. The other is that early microbial exposure alters the developmental programming of adult sensory circuits, thereby modifying their responsiveness to bacterial signals. These possibilities could be distinguished by tracing the fate of larval Gr66a+ neurons and their downstream circuits through metamorphosis, and by investigating whether early microbial exposure activates signaling pathways, such as endocrine signaling, that influence the development and function of adult ppk23+ neurons. Given the broader sensory and behavioral roles of ppk23+ neurons, it will also be interesting to ask whether Gr66a+ neuron-dependent developmental priming selectively affects ppk23+ neuron-mediated peptidoglycan avoidance or more broadly alters other ppk23+ neuron-dependent behaviors, such as pheromone sensing and courtship.

Another important question is why such developmental priming might have been favored through evolution. Early microbial encounters may provide information about environmental conditions likely to be encountered again, allowing later behavior to reduce future risk. Whether priming actually protects adult flies from infection or improves fitness, however, remains unknown. Comparing pathogen burden, tissue damage, survival, and reproductive success between primed and unprimed adults could test this possibility. For now, the study establishes the mechanism of the pathway without claiming a survival advantage for the primed flies.

The broader significance of the work lies in demonstrating that early sensory experiences can have lasting effects on adult behavior, extending this principle to host–microbe interactions. The study shows how a microbial signal encountered during development is translated through host signaling and a defined sensory neuron into a persistent behavioral change. With its powerful genetic tools and well-defined microbial associations, Drosophila provides a tractable system for uncovering how transient microbial encounters leave lasting effects on the nervous system and behavior, offering a framework that may illuminate how developmental microbial exposure shapes behavior in other animals as well.

Subject of Research: How a larval gut bacterial signal primes adult feeding avoidance in fruit flies

Article Title: How early microbial encounters shape adult behavior

Article References: Cho, K.-C., & Lee, W.-J. (2026). How early microbial encounters shape adult behavior. PLOS Biology, 24(10), e3004101. https://doi.org/10.1371/journal.pbio.3004101

Image Credits: AI Generated

DOI: 10.1371/journal.pbio.3004101

Keywords: Drosophila, microbiome, uracil, priming, Gr66a neurons, TrpA1, ppk23 neurons, peptidoglycan, Duox, reactive oxygen species, gut-brain pathway, developmental neurobiology