The Problem
Psychological stress damages the gut. This link is well-established clinically—stress exacerbates inflammatory bowel disease, irritable bowel syndrome, and intestinal permeability—yet the signalling pathway connecting stress perception in the brain to oxidative damage in the intestine remains unmapped. We know stress hormones exist; we know the gut has receptors; we know ROS accumulates. But the molecular cascade linking these observations is essentially a black box.
Recent work, including our own, has begun to illuminate this pathway. Studies in Drosophila identified gut ROS accumulation as a lethal consequence of chronic stress, with d-serine as one mediator. Critically, our laboratory has developed methods that cleanly separate stress effects from other experimental manipulations, allowing us to isolate the stress-to-gut axis for systematic investigation. The machinery is conserved: we observe identical stress-induced intestinal ROS intestinal ROS across Phylum, suggesting findings will translate. (Note: This PhD studentship will involve invertebrate models only).
The Opportunity
We now have the tools to systematically dissect this pathway. The questions are clear: Which neurons sense stress and initiate gut-directed signalling? What hormones carry the message? How does the gut epithelium receive these signals and produce ROS? What genes modify individual sensitivity? Answering these questions would transform our understanding of stress biology and create a mechanistic framework for evaluating compounds that claim to protect against stress-related gut damage.
The Approach
Years 1–2: Fundamental pathway mapping
- Identify stress-sensing neurons using intersectional genetics (activation/silencing of candidate circuits)
- Characterise systemic mediators (octopamine, insulin, stress peptides)
- Map gut reception mechanisms (receptors, kinases, ROS-generating enzymes)
- Forward genetic screen (DGRP) to discover novel pathway components
We will use multiple complementary stress paradigms (social defeat, mechanical, temperature) since no single model perfectly recapitulates human psychological stress. Convergent hits across paradigms reveal core pathway components.
Year 3: Compound profiling
Apply the pathway map to classify bioactive compounds by mechanism of action—distinguishing compounds that block stress perception, interrupt signalling, or scavenge ROS directly. This transforms screening from binary efficacy testing into mechanistic characterisation.
Year 4: Integration and translation
Complete pathway model, compound-mechanism database, synergy studies for rational formulation.
Expected Outputs
- 2+ peer-reviewed publications (pathway mapping, genetic architecture, compound profiling)
- Mechanistic classification of compound library
- Novel intervention targets in the stress-gut axis
- Training of one PhD student with combined academic/industrial experience
References:
Guo, L., Ferretti, V., & Gilestro, G. F. (2025) Sleep Deprivation Primes Synaptic Vulnerability Without Inducing Oxidative Damage: A Mechanistic Reappraisal. bioRxiv DOI: 10.1101/2025.09.05.674430
Gilestro, G.F. (2025) Refining the sleep circuits one neuron at a time. PLOS Biology
DOI: 10.1371/journal. pbio.3003101
Joyce, M., Falconio, F. A., Blackhurst, L., Prieto-Godino, L., French, A. S. & Gilestro, G.F. (2024) Divergent evolution of sleep in Drosophila species. Nature Communications. 15:5091. DOI: 1 0.1038/s41467-024-49501-9
Blackhurst, L. & Gilestro, G.F. (2023) Ethoscopy and ethoscope-lab: a framework for behavioural analysis to lower entrance barrier and aid reproducibility. Bioinformatics Advances. DOI: 10.1093/bioadv/vbad132
Vaccaro, A., Dor, J. K., Nambara, K., Pollina, E. A., Lin, C., Greenberg, M. E. & Rogilja, D. (2020) Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut. Cell, 18: 1307–1328. DOI: 10.1016/j.cell.2020.04.049