Researchers at Worcester Polytechnic Institute (WPI), in collaboration with researchers at Baylor College of Medicine, have developed a simple, scalable method to study how specific neuropeptides affect behavior by programming common lab bacteria to deliver peptides directly to worms. 

The research also suggests a possible microbial approach for the future design of peptide therapeutics. 

The study, “Harnessing microbial tools: Escherichia coli as a vehicle for neuropeptide functional analysis in Caenorhabditis elegans,” was published in GENETICS in August 2025.

Neuropeptides—small protein messengers that fine-tune brain circuits—are notoriously tricky to evaluate one by one. Traditional approaches often rely on creating transgenic animals or purchasing synthetic peptides, both of which are time-consuming and expensive. 

The WPI team instead engineered the bacteria Escherichia coli (E. coli) to produce single neuropeptides, then fed those bacteria to Caenorhabditis elegans (C. elegans) worms with a neuropeptide loss-of-function genetic mutation. The researchers then measured whether native behaviors—such as mate-searching, chemotaxis, and pheromone avoidance—were restored.

“Our approach turns bacteria into on-demand couriers for the nervous system,” says Jagan Srinivasan, senior author and associate professor in WPI’s Department of Biology and Biotechnology. “When a behavior snaps back only if the matching receptor is present, you get direct, in-vivo evidence for which peptide talks to which circuit—and which ones are redundant versus uniquely powerful.”

Because the method delivers intact, sequence-defined peptides through engineered microbes, it suggests a new peptide therapeutic strategy: using microbial “chassis” to produce and deliver short, bioactive peptides in vivo. While this study focuses on worms, the same design principles—sequence control, receptor specificity, dosing through diet—could guide the development of next-generation microbial or probiotic therapies in more complex systems.

“We see this as a proof of concept for microbial peptide therapeutics,” says first author Liz DiLoreto, PhD '25. “In true WPI fashion—hands-on and collaborative—our tiny teachers (C. elegans) let us learn the rules fast: which sequences work, how to dose them, and how receptor context shapes outcomes. Those rules can guide adapting the approach to mammalian models.”

“What excites me is the accessibility,” adds second author and graduate student Shruti Shastry. “Because the method uses standard E. coli and simple feeding, it’s easy to scale and share, empowering more labs and students to test many peptides and build the design playbook for translational work.”

Beyond developing a new toolkit for worm neuroscience, the method opens the door to broader discoveries. Because it cleanly separates individual peptides, it can help researchers identify new peptide-receptor pairs, examine peptide processing and uptake, and investigate how neuromodulators change circuit “states” during complex decision-making.