Summary: Researchers have decoded how bacteria in the gut can directly signal the nervous system by identifying the exact chemical cues and receptors involved. Using the nematode Caenorhabditis elegans as a model, the study reveals specific bacterial polysaccharides and pigments that activate or inhibit an enteric sensory neuron, offering a clear chemical pathway by which the microbiome can influence behavior and brain-related processes.
The work moves beyond correlations between the gut microbiome and brain disorders such as depression and Parkinson’s disease by revealing precise molecules—peptidoglycan and prodigiosin—and the ion channels—acid-sensing ion channels (ASICs)—that allow bacteria to “speak” to neurons. Because similar ion channels exist in mammals, these findings provide a chemical blueprint likely relevant to human gut–brain communication.
Key Breakthroughs
- Mechanistic clarity: The study pinpoints the bacterial molecules that directly activate an enteric sensory neuron and identifies the ASICs that detect those molecules.
- Evolutionary relevance: Equivalent ion channels occur in mammals, suggesting the mechanism is conserved and may underlie bacterial influence on mammalian nervous systems.
- Therapeutic potential: Knowing the exact signals and receptors opens opportunities for targeted interventions—drugs, probiotics, or supplements—that can modulate specific bacterial signals to influence behavior or neurodegeneration.
Source: Picower Institute at MIT
Background
Animals, including humans, live in close association with vast communities of bacteria. The gut microbiome has been linked to many aspects of health and disease, including mood disorders and neurodegenerative conditions. However, most studies to date report associations rather than identify precise molecular mechanisms. To bridge that gap, neuroscientists at the Picower Institute for Learning and Memory, MIT, investigated how enteric sensory neurons detect and respond to bacterial molecules in a well-characterized model organism.
The team focused on C. elegans, a transparent nematode that evolved as a bacterial specialist—its diet consists largely of bacteria, and its nervous system is tuned to distinguish edible microbes from harmful ones. This specialization makes C. elegans an excellent experimental system to map the molecular steps that connect bacterial presence to neural and behavioral responses.
Enteric neuron NSM and acid-sensing ion channels
Previous work from this group showed that the enteric sensory neuron NSM, which interfaces directly with the pharyngeal lumen, responds to bacterial ingestion and releases serotonin to modulate feeding and locomotion. NSM expresses two acid-sensing ion channels (ASICs), DEL-3 and DEL-7, analogous to channels found in mammalian neurons. The new study set out to discover which bacterial molecules actually trigger NSM activation through these channels.
The investigators exposed worms to a panel of bacterial species and then fractionated bacteria into component classes—DNA, lipids, proteins, simple sugars, and complex polysaccharides—to test which fractions activated NSM. The experiments demonstrated that bacterial polysaccharides, not DNA, lipids, proteins, or simple monosaccharides, were the sufficient signals for NSM activation. In particular, peptidoglycan from Gram-positive bacteria proved to be a clear activator.
Functionally, ingestion of polysaccharides or peptidoglycan enhanced feeding behavior and reduced locomotion, matching NSM’s known behavioral effects. Genetic deletion of the ASICs abolished NSM activation and the associated behavioral changes, confirming that DEL-3 and DEL-7 are required for polysaccharide detection and downstream responses.
Avoiding danger: prodigiosin and pathogenic masking
The team also explored signals from pathogenic bacteria. They tested Serratia marcescens, a bacterium pathogenic to worms and infectious in humans, noting that pigmented strains produce the red metabolite prodigiosin. When prodigiosin was present, NSM activation by otherwise nutritious bacteria was suppressed and worms avoided feeding. Introducing prodigiosin onto normally attractive bacteria reduced NSM responses and blocked the typical feeding and slowing behaviors. This demonstrates that pathogenic metabolites can mask nutritious bacterial cues, guiding the animal away from harmful food sources.
By identifying both nutritive and antagonistic bacterial signals and linking them to defined ion channels and behaviors, the study provides a tractable mechanistic framework for how gut bacteria can influence enteric sensory neurons. Because similar molecular players exist across species, these findings will likely inform research into mammalian gut–brain signaling and potential clinical strategies.
The research team includes Cassi E. Estrem (lead postdoctoral researcher), Malvika Dua, Colby P. Fees, Greg J. Hoeprich, Matthew Au, Bruce L. Goode, Lingyi L. Deng, and Steven W. Flavell. Funding came from the National Institutes of Health, the McKnight Foundation, the Alfred P. Sloan Foundation, the Howard Hughes Medical Institute, and The Freedom Together Foundation.
Key Questions Answered:
A: C. elegans is specialized for bacterial sensing and has a compact, well-defined nervous system. Its enteric neuron NSM and the ASIC channels it uses are homologous to molecular components in mammals, so the worm offers a simplified model to map core mechanisms that likely operate in more complex animals.
A: Not simple sugar, but bacterial polysaccharides—complex sugar chains that form bacterial coatings—act as distinguishing chemical patterns. Neurons appear to detect these polysaccharide patterns to decide whether a bacterium is nutritive or potentially harmful.
A: Identifying the exact chemical signals and their receptors is a critical first step. It opens possibilities for targeted interventions—such as molecules that block harmful signals like prodigiosin or therapies that amplify beneficial polysaccharide signaling—though translating this to humans will require further research.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to clarify experimental details and implications.
About this neuroscience research news
Author: David Orenstein
Source: Picower Institute at MIT
Contact: David Orenstein – Picower Institute at MIT
Image: The image is credited to Neuroscience News
Original Research: Open access. “Identification of bacterial signals that modulate enteric sensory neurons to influence behavior in C. elegans” by Cassi E. Estrem, Malvika Dua, Colby P. Fees, Greg J. Hoeprich, Matthew Au, Bruce L. Goode, Lingyi L. Deng, and Steven W. Flavell. Current Biology
DOI: 10.1016/j.cub.2026.03.070
Abstract
Identification of bacterial signals that modulate enteric sensory neurons to influence behavior in C. elegans
The bacterial microbiome shapes many aspects of animal physiology and behavior. While immune and epithelial cells recognize bacterial molecules through well-characterized pathways, neurons can also directly sense bacterial signals, yet the neuronal sensory mechanisms are less understood. In C. elegans, the enteric sensory neuron NSM innervates the pharyngeal lumen and activates in response to bacterial ingestion, releasing serotonin to drive feeding-related behaviors.
This study used biochemical fractionation to probe bacterial macromolecules and found that bacterial polysaccharides are sufficient to activate NSM. Peptidoglycan from Gram-positive bacteria stands out as a specific activator. NSM responses depend on the acid-sensing ion channels DEL-3 and DEL-7, which localize to the sensory dendrite in the pharyngeal lumen. Ingestion of bacterial polysaccharides promotes feeding and reduces locomotion, aligning with NSM’s behavioral role. The study also identifies prodigiosin, a metabolite from pathogenic Serratia marcescens, which blocks NSM activation by nutritive signals, revealing how pathogenic metabolites can mask beneficial bacterial recognition.
Overall, these results define molecular signals that underlie neuronal recognition of nutritive bacteria in the alimentary canal and identify competing pathogenic signals that interfere with this recognition, providing a framework to explore gut–brain signaling across species.