Allergies | Digestive Disorders | Research
Ramnik Xavier , MD, PhD, of the Department of Molecular Biology at Massachusetts General Hospital, is the senior author of a paper published in Science, " Regional encoding of enteric nervous system responses to microbiota and type 2 inflammation ."
Q: How would you summarize your study for a lay audience?
The enteric nervous system (ENS) is a vast network of nerves built into the walls of the intestine. While it is well known for its role in regulating digestion and the movement of food through the intestine, researchers are learning that its influence extends much further.
Our study adds to accumulating evidence showing that the ENS works closely with the immune system to help the body respond to bacteria, parasites and allergens. Far from serving only as the gut's control center for digestion and movement, the ENS also plays a key role in how the body maintains balance and protects itself from harm.
Q: What knowledge gap does your study help to fill?
The gastrointestinal tract is constantly challenged by changes driven by the microbiota, pathogens and the immune system. However, scientists still know little about how the network of nerves in the gut that comprises the ENS responds to these shifting conditions, partly because it has been hard to study these neurons in detail.
To address this, we investigated mouse models with distinct, carefully selected gut microbiomes and others exposed to allergens or parasitic infections. In each case, we profiled the ENS across different regions of the intestine to define its responses to these conditions.
Q: What methods or approach did you use?
We used a special type of mouse model with a fluorescent tagging system that made the nuclei of enteric neurons glow. This allowed us to identify and sort neurons from the rest of the gut tissue and study the nuclei of these cells one-by-one to understand their genetic activity. Our approach enabled us to see which genes were active in each cell — in fact, we detected over 6,000 genes per neuron, on average, including lowly expressed genes that can be hard to detect with standard methods.
Additionally, to investigate how these neurons adapt to different conditions, we used a viral tool to delete specific genes of interest. This process helped us get a clearer picture of which genes control how neurons behave and respond.
Q: What did you find?
By studying gene activity in individual neurons of the gut, we uncovered two main patterns that reveal how diverse and adaptable the ENS is. One group of sensory neurons showed large variations in cell numbers across sites and conditions. These sensory neurons stood out for their specialized communication, including response signals to many immune molecules produced during allergic responses or parasitic infection. Another group, the motor neurons that control gut movement, showed more gradual shifts in the genes they expressed across different conditions while maintaining stable numbers.
Strikingly, these patterns were seen across very different conditions — from allergy to parasitic infection to germ-free states — suggesting that the gut's nervous system coordinates its activity to keep the intestine in balance, no matter the challenge.
Q: What are the implications?
Together, these findings create the most detailed roadmap to date of how the gut's nervous system responds to different environmental challenges. Our study shows that changes in the activity of enteric neurons are closely linked to how the intestine functions, connecting cellular behavior to broader gut physiology. By revealing these connections, we've laid the foundation for future research into how the ENS supports gut health, as well as what happens when that balance is disrupted in disease.
Q: What are the next steps?
By charting how enteric neurons change during inflammation, we're now set up to explore if and how the gut's nervous system can directly influence inflammatory responses. To advance therapeutic progress, we'll also study patient samples and laboratory-grown gut models to determine how these findings apply to humans.
Last, but not least, because enteric neurons also communicate with other nerves that connect to the brain — influencing appetite, food intake and more — understanding how inflammation-related changes in the ENS affect these wider nerve networks could reveal more about the gut's role in overall health and disease.
Paper cited: Tan, P., et al. "Regional encoding of enteric nervous system responses to microbiota and type 2 inflammation." Science. DOI: 10.1126/science.adr3545.
Funding: This work was supported by grants from the Leona M. and Harry B. Helmsley Charitable Trust (to RJX), the Crohn's and Colitis Foundation (to RJX), a grant from the Food Allergy Research & Education (FARE) and the Food Allergy Science Initiative (to JD, RJX), funding from the National Institutes of Health (DK135492 and DK043351, both to RJX) and the Klarman Cell Observatory (to RJX).
Disclosures: RJX is co-founder of Jnana Therapeutics and Convergence Bio, Board Director at MoonLake Immunotherapeutics, consultant to Nestle, and a member of Magnet Biomedicine and Arena Bioworks' scientific advisory boards; JD is a member of Biorender's scientific advisory board. These organizations had no role in this study. All other authors declare no competing interests.
