CAMBRIDGE, Mass. — A landmark study published in Science by researchers at the Broad Institute of MIT and Harvard, in collaboration with the Food Allergy Science Initiative (FASI), has produced the first high-resolution atlas of the gut’s enteric nervous system, showing in unprecedented detail how microbes and allergic inflammation reshape neuronal behavior. The findings redefine the understanding of gut–brain interactions and open the door to a new generation of neuron-targeting treatments for allergies, inflammatory diseases, and disorders of gut motility.
Using advanced single-cell sequencing, the research team mapped the full diversity of excitatory and inhibitory neurons that regulate the small and large intestines. They found that enteric neurons constantly adapt to their environment—responding to changes in the gut microbiome, antibiotic exposure, and allergic inflammation. One striking discovery was the expansion of sensory neurons expressing gastrin-releasing peptide (Grp) in the colon under conditions of low microbial diversity, such as after antibiotic use. Because Grp is key to controlling hormones, satiety, and intestinal movement, the results suggest that microbes directly influence gut motility by modulating neuronal circuits between Grp-expressing neurons and neighboring glial cells.
Beyond mapping, the researchers also identified the genetic “master switches” that govern neuronal behavior. By combining viral gene delivery with CRISPR-based screening, they pinpointed regulators such as Edf1 and Mitf that drive neuronal differentiation and alter gut function. Knocking out these genes dramatically changed neuron composition and gastrointestinal transit times, highlighting potential new targets for treating motility disorders.
The team also explored how food allergies and parasite infections reshape neuronal communication networks. They found that exposure to food allergens suppressed neurons producing neuromedin U (Nmu) and triggered stress-linked gene expression, including Gpr158. The study confirmed that key cytokines involved in type 2 inflammation—IL-4 and IL-13—directly reprogram these neurons. Blocking those cytokine signals stopped the allergic neuronal response. The same Nmu-expressing neurons also carried receptors for leukotrienes, inflammatory molecules that drive anaphylaxis, demonstrating that allergic mediators can directly activate gut neurons during immune reactions.
“By identifying which neuronal subtypes are altered by specific environmental and immune signals, we can now begin to design highly targeted therapies—moving away from broad immunosuppression toward precision modulation of gut neurons,” said Ramnik Xavier, principal investigator of the study, FASI investigator, Professor of Medicine at Harvard Medical School, and Core Institute Member of the Broad Institute.
The work represents a major advance in neurogastroenterology, revealing how the gut’s neural circuits integrate signals from microbes, immune cells, and the environment to maintain intestinal health. The new enteric atlas provides a foundational resource for developing neuron-targeted treatments for food allergies, inflammatory and metabolic diseases, and gastrointestinal motility disorders.
This research was supported by the Food Allergy Science Initiative (FASI), the National Institutes of Health, the Crohn’s and Colitis Foundation, the Food Allergy Research & Education (FARE), and the Klarman Cell Observatory.
