A breakthrough single-cell enteric nervous atlas charts how microbes and allergic inflammation can rewire neuronal and intestinal function—paving the way for a new generation of neuron-targeting therapeutics

The Food Allergy Science Initiative, Inc. (FASI)—In a groundbreaking study [1] published in Science, researchers from the Broad Institute of MIT and Harvard and collaborators unveiled the first high-resolution atlas of how enteric neurons adapt to environmental changes—such as microbiome manipulation and allergic inflammation, including food allergy and parasite infection. This work redefines neurogastroenterology and the allergic response, paving the way for gut-targeted therapies aimed at specific neuronal populations and neuronal circuits.

Defining Gut Neuronal Adaptations to the Environment

Unlike other populations, enteric neurons are buried in the wall of the intestine. This unique position suggests a close relationship with the environment of the gut, but has long limited researchers’ ability to study these cells. Using optimized single-cell sequencing to capture enteric neurons, the team mapped the diverse landscape of excitatory and inhibitory motor and sensory neurons across the small and large intestines under various perturbations, thereby uncovering novel markers to distinguish specific subtypes and states. The team further constructed a cell-to-cell communication network by identifying the signaling molecules produced by neurons and their corresponding receptors on nearby non-neuronal cells. One key finding was the expansion of sensory neurons expressing gastrin-releasing peptide (Grp) in the colon, but not the ileum, under conditions of low microbial diversity—similar to what occurs after antibiotic treatment. Grp plays a critical role in regulating hormone release, satiety, and gut motility. The study showed that gut microbes influence Grp expression in neurons and its receptor, Grpr, in glial cells, suggesting a functional cellular circuit whereby microbes can modulate intestinal transit via enteric neurons.

These findings underscore the dynamic nature of enteric neurons as environmental sensors that adapt their gene expression to maintain gut function. The resulting atlas offers valuable insights into how neurons and their cellular circuits may become disrupted during inflammation or prolonged antibiotic exposure.

Identifying “Genetic Switches” That Drive Neuronal Responses

The high neuronal plasticity induced by environmental states suggested that specific genes govern neuronal differentiation and activate transcriptional programs. To uncover these master “genetic switches,” researchers engineered an innovative approach combining viral gene delivery with a CRISPR-based screening system to evaluate pools of candidate genes delivered directly into peripheral neurons. The team identified key genetic regulators capable of altering enteric neuron abundance, transcriptional programs, and influencing motor neuron differentiation. Targeted knockout of individual master regulators—such as Edf1 and Mitf—resulted in profound neuronal changes, as well as measurable shifts in gastrointestinal transit time.

These findings establish a direct link between master “genetic switches” capable of modifying neuronal function and intestinal physiology, and offer promising new targets for therapeutic development aimed at treating gut motility disorders.

Neuronal Communication Networks Rewired in Food Allergy

The researchers profiled gut neuron responses during food allergy and helminth infection and found unique gene signatures for each condition, along with shared markers reflecting a broader response to type 2 inflammation. Notably, exposure to food allergens suppressed neurons that produce neuromedin U (Nmu) and altered their gene expression, including inducing Gpr158, a glycine receptor linked to stress responses. Building on earlier findings from the Food Allergy Science Initiative (FASI) [2], which showed that Nmu-expressing neurons uniquely express Il13ra1 and Il4ra (key receptors for sensing type 2 cytokines), the current study confirmed that these cytokines drive enteric neuron responses. During anaphylactic shock, transcriptional programs in these neurons were upregulated, while blocking IL-4 and IL-13 signaling halted the response. These Nmu-expressing neurons also express Cysltr2, a receptor for leukotrienes. Recent studies published in Science by FASI investigators showed that leukotrienes are key inflammatory molecules released by mast cells and tuft cells that drive anaphylaxis during food allergen exposure [3, 4]. Using live imaging, researchers in this study show that type 2 cytokines and leukotrienes can directly activate Nmu-expressing neurons, demonstrating these receptors are functional on these neurons.

"Understanding which neuronal subpopulations are uniquely altered by different environmental triggers gives researchers new molecular handles to develop precise interventions — moving from broad immunosuppression toward cell-specific modulation,” said principal investigator of the study, Ramnik Xavier, a Food Allergy Science Initiative (FASI) investigator, Professor of Medicine at Harvard Medical School, and Core Institute Member of the Broad Institute of MIT and Harvard.

This body of work marks a major step forward in defining the cellular and molecular pathways underlying type 2 inflammation in the gut, further underscoring the intimate communications between gut neurons and immune cells during food allergies. This atlas provides entry points for genetic and molecular mapping of the enteric nervous system, and a blueprint for developing the next generation of therapies targeting enteric neurons and their cellular circuits to regulate gut physiology, disorders of gastrointestinal motility, metabolic health, and gut-related immune disorders, such as food allergies.

The work was made possible by funding from 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.

About FASI

The Food Allergy Science Initiative, Inc. (FASI) was founded in 2016 at the Broad Institute of MIT and Harvard and spun out in 2021 into an independent 501(c)3 nonprofit organization. FASI comprises an extensive research network that encompasses 20+ world-class labs across the U.S. and over 100+ scientists dedicated to unraveling the biology underlying food allergies. FASI’s interdisciplinary and collaborative approach aims to accelerate the delivery of breakthrough therapies that will transform the lives of individuals living with food allergies. FASI is funded by philanthropic donations to support its groundbreaking research, with 100% of all contributions going directly towards research. To learn more about FASI, please visit our website or contact Sydney Erickson, serickson@foodallergyscience.org.

Citations

[1] Tan P, Jaiswal A, Murphy SP, Brown EM, Wheeler H, Su CW, Finan EP, Guadalupe JJ, Shi HN, Graham DB, Delorey TM, Deguine J, Xavier RJ. Regional encoding of enteric nervous system response to microbiota and type 2 inflammation. Science. 2025 Oct 30;391:eadr3545. doi: 10.1126/science.adr3545. Epub 2025 Oct 30.

[2] Barilla RM, Berard C, Sun L, Sandhu S, Zaghouani S, Iyer KS, Altun G, Su CW, Deguine J, Singh V, Hou Y, Kusumakar K, Rutlin ML, Rao M, Zaghouani H, Shi HN, Xavier RJ, Kuchroo VK. Type 2 cytokines act on enteric sensory neurons to regulate neuropeptide-driven host defense. Science. 2025 Jul 17;389(6757):260-267. doi: 10.1126/science.adn9850. Epub 2025 May 22. PMID: 40403128.

[3] Bachtel ND, Cullen JL, Liu M, Erickson SA, Kutyavin VI, El-Naccache DW, Florsheim EB, Lim J, Sullivan ZA, Imaeda R, Hudak A, Zhang C, Medzhitov R. Intestinal mast cell-derived leukotrienes mediate the anaphylactic response to ingested antigens. Science. 2025 Aug 7;389(6760):eadp0246. doi: 10.1126/science.adp0246. Epub 2025 Aug 7. PMID: 40773543; PMCID: PMC12513082.

[4] Hoyt LR, Liu E, Olson EC, Jacobsen DR, Siniscalco ER, Krier-Burris RA, Greenfield KG, McBride CD, Alfajaro MM, Amat JAR, Zhao Z, Xu L, Philip V, Verma A, Fourati S, Senger DL, Zhang L, Bunyavanich S, Glass SE, Coffey RJ, Wilen CB, Williams A, Eisenbarth SC. Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice. Science. 2025 Aug 7;389(6760):eadp0240. doi: 10.1126/science.adp0240. Epub 2025 Aug 7. PMID: 40773557; PMCID: PMC12333546.

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