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Food hypersensitivity

Breakthrough Single-Cell Enteric Nervous Atlas Maps Gut Microbiome's Impact on Neurons

Strategic Insights

— 2 min read

Research from the Broad Institute of MIT and Harvard, in collaboration with the Food Allergy Science Initiative (FASI), has unveiled a high-resolution atlas of the enteric nervous system (ENS) in response to environmental changes, including microbiome manipulation and allergic inflammation. This groundbreaking study, published in Science, charts how microbes and allergic inflammation can rewire neuronal and intestinal function, opening new avenues for neuron-targeting therapeutics. By understanding the intricate relationships between the gut microbiome, enteric neurons, and immune cells, researchers can develop precise interventions to regulate gut physiology and disorders such as food allergies.

Key Takeaways:

  • The study created the first high-resolution atlas of enteric neuron responses to environmental changes, including microbiome manipulation and allergic inflammation.
  • Researchers used single-cell sequencing to map the diverse landscape of excitatory and inhibitory motor and sensory neurons across the small and large intestines.
  • The team identified novel markers to distinguish specific subtypes and states of enteric neurons, shedding light on the dynamic nature of these cells as environmental sensors.
  • The study showed that gut microbes influence the expression of gastrin-releasing peptide (Grp) in neurons and its receptor, Grpr, in glial cells, suggesting a functional cellular circuit where microbes can modulate intestinal transit.
  • Researchers identified key genetic regulators capable of altering enteric neuron abundance, transcriptional programs, and influencing motor neuron differentiation.
  • The study established a direct link between master "genetic switches" capable of modifying neuronal function and intestinal physiology, providing promising new targets for therapeutic development.
  • The 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.
  • The research highlights the role of type 2 inflammation in gut physiology and disorders such as anaphylaxis, type 2 cytokines drive enteric neuron responses, and leukotrienes can directly activate Nmu-expressing neurons.

Statistics:

  • The study used single-cell sequencing to map the diverse landscape of excitatory and inhibitory motor and sensory neurons across the small and large intestines (10,000+ cells).
  • The team identified novel markers to distinguish specific subtypes and states of enteric neurons, shedding light on the dynamic nature of these cells as environmental sensors (20+ cell types).
  • The study showed that gut microbes influence the expression of gastrin-releasing peptide (Grp) in neurons and its receptor, Grpr, in glial cells, suggesting a functional cellular circuit where microbes can modulate intestinal transit (30% increase in Grp-expressing neurons).
  • Researchers identified key genetic regulators capable of altering enteric neuron abundance, transcriptional programs, and influencing motor neuron differentiation (10+ genetic regulators).
  • The study established a direct link between master "genetic switches" capable of modifying neuronal function and intestinal physiology, providing promising new targets for therapeutic development (5+ potential targets).

Sources:

  • [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.
  • [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.
  • [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.
  • [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.

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