Neuro-epithelial circuits promote sensory convergence and intestinal immunity
Article meta
Article Date: 07 January 2026
Article URL: https://www.nature.com/articles/s41586-025-09921-z
Article Title: Neuro-epithelial circuits promote sensory convergence and intestinal immunity
Article Image: (not provided)
Summary
This Nature paper describes how gut-innervating TRPV1+ nociceptor sensory neurons influence intestinal epithelial cell programmes and local type 2 immunity. Activation of these nociceptors releases the neuropeptide CGRP, which acts on epithelial cells — notably progenitors and tuft cells via the CGRP receptor complex (CALCRL/RAMP1) — to drive differentiation, tuft cell activation and a Tuft-2 effector programme (leukotrienes, prostaglandins, alarmins). These epithelial changes amplify ILC2 and Th2 responses and promote goblet cell/mucus responses and helminth expulsion. The work uses chemogenetics, neuron ablation, spatial transcriptomics (Xenium), scRNA-seq and organoid assays to map the neuro-epithelial-immune circuit and demonstrate CGRP-dependent control of tuft cell homeostasis and anti-helminth immunity.
Key Points
- TRPV1+ nociceptors in the gut release CGRP on activation and are necessary for normal tuft cell numbers and type 2 responses.
- Neuronal CGRP signals through epithelial CALCRL/RAMP1 to drive progenitor differentiation and tuft cell activation (Tuft-2 gene programme).
- Activated tuft cells produce mediators (cysteinyl leukotrienes, prostaglandins, alarmins, acetylcholine in related work) that expand/activate ILC2s and Th2 cells.
- Neuro-epithelial-immune convergence enhances goblet cell mucus, epithelial turnover and smooth muscle responses that aid nematode expulsion.
- Findings are supported by chemogenetic activation/inhibition, RTX ablation, scRNA-seq, spatial transcriptomics and organoid assays, plus helminth infection models.
Content summary
The authors show that silencing or ablating TRPV1+ nociceptors reduces tuft cell abundance and impairs type 2 immunity to helminths, while acute nociceptor activation increases tuft cell numbers and boosts ILC2/Th2 responses. Spatial transcriptomics and single-cell RNA sequencing reveal epithelial compartment changes after nociceptor activation, including upregulation of tuft cell effector genes and altered progenitor programmes. Pharmacological and genetic approaches identify CGRP and its receptor components on epithelial cells as key mediators. Organoid experiments indicate CGRP cooperates with type 2 cytokines to regulate tuft cell markers. Overall, the data support a model in which sensory neurons directly instruct epithelial fate and function to shape mucosal immunity.
Context and relevance
This study sits at the intersection of neurobiology and mucosal immunology, adding mechanistic insight into how sensory neurons shape barrier immunity. It links neuronal sensory signalling (TRPV1, CGRP) to epithelial cell fate decisions and downstream type 2 immune circuits that are critical for defence against helminths and for barrier homeostasis. The work complements and extends prior findings on tuft cells, ILC2s and neuro-immune crosstalk, and highlights potential therapeutic nodes (CGRP signalling, epithelial receptors) relevant to infections, allergic inflammation and barrier disorders such as IBD.
Why should I read this
Quick and to the point: if you care about how the nervous system talks to the gut and why that matters for immunity and parasite clearance, this paper is gold. It shows neurons aren’t just sensing — they actively reprogramme epithelial cells to beef up type 2 defence. Saves you hours of digging through scattered studies by pulling genetics, spatial profiling and functional models into one clear circuit.
Author note
Punchy take: this is a well-controlled, multi-modal study that convincingly positions CGRP-releasing nociceptors as upstream regulators of epithelial and type 2 immune programmes. If you work on barrier immunity, neuro-immune signalling or epithelial cell biology, read the figures — they matter.