Maladaptive sensory coding in the enteric nervous system playing a role in gastrointestinal disorders.

Maladaptive sensory coding within the enteric nervous system (ENS) is increasingly implicated in gastrointestinal dysmotility, abnormal secretion, neuroimmune dysfunction, and visceral hypersensitivity. Intrinsic primary afferent neurons (IPANs), classically corresponding to Dogiel type II/AH neurons, constitute a major sensory arm of intrinsic enteric reflex circuits. They detect mechanical, chemical, epithelial, microbial, and immune-derived signals and relay this information to interneurons, motor neurons, and secretomotor pathways, thereby coordinating gastrointestinal function independently of central input. Experimental studies demonstrate that IPAN excitability is highly plastic: inflammation, serotonergic signaling, cytokines, neurotrophins, microbial products, and other mediators can alter firing thresholds, slow afterhyperpolarization (sAHP), and synaptic transmission. Molecularly defined IPAN populations are sufficient to initiate specific motor programs, microbial colonization is required for normal AH-neuron excitability, and cytokine-responsive subsets participate directly in neuroimmune circuits. These findings support a model in which persistent increases or decreases in sensory gain may distort enteric reflex output and contribute to disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), chronic constipation, diarrhea, and visceral pain. However, evidence linking IPAN dysfunction directly to disease remains limited. Few studies have selectively manipulated IPANs in disease models, and definitive demonstrations of IPAN-specific dysfunction causing a gastrointestinal phenotype and its reversal by targeted rescue are lacking, particularly in humans. Major unresolved questions include whether maladaptive IPAN coding is a primary driver, amplifier, or consequence of disease; how intrinsic and extrinsic afferent pathways interact; and how microbial and immune signals reshape IPAN identity over time. Resolving these issues will be essential for establishing maladaptive enteric sensory coding as a therapeutic target.