A coupled duodenal mast-cell–sensory-nerve mechanism with autonomic features: an n-of-1 post-exposure case report and hypothesis

Background. Functional dyspepsia (FD) has been reconceptualised from a gastric-motility disorder into a duodenal disorder of gut–brain interaction characterised by low-grade mucosal immune activation — increased eosinophils and mast cells, impaired barrier integrity, and mast-cell–sensory-nerve signalling. Separately, mast-cell-activation features and autonomic symptoms co-occur with FD more often than chance. We report a single patient whose illness instantiates this biology but departs from textbook FD. We do not claim a new mechanism; the contribution is an n-of-1 instantiation in a genotyped individual, with a named amplifier set, a painless nocturnal vagal-dominant phenotype, an acute single-exposure adult onset, and a falsifier tightened against the construct. Case. A 46-year-old man, with no prior gastrointestinal diagnosis and a clinical-grade (30×, CLIA/CAP-certified) whole genome, developed a multisystem, central-nervous-system-dominant illness within hours of ingesting roughly 71 mg of a capsule marketed as a lion's-mane (Hericium erinaceus) mushroom extract. The course was relapsing–remitting, food-reactive, without gastrointestinal pain, and most reliably relieved by fasting; symptoms clustered at sleep onset and overnight, spanning gastrointestinal, laryngeal, cardiac/autonomic and neurocognitive domains. A baseline serum tryptase drawn on day 73 resulted 5.1 ng/mL against a threshold pre-registered at < 8, excluding hereditary α-tryptasemia and banking a comparator (≥ 8.1 ng/mL) for a future within-flare draw. No mucosal histology has been obtained; a D1/D2 duodenal biopsy remains the single open objective anchor. Proposed mechanism. We frame the illness as a directed cascade with an ignition, a trunk and two branches. Ignition: the ingested species induces nerve growth factor, and NGF drives visceral sensitisation by remodelling the afferent terminal — raising TRPV1 expression rather than altering membrane voltage — so the activation threshold moves down and stays down. Trunk and branches: established duodenal micro-inflammation forms the trunk, with the eosinophil as the disease-modifying node; common susceptibility variants escalate it, recruiting a neurogenic mast-cell ↔ sensory-nerve branch (IgE-independent activation via the substance-P receptor MRGPRX2, with histamine lowering the afferent firing threshold) and a downstream vagal/autonomic branch supplying the multisystem reach and the absence of pain. Persistence is attributed to wind-up: substance P, the peptide that degranulates the mast cell peripherally at MRGPRX2, acts centrally at NK1 to strip the voltage-dependent magnesium block from the NMDA receptor, after which repetitive input progressively enhances current flow. Because wind-up requires repetition, the model predicts that reducing the frequency of visceral input should quieten the loop without any drug. Status. The construct is hypothesis-generating, of very low certainty (single unblinded, non-randomised patient). The event-related tryptase rise that objective MCAS criteria require has not been captured, so we describe features of mast-cell activation, not MCAS. Hereditary α-tryptasemia has been excluded by the pre-registered screen; a normal basal tryptase does not, however, argue for the construct. The falsifier has been tightened against the construct: a count-only histological read does not falsify it, and refutation requires counts plus a graded degranulation read. This version is published in advance of both outstanding measurements, and deliberately so: the contribution offered is a mechanistic framework with its refutation conditions fixed beforehand, not a body of evidence. We present testable predictions to motivate validation, not clinical action. This is version 2. Substantive changes from version 1: the falsifier tightened to require a graded degranulation read; hereditary α-tryptasemia tested and excluded; the postural-tachycardia label withdrawn while the autonomic arm is retained; an ignition mechanism added; wind-up added as the persistence mechanism, with an NMDA-directed prediction; the claim of a novel mechanism withdrawn; follow-up extended to day 103; a reported adverse episode reattributed from one agent to another, with the correction set out in full; and a new, deliberately separated section proposing histamine clearance as a candidate axis beyond this case. Version 1 remains available unaltered at https://doi.org/10.5281/zenodo.21519838.