A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis

Abstract The gastroesophageal junction (GEJ) is continuously exposed to refluxed bile acids and microbial perturbations, yet how these environmental cues are converted into persistent oncogenic signaling is unknown. Here we show that bile acid remodeling enriches the oral commensal Prevotella melaninogenica at the GEJ, where bacterial succinate activates both vagal sensory neurons and SUCNR1-expressing tuft cells. Activated tuft cells release 15-deoxy-Δ12,14-prostaglandin J2(15-d-PGJ2), which sensitizes sensory neurons and sustains nerve remodeling, while neuronal CGRP drives expansion and tuft-cell differentiation of neuro-responsive epithelial progenitors through RAMP1. This self-reinforcing microbiota–neuron– epithelium circuit promotes dysplastic progression, and its disruption—genetic or pharmacological, including with the approved CGRP antagonist rimegepant—suppresses tumor development, revealing an interceptable mechanism linking environmental dysbiosis to cancer initiation through neural circuits. One-sentence summary Bile acids enrich an oral bacterium that initiates a nerve–epithelium circuit driving gastroesophageal junction cancer.