A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis
Year: 2026
Type: preprint
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.
Authors: Yi Zeng, Zaisheng Ye, Feijing Wu, Puran Zhang, Hiroki Kobayashi, Junya Arai, Xiaofei Zhi, Martin Borgmann, Jin Qian, Shuang Li, Biyun Zheng, Hualong Zheng, Ruhong Tu, Juli Lin, Masahiro Hata, Yosuke Ochiai, Quin T. Waterbury, Nagendra Harry, Leah B. Zamechek, Kara L. Vasilew, Michael Quante, Julian A. Abrams, James G. Fox, Timothy C. Wang
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, Wilhelm Sander-Stiftung, DeGregorio Family Foundation, Deutsche Forschungsgemeinschaft, Southwest University, Tianjin Medical University, National Institutes of Health, Mega-projects of Science Research for the 10th Five-Year Plan, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W7221872845