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-12,14-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 genetic or pharmacological disruption, including with the approved CGRP antagonist rimegepant, suppresses tumor development, revealing an interceptable mechanism linking environmental dysbiosis to cancer initiation through neural circuits.

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BibTeX RIS

BibTeX

@misc{zeng2026microbiotadriven,
  title = {{A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis}},
  author = {Y. Zeng and Z. Ye and F. Wu and P. Zhang and H. KOBAYASHI and J. Arai and X. Zhi and M. Borgmann and J. Qian and S. Li and B. Zheng and H. Zheng and R. Tu and J. Lin and M. Hata and Y. Ochiai and Q. Waterbury and N. Harry and L. Zamechek and K. Vasilew and M. Quante and J. Abrams and J. G. Fox and T. C. WANG},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.13.759004},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.13.759004v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis
AU  - Y. Zeng
AU  - Z. Ye
AU  - F. Wu
AU  - P. Zhang
AU  - H. KOBAYASHI
AU  - J. Arai
AU  - X. Zhi
AU  - M. Borgmann
AU  - J. Qian
AU  - S. Li
AU  - B. Zheng
AU  - H. Zheng
AU  - R. Tu
AU  - J. Lin
AU  - M. Hata
AU  - Y. Ochiai
AU  - Q. Waterbury
AU  - N. Harry
AU  - L. Zamechek
AU  - K. Vasilew
AU  - M. Quante
AU  - J. Abrams
AU  - J. G. Fox
AU  - T. C. WANG
PY  - 2026
DA  - 2026/10/13
PB  - bioRxiv
DO  - 10.64898/2026.10.13.759004
UR  - https://www.biorxiv.org/content/10.64898/2026.10.13.759004v1
AB  - 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-12,14-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 genetic or pharmacological disruption, including with the approved CGRP antagonist rimegepant, suppresses tumor development, revealing an interceptable mechanism linking environmental dysbiosis to cancer initiation through neural circuits.
ER  -

Abstract

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