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Updated: Apr 5, 2026
Diagnosis of Hirschsprung's Disease by Immunostaining Rectal Suction Biopsies for Calretinin, S100 Protein and Protein Gene Product 9.5
Published on: April 26, 2019
Gordonibacter-associated regulatory T cell dysfunction and S100A11-mediated neural impairment in Hirschsprung's
Ting Yao1, Meili Fan1, Zenghui Hao1
1Department of Pediatric Surgery, The Sixth Affiliated Hospital of Harbin Medical University, Aiying Street 998, Songbei District, Harbin, 150028, Heilongjiang, People's Republic of China.
Background:
Hirschsprung's disease (HSCR) is a congenital disorder characterized by intestinal aganglionosis. Despite evidence linking gut microbiota and immune cells to various gastrointestinal diseases, their role in HSCR pathogenesis remains poorly understood. We investigated associations between gut microbiota composition, immune cell phenotypes, and neural impairment in HSCR patients.
Results:
Mendelian randomization analysis identified associations between Gordonibacter species and elevated HSCR risk (OR = 2.74, 95% CI 1.42-5.28), potentially mediated through CD28⁺CD39⁺ regulatory T cells. Multi-omics profiling revealed notable S100A11 upregulation in HSCR tissues. CD28⁺CD39⁺ Tregs from HSCR patients exhibited functional alterations, including reduced suppressive capacity alongside elevated S100A11 production. Both CD4⁺ T cells and CD68⁺ macrophages expressed S100A11 by immunohistochemistry. S100A11 treatment activated RAGE-NF-κB signaling in vitro, accompanied by suppression of neural developmental markers (SOX10, RET, PHOX2B) and impaired neuronal migration. Serum S100A11 showed diagnostic potential (AUC = 0.947). Microbiome profiling demonstrated differential bacterial enrichment, while antibiotic depletion experiments indicated microbiota-dependent modulation of immune-neural interactions.
Conclusion:
Our findings link gut microbiota alterations, immune dysregulation, and neural developmental impairment in HSCR, implicating S100A11-RAGE-NF-κB signaling as a pathway deserving mechanistic investigation.
