Sympathetic Nervous System Overactivation Induces Colonic Eosinophil-Associated Microinflammation and Contributes to the Pathogenesis of Irritable Bowel Syndrome

  1. Shaoqi Duan
  2. Hirosato Kanda
  3. Feng Zhu
  4. Masamichi Okubo
  5. Taro Koike
  6. Yoshiya Ohno
  7. Toshiyuki Tanaka
  8. Yukiko Harima
  9. Kazunari Miyamichi
  10. Hirokazu Fukui
  11. Shinichiro Shinzaki
  12. Yilong Cui
  13. Koichi Noguchi
  14. Yi Dai
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Abstract

Objective

Mucosal microinflammation is a characteristic clinical manifestation of irritable bowel syndrome (IBS), and its symptoms are often triggered by psychological stress. In the present study, we aimed to investigate the impact of early life stress-associated dysfunction of the sympathetic nervous system (SNS) on mucosal immune changes in the gastrointestinal tract (GI) and its contribution to IBS pathogenesis.

Design

We utilised a traditional animal model of IBS with maternal separation (MS) and evaluated colorectal hypersensitivity, immune alterations, and SNS activity in adult rats with MS. We conducted a series of experiments to manipulate peripheral SNS activity pharmacologically and chemogenetically to explore the interaction between SNS activity and GI events.

Results

The MS-induced IBS model exhibited visceral hypersensitivity and eosinophilic infiltration in the colonic mucosa, along with SNS overactivation. Degeneration of the SNS using 6-OHDA neurotoxin decreased eosinophil infiltration and visceral hypersensitivity in the MS model. Notably, specific chemogenetic activation of the peripheral SNS induced eosinophil infiltration in the intestinal mucosa through the noradrenergic signalling-mediated release of eotaxin-1 from mesenchymal cells.

Conclusion

This study highlights the critical role of SNS overactivation in eotaxin-1-driven eosinophil infiltration in the colon, leading to the development of visceral hypersensitivity in IBS. The results provide important insights into the mechanistic links among increased sympathetic activity, mucosal microinflammation, and visceral hypersensitivity in individuals with IBS, suggesting potential therapeutic approaches.

What is already known on this topic

  • A subgroup of patients with irritable bowel syndrome (IBS) presents with microinflammation in the gastrointestinal tract (GI).

  • Early life stress is recognised as a major risk factor for the development of IBS in adulthood.

  • Overactivation of the sympathetic nervous system (SNS) is frequently associated with IBS.

What this study adds

  • Maternal separation (MS) stress induces eosinophil-associated microinflammation in the colonic mucosa of adult rats.

  • Inhibition of SNS activity suppresses eosinophil infiltration and mitigates visceral hypersensitivity in the MS model.

  • Noradrenergic signalling within the peripheral sympathetic activation stimulates mesenchymal cells to release eotaxin-1, leading to substantial eosinophil-predominant immune alterations in the colon.

How this study might affect research, practice, or policy

  • Treatment with fibroblast-derived eotaxin-1 and targeting eosinophil-associated microinflammation could be a potential strategy to alleviate visceral pain in patients with IBS.

  • The chemogenomic method specifically manipulates peripheral SNS and provides a valuable tool for future research.

Article activity feed

  1. Version published to 10.1101/2024.07.22.604223v1 on bioRxiv