Abstract
Background: A low-level inflammation has been hypothesized to mediate visceral hypersensitivity in functional bowel disorders that persist after or even in the absence of gut inflammation. We aimed to test the efficacy of a steroidal anti-inflammatory treatment, and identify local inflammatory molecules mediating post- and non-inflammatory colorectal hypersensitivity using two mouse models. Methods: Visceromotor responses to colorectal distension were quantified as a measure of colorectal sensitivity. On day 1, mice received intracolonic saline (control), trinitrobenzenesulfonic acid (postinflammatory on day 15), or acidified hypertonic saline (non-inflammatory). Colorectal sensitivity before (day 10) and after (day 15) 4-day dexamethasone (Dex) treatment was compared, and colonic gene expression of inflammatory molecules was quantified. Key Results: Dexamethasone effectively inhibited gene expression of inflammatory molecules such as interleukin (IL)-1β and mast cell protease-1 in the colon, but did not attenuate colorectal hypersensitivity in either model. Gene expression of inflammatory molecules in the colon did not differ between control and the non-inflammatory model, but the postinflammatory model showed increased IL-10 and tight junction protein 2, and decreased IL-6, transforming growth factor (TGF)-β, a precursor of β-endorphin, occludin, and mucin 2. While no common molecule explained colorectal hypersensitivity in these models, hypersensitivity was positively correlated with TGF-β2 mRNA in control, and with IL-1β, inhibin βA, and prostaglandin E2 synthase in the Dex-treated postinflammatory model. In the non-inflammatory model, cyclooxygenase-2 mRNA was negatively correlated with colorectal sensitivity. Conclusions & Inferences: These results suggest that persistent functional colorectal hypersensitivity is mediated by condition-specific mediators whose gene expression in the colon is not inevitably sensitive to steroidal anti-inflammatory treatment. This study demonstrates the presence of condition-specific, steroid-insensitive inflammatory molecules in the colon for mediating persistent visceral hypersensitivity in post- and non-inflammatory conditions, suggesting multiple pathogenic players depending on disease conditions, and questioning effectiveness of steroid treatments on sensory symptoms in quiescent IBD and IBS.
Original language | English (US) |
---|---|
Pages (from-to) | 1730-1742 |
Number of pages | 13 |
Journal | Neurogastroenterology and Motility |
Volume | 26 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2014 |
Externally published | Yes |
Keywords
- Colorectal hypersensitivity
- Cytokines
- Inflammation
- Inflammatory molecules
ASJC Scopus subject areas
- Physiology
- Endocrine and Autonomic Systems
- Gastroenterology