Developmental origins of colon smooth muscle dysfunction in IBS-like rats.

Epidemiological studies show that subsets of adult and pediatric patients with irritable bowel syndrome (IBS) have prior exposures to psychological or inflammatory stress. We investigated the cellular mechanisms of colonic smooth muscle dysfunction in adult rats subjected to neonatal inflammation. Ten-day-old male rat pups received 2,4,6-trinitrobenzene sulfonic acid to induce colonic inflammation. Colonic circular smooth muscle strips were obtained 6 to 8 wk later. We found that about half of the neonate pups subjected to inflammatory insult showed a significant increase in expression of the pore-forming α1C-subunit of Cav1.2b channels in adult life. These were the same rats in whom Vip mRNA increased in the colon muscularis externae. Additional experiments showed reduced interaction of histone deacetylase (HDAC) 3 with α1C1b promoter that increased the acetylation of histone H3 lysine 9 (H3K9) in the core promoter region. Vasoactive intestinal peptide (VIP) treatment of naïve muscularis externae swiftly recruited CREB-binding protein (CBP) to the α1C1b promoter and dissociated HDAC3 from this region to initiate transcription. The CBP interaction with the α1C1b promoter was transient, but the dissociation of HDAC3 persisted to sustain H3K9 hyperacetylation and increase in transcription. Intraperitoneal treatment of adult naïve rats with butyrate mimicked the effects of neonatal colon inflammation. We concluded that neonatal inflammation upregulates VIP in the colon muscularis externae, which modulates epigenetic events at the α1C1b promoter to activate α1C1b gene transcription. Inflammatory insult in early life may be one of the etiologies of smooth muscle dysfunction in adult life, which contributes to the altered motility function in patients with diarrhea-predominant IBS.
AuthorsQingjie Li, John H Winston, Sushil K Sarna
JournalAmerican journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 305 Issue 7 Pg. G503-12 (Oct 1 2013) ISSN: 1522-1547 [Electronic] United States
PMID23886858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Cacna1c protein, rat
  • Calcium Channels, L-Type
  • Crebbp protein, rat
  • L-type calcium channel alpha(1C)
  • Vasoactive Intestinal Peptide
  • CREB-Binding Protein
  • Histone Deacetylases
  • histone deacetylase 3
  • Animals
  • Animals, Newborn
  • CREB-Binding Protein (genetics, metabolism)
  • Calcium Channels, L-Type (genetics, metabolism)
  • Colon (pathology)
  • Gene Expression Regulation (physiology)
  • Histone Deacetylases (genetics, metabolism)
  • Inflammatory Bowel Diseases (chemically induced, pathology)
  • Male
  • Muscle, Smooth (metabolism, pathology)
  • Promoter Regions, Genetic
  • Rats
  • Rats, Sprague-Dawley
  • Vasoactive Intestinal Peptide (genetics, metabolism)

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