Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life

Area of Science:

• Gastroenterology
• Immunology
• Epigenetics

Background:

• Early life adversity is a known risk factor for gastrointestinal diseases, including inflammatory bowel disease (IBD).
• Neonatal colonic inflammation may predispose individuals to heightened inflammatory responses later in life.

Purpose of the Study:

• To investigate the hypothesis that early life colonic inflammation leads to susceptibility to aggravated interleukin-1 beta (IL-1β) overexpression.
• To explore the underlying epigenetic mechanisms and the role of stress hormones in this heightened inflammatory response.

Main Methods:

• A two-hit rat model was established, inducing neonatal inflammation (NI) followed by adult inflammation (AI) using trinitrobenzene sulfonic acid.
• Analysis of immune responses, cytokine levels, histone modifications (H4K12 acetylation), transcription factor binding (NF-κB), and stress hormone levels.
• Intervention with propranolol (a β-blocker), adrenalectomy, and yohimbine to assess their effects on inflammation and IL-1β expression.

Main Results:

• Rats with NI + AI exhibited aggravated immune responses, including sustained IL-1β upregulation and increased histone H4K12 acetylation.
• Stress hormones (norepinephrine/epinephrine) correlated with increased NF-κB binding to the IL-1β promoter.
• Propranolol treatment significantly reduced inflammation and IL-1β overexpression by mitigating epigenetic changes.
• Adrenalectomy reduced susceptibility, while yohimbine increased it. Macrophages from NI rats showed hypersensitized IL-1β production.

Conclusions:

• Neonatal inflammation sensitizes the colon epithelium to exacerbated IL-1β activation via stress hormones and histone hyperacetylation.
• This epigenetic modification enhances nuclear factor-κB access to the IL-1β promoter, increasing susceptibility to severe immune responses.
• Beta-blockers demonstrate therapeutic potential for IBD susceptibility, suggesting a novel paradigm of NI-induced epigenetic vulnerability.