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Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation
  1. Giuseppe Esposito1,
  2. Elena Capoccia1,
  3. Fabio Turco2,
  4. Ilaria Palumbo2,
  5. Jie Lu3,
  6. Antonio Steardo4,
  7. Rosario Cuomo2,
  8. Giovanni Sarnelli2,
  9. Luca Steardo1
  1. 1Department of Physiology and Pharmacology ‘Vittorio Erspamer’, La Sapienza University of Rome, Rome, Italy
  2. 2Department of Clinical Medicine and Surgery, ‘Federico II’ University of Naples, Naples, Italy
  3. 3Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  4. 4La Sapienza University of Rome, Rome, Italy
  1. Correspondence to Professor Giuseppe Esposito, Department of Physiology and Pharmacology ‘Vittorio Erspamer’, La Sapienza University of Rome; giuseppe.esposito{at}; Dr Giovanni Sarnelli, Department of Clinical Medicine and Surgery, ‘Federico II’ University of Naples, Naples, Italy; sarnelli{at}


Objective Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice.

Design Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs.

Results PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans.

Conclusions Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.


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