Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease

Antonio Di Sabatino, Paolo Giuffrida, Alessandro Vanoli, Ombretta Luinetti, Rachele Manca, Paolo Biancheri, Gaetano Bergamaschi, Costanza Alvisi, Alessandra Pasini, Chiara Salvatore, Federico Biagi, Enrico Solcia, Gino Roberto Corazza

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


OBJECTIVES: Several immune-mediated gastrointestinal disorders, including celiac disease (CD), are associated with neuroendocrine cell hyperplasia. However, neuroendocrine cells have never been explored in refractory CD (RCD).

METHODS: Serial duodenal sections from 17 patients with RCD (6 type 1 and 11 type 2), 16 uncomplicated CD patients before and after gluten-free diet, 14 patients with potential CD, 27 patients with non-CD villous atrophy, i.e., common variable immunodeficiency (n=12), Whipple's disease (n=10) and giardiasis (n=5), and 16 healthy subjects were processed for the immunohistochemical detection of chromogranin A (CgA), serotonin, and somatostatin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative reverse transcription-PCR. Serum CgA and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) were assessed. Biopsies from treated CD patients were cultured with serotonin or peptic tryptic digest of gliadin (PT-gliadin), and interferon (IFN)-γ was detected by ELISA in culture supernatants.

RESULTS: Epithelial cells positive for CgA and serotonin, but not somatostatin, were significantly increased in RCD. Raised mucosal transcripts of TpH-1, but not SERT, were found in RCD. On biopsies from treated CD patients, serotonin upregulated IFN-γ production at levels comparable to those induced by PT-gliadin. Serum CgA, but not urine 5-HIAA, was increased in RCD. No significant difference was found between RCD type 1 and type 2 in terms of neuroendocrine cells, mucosal TpH-1 transcripts, and serum CgA.

CONCLUSIONS: Serotonin-producing neuroendocrine cells are increased in RCD mucosa. IFN-γ upregulation induced by serotonin suggests that this monoamine may have a role in sustaining the local inflammatory response in CD.

Original languageEnglish
Pages (from-to)258-269
Number of pages12
JournalThe American Journal of Gastroenterology
Issue number2
Early online date7 Jan 2014
Publication statusPublished - Feb 2014
Externally publishedYes


  • Adult
  • Aged
  • Biopsy, Needle
  • Case-Control Studies
  • Celiac Disease/pathology
  • Diet, Gluten-Free
  • Duodenoscopy/methods
  • Duodenum
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Immunohistochemistry
  • Interferon-gamma/metabolism
  • Intestinal Mucosa/metabolism
  • Male
  • Middle Aged
  • Neuroendocrine Cells/cytology
  • Prognosis
  • RNA, Messenger/metabolism
  • Real-Time Polymerase Chain Reaction
  • Reference Values
  • Retrospective Studies
  • Serotonin/metabolism
  • Somatostatin/metabolism
  • Statistics, Nonparametric
  • Treatment Failure
  • Up-Regulation

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