Elevated Poster Presentation International Celiac Disease Symposium 2026

Gluten-induced disruption of intestinal neuronal signalling affects the brain and is reversible by transglutaminase inhibition in coeliac disease (143432)

Aline Pesi 1 , Fabian Schmitt 1 , Valeriia Dotsenko 2 , Ralf Mohrbacher 3 , Markku Mäki 4 , Keijo Viiri 4 5 , Premysl Bercik 6 , Elena F. Verdu 6 , Thierry Schmidlin 1 , Detlef Schuppan 1 7
  1. University Medicine Mainz, Mainz, RHEINLAND-PFALZ, Germany
  2. Department of Virology, University of Helsinki, Helsinki, Finland
  3. Dr. Falk Pharma GmbH, Freiburg, Germany
  4. Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland
  5. Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
  6. Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
  7. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Background

Celiac disease (CeD) is associated with fatigue and neuropsychiatric symptoms, suggesting altered gut-brain communication. While inflammation-driven sickness behaviour has been linked to cytokines and tryptophan metabolism, the impact of intestinal inflammation on neuronal signalling programs remains unclear. We aimed to define inflammation-associated changes in intestinal neuronal gene programs and assess their reversibility under therapeutic intervention.

Methods

Gluten-induced inflammation was assessed in humanized NOD-DQ8 mice (n=8/group) and in duodenal biopsies from patients with CeD in remission (n=116) who participated in a randomised, placebo-controlled 6-week gluten challenge trial with or without the oral transglutaminase 2 (TG2) inhibitor ZED1227 (CEC-3 study; 1,2). Murine intestinal and cerebral transcripts were analysed by quantitative PCR and human biopsies by bulk RNA sequencing. Targeted LC-MS metabolomics was performed in murine faeces, jejunum and plasma.

Results

Gluten challenge in CeD mice induced a robust inflammatory response, with 2-6 fold increases in IL6, IL17A and IL23A transcripts. This was accompanied by activation of the kynurenine pathway, with increased kynurenine and reduced kynurenate levels across compartments (p≤0.01), indicating a consistent shift in tryptophan metabolism.

Bulk RNA sequencing revealed coordinated downregulation of intestinal neuronal receptor and neuroplasticity gene programs (log2FC −0.3 to −0.6, FDR<0.05), including NPTN, GABRE, PLAT and QPRT. These changes correlated with histological disease severity (Spearman ρ up to 0.47, p<10⁻⁶).

In the human duodenal samples, gluten challenge under placebo treatment resulted in marked suppression of neuronal signalling programs, whereas ZED1227 treatment preserved and restored these transcriptional signatures towards baseline. Murine data supported these findings, demonstrating inflammation-associated alterations in neurotransmitter-related pathways and behaviour.

Conclusion

Gluten-induced inflammation in CeD is associated with activation of tryptophan metabolism and suppression of intestinal neuronal signalling correlating with mucosal damage. TG2 inhibition identifies a reversible mucosal neuroplasticity axis and suggests a mechanistic link between intestinal inflammation and neuropsychiatric manifestations in celiac disease.

 

  1. Schuppan D, Mäki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, Popp A, Koskenpato J, Langhorst J, Hovde Ø, Lähdeaho ML, Fusco S, Schumann M, Török HP, Kupcinskas J, Zopf Y, Lohse AW, Scheinin M, Kull K, Biedermann L, Byrnes V, Stallmach A, Jahnsen J, Zeitz J, Mohrbacher R, Greinwald R; CEC-3 Trial Group. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021 Jul 1;385(1):35-45. doi: 10.1056/NEJMoa2032441. PMID: 34192430.
  2. Dotsenko V, Tewes B, Hils M, Pasternack R, Isola J, Taavela J, Popp A, Sarin J, Huhtala H, Hiltunen P, Zimmermann T, Mohrbacher R, Greinwald R, Lundin KEA, Schuppan D, Mäki M, Viiri K; CEC-3 Investigators. Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. Nat Immunol. 2024 Jul;25(7):1218-1230. doi: 10.1038/s41590-024-01867-0. Epub 2024 Jun 24. PMID: 38914866; PMCID: PMC11224021.