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  • Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence

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Inflammatory bowel disease
Original research
Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence
  1. Sevana Khaloian1,
  2. Eva Rath1,
  3. Nassim Hammoudi2,
  4. Elisabeth Gleisinger1,
  5. Andreas Blutke3,
  6. Pieter Giesbertz4,
  7. Emanuel Berger1,
  8. Amira Metwaly1,
  9. Nadine Waldschmitt1,
  10. Matthieu Allez2,
  11. Dirk Haller1,5
  1. 1 Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
  2. 2 Department of Gastroenterology, Hôpital Saint-Louis, APHP, INSERM U1160, Université de Paris 1, Paris, Île-de-France, France
  3. 3 Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
  4. 4 Chair of Nutrition Physiology, Technische Universität München, Freising-Weihenstephan, Germany
  5. 5 ZIEL Institute for Food & Health, Technische Universität München, München, Germany
  1. Correspondence to Professor Dirk Haller, Chair of Nutrition and Immunology, Technische Universität München, München, Bayern 85350, Germany; dirk.haller{at}tum.de

Abstract

Objective Reduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn’s disease (CD). PCs reside in proximity to Lgr5+ intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance.

Design Ileal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60Δ/ΔISC) and CD-like ileitis (TNFΔARE), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function.

Results In patients with CD and TNFΔARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNFΔARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNFΔARE mice-derived crypts to form organoids.

Conclusion We provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.

  • inflammatory bowel disease
  • Crohn's disease
  • intestinal stem cell
  • energy metabolism
  • intestinal epithelium
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-319514

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    Footnotes

    • SK and ER contributed equally.

    • Contributors SK, ER and DH designed the experiments, performed data analysis and wrote the manuscript. SK, ER and EB performed mouse and organoid culture experiments. SK performed tissue analysis of patients. AB performed the transmission electron microscopy. EG, NW, AM and PG supported analyses. MA and NH provided patient samples.

    • Funding DH received funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB 1371 (Projektnummer 395357507; P01) and Priority Programme SPP 1656. DH and MA received funding from the Helmsley Cheritable Trust (IBDOT).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Additional data are available on request.

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