Ruth Park

Background: Crohn’s disease (CD) is a type of an inflammatory bowel disease (IBD) commonly affecting the terminal ileum and colon.¹ A key feature of ileal CD is a dysfunction in Paneth Cells (PC) which are intestinal epithelial cells at the base of the small intestinal crypts that secrete antimicrobial proteins and peptides (AMP).^2,3 Patients with ileal CD show reduced PC numbers and decreased AMP production.³ Mitochondrial activity in Lgr5+ intestinal stem cells (ISCs) determines intestinal epithelial cell differentiation.^1,3 Emerging evidence suggests that mitochondrial dysfunction in ISCs underlies abnormal PC differentiation, representing the primary epithelial defect in ileal CD.^4,5 Therapeutic approaches include corticosteroids for remission and immunomodulators like Azathioprine (AZA) for maintenance.¹ Recent studies demonstrate that AZA also acts directly on the intestinal epithelium by causing a metabolic shift from glycolysis to oxidative phosphorylation that is associated with stem cell differentiation into Paneth Cells, suggesting therapeutic potential beyond immune modulation.³

Objective: This review explores the mechanistic role of mitochondrial dysfunction in PC differentiation and ileal CD pathogenesis and examines mitochondrial-targeted therapies for restoring normal PC function.

Methods: PubMed and Google Scholars were searched for publications from 2018-2026 using keywords such as “Crohn’s disease”, “Crohn’s disease AND Paneth cells”, “Crohn’s disease AND Paneth cells AND azathioprine”, “Crohn’s disease AND mitochondrial dysfunction.”

Results: The Foxo/Notch/Mitochondrial fission axis has been identified as a key regulator in determining ISC differentiation; inhibition of both Foxo transcription factor pathway and Notch signaling triggered mitochondrial fission, driving PC differentiation.⁶ Inflammation-induced mitochondrial dysfunction in ISC produced abnormal PC with loss of normal AMP secretion.⁴ Deletion of Prohibitin 1 (PHB1), an inner mitochondrial membrane protein, exclusively in PC was sufficient to induce spontaneous ileal inflammation. Mitochondrial-targeted antioxidant, Mito-Tempo, restored normal PC functions and reversed mitochondrial dysfunction effects triggering ileitis, potentially by reducing excessive mitochondrial reactive intermediates that interfere with normal PC differentiation.⁵ CD patient biopsies treated ex vivo with Mito-Tempo also restored functions such as CD-associated interleukin (IL)-17/IL-23 signaling to comparable levels of non-IBD controls.⁷ AZA-treatment of ileal biopsies increased PC marker expression and decreased cell proliferation. In 3D-small intestinal organoids, Atp8-mutant strains demonstrated increase in size, enhanced glycolysis, and decrease in PC marker expressions. With AZA, PC functions were restored in 3D-organoids with impaired mitochondrial OXPHOS function.³

Conclusions: Studies have found that ileal Crohn’s disease originates from an intrinsic epithelial defect in mitochondrial metabolism that impairs PC differentiation. Mitochondrial targeted interventions, particularly Mito-Tempo and AZA, provide therapeutic potential by reversing the metabolic defect and restoring the function of Paneth cells in both murine models and human tissues.^3,7 The mechanism of action of AZA is redefined with its action beyond immunosuppression. With a better understanding of the importance of mitochondrial metabolism in intestinal epithelial homeostasis, these findings suggest that more targeted therapy will be available for ileal CD patients. Future research should aim to investigate whether AZA’s ability to restore PC function extends to broader changes in gut microbiome and lipid metabolism.³

Works Cited

1. Dolinger M, Torres J, Vermeire S. Crohn’s disease. The Lancet. 2024;403(10432):1177-1191. doi:10.1016/S0140-6736(23)02586-2
2. Yang E, Shen J. The roles and functions of Paneth cells in Crohn’s disease: A critical review. Cell Prolif. 2020;54(1):e12958. doi:10.1111/cpr.12958
3. Ragab M, Schlichting H, Hicken M, et al. Azathioprine promotes intestinal epithelial cell differentiation into Paneth cells and alleviates ileal Crohn’s disease severity. Accessed February 3, 2026. https://doi.org/10.1038/s41598-024-63730-4
4. Khaloian S, Rath E, Hammoudi N, et al. Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence. Gut. 2020;69(11):1939-1951. doi:10.1136/gutjnl-2019-319514
5. Jackson DN, Panopoulos M, Neumann WL, et al. Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis. Gut. 2020;69(11):1928-1938. doi:10.1136/gutjnl-2019-319523
6. Ludikhuize MC, Meerlo M, Gallego MP, et al. Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis. Cell Metab. 2020;32(5):889-900.e7. doi:10.1016/j.cmet.2020.10.005
7. Alula KM, Jackson DN, Smith AD, et al. Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease. Cells. 2021;10(6):1349. doi:10.3390/cells10061349