ABSTRACT
Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.
Subject(s)
Azathioprine , Cell Differentiation , Crohn Disease , Intestinal Mucosa , Paneth Cells , Crohn Disease/drug therapy , Crohn Disease/pathology , Crohn Disease/metabolism , Azathioprine/pharmacology , Paneth Cells/metabolism , Paneth Cells/drug effects , Paneth Cells/pathology , Humans , Cell Differentiation/drug effects , Animals , Mice , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Female , Male , Ileum/drug effects , Ileum/metabolism , Ileum/pathology , Adult , Organoids/drug effects , Organoids/metabolism , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , Cell Proliferation/drug effects , Middle Aged , Cell Line , Severity of Illness IndexABSTRACT
Background: Crohn's disease (CD) and ulcerative colitis (UC) are associated with reduced health-related quality of life (HRQoL), but findings differ between studies. The aim of this study was to analyse the impact of disease activity and social factors on HRQoL. Method: A total of 513 patients diagnosed with UC and CD between 2003 and 2004, in a population-based setting, were followed for 7 years. HRQoL was assessed using the Short Form-12, the Short Inflammatory Bowel Disease (IBD) Questionnaire (SIBDQ), the Work Productivity and Activity Impairment Questionnaire: General Health and a national health survey. Associations were assessed using multiple linear regressions. Results: A total of 185 of the eligible patients (UC: 107 (50.2%) and CD: 78 (50.3%)) were included. No differences in disease-specific or generic HRQoL were found between CD and UC patients, and IBD patients did not differ compared with the background population. The majority of CD (73.1%) and UC (85.0%) patients had 'good' disease-specific HRQoL using the SIBDQ. Unemployment for ≥ 3 months occurred more in CD vs UC patients(30.6 vs 15.5%, p = 0.03); however, sick leave for ≥ 3 months did not differ significantly (17.4 vs 11.4%, p = 0.4). Using multiple linear regressions, unemployment, sick leave and disease activity were the factors most frequently associated with reduced HRQoL. Conclusion: In a population-based cohort with 7 years of follow-up, HRQoL did not differ between patients and the background population.
