P007 GC1qR driven oxidative phosphorylation is essential for intestinal goblet cell differentiation

Abstract

Abstract Background Induction of goblet cell differentiation during inflammation has been shown to be impaired in ulcerative colitis (UC) but not Crohn’s disease (CD), possibly explaining the intestinal goblet cell and mucus reduction observed in active UC. A metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) is necessary for terminal differentiation of intestinal stem cells towards goblet cells. Interestingly, intestinal energy deficiency in general and reduced level of OXPHOS in specific have been attributed to UC pathogenesis more than 30 years ago. The c1q binding protein (C1QBP; gC1qR) is indispensable for the maintenance of OXPHOS. Nevertheless, experimental evidence linking mitochondrial dysfunction with goblet cell depletion and C1QBP expression are still missing. Methods Goblet cell differentiation was studied in human biopsies from UC patients in remission, in mucus-producing HT29MTX cells and in a conplastic mouse strain with diminished mitochondrial OXPHOS activity. Furthermore, mice were fed an experimental diet to shift cellular energy production from glycolysis to OXPHOS and mucosal cell differentiation was compared with mice on an isocaloric control diet. Results In vitro, siRNA experiments in HT29MTX cells showed that butyrate-induced expression of goblet cell differentiation factor KLF4 is highly dependent on gC1qR expression. Interestingly, the latter was significantly reduced in human ileal and colonic sections of UC patients in remission compared with HN. OXPHOS-deficient conplastic B6-mt FVB mice further confirmed these findings by depicting diminished klf4 expression, lowered goblet cell numbers, a thinned intestinal mucus layer and signs of intestinal inflammation. Finally, via nutritional intervention in C57BL/6 mice we were able to increase gC1qR level and to induce goblet cell differentiation via hath1 and klf4 compared with controls. Conclusion Taken together, we here describe a new pathway linking low intestinal expression of OXPHOS-regulating gC1qR to impaired goblet cell differentiation, mucus reduction and mucosal inflammation, which could be possibly reversed by nutritional intervention.