INTESTINAL GLUCONEOGENESIS IS DOWNREGULATED IN PAEDIATRIC PATIENTS WITH COELIAC DISEASE

ABSTRACT Objective Untreated coeliac disease (CD) patients have increased levels of blood glutamine and a lower duodenal expression of glutaminase (GLS). Intestinal gluconeogenesis (IGN) is a process through which glutamine is turned into glucose in the small intestine, for which GLS is crucial. Animal studies suggest impaired IGN may have long-term effects on metabolic control and be associated with development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to thoroughly investigate IGN at the gene expression level in children with untreated coeliac disease. Design Quantitative polymerase chain reaction (qPCR) was used to quantify expression of 11 target genes related to IGN using the delta-delta Ct method with three reference genes ( GUSB, IPO8 and YWHAZ ) in duodenal biopsies collected from 84 children with untreated coeliac disease and 58 disease controls. Results Significantly lower expression of nine target genes involved in IGN was seen in duodenal biopsies from CD patients compared with controls: FBP1, G6PC, GLS, GPT1, PCK1, PPARGC1A, SLC2A2, SLC5A1 , and SLC6A19 . No significant differences in expression were seen for G6PC3 and GOT1 . Conclusion Children with untreated coeliac disease have lower expression of genes important for IGN. Further studies are warranted to disentangle whether this is a consequence of intestinal inflammation or due to an impaired metabolic pathway shared with other chronic metabolic diseases. Impaired IGN could be a mechanism behind the increased risk of NAFLD seen in CD patients. SIGNIFICANCE OF THIS STUDY What is already known about this subject? Genome-wide association studies have shown an association between coeliac disease (CD) and glutaminase ( GLS) . Intestinal gluconeogenesis (IGN) is a process with a recently described important function in energy homeostasis and metabolic disease. GLS is critical for IGN by enabling it to use glutamine, its main substrate. CD patients are at an increased risk of non-alcoholic fatty liver disease (NAFLD) as adults. What are the new findings? Nine genes involved in IGN are downregulated at the gene expression level in the small intestine of children with untreated CD, suggesting impairment of IGN. How might it impact on clinical practice in the foreseeable future? Impaired IGN might be a mechanism behind the increased risk of NAFLD seen in CD patients as adults. Early diagnosis and treatment of CD may restore IGN and prevent CD patients from NAFLD later in adulthood.