Home Moral guidelines Intestinal gluconeogenesis is downregulated in pediatric patients with celiac disease | BMC Medicine

Intestinal gluconeogenesis is downregulated in pediatric patients with celiac disease | BMC Medicine

0

The present study shows that children with untreated CD have lower expression of genes involved in IGN in duodenal biopsies compared to children with normal intestinal mucosa. Decreased expression correlates with higher Marsh score and, to a lesser extent, tTG antibody levels. These results suggest that CD patients may have impaired IGN function, either due to chronic intestinal inflammation in untreated disease or due to an altered metabolic pathway shared with other metabolic diseases. chronicles suggested by the large number of traits associated with the GLS/STAT1/STAT4 region of the gene. From a long-term perspective, lower expression of these genes, which are central for IGN and therefore important for metabolic homeostasis, may lead to other chronic diseases like NAFLD and diabetes if not addressed. recognized.

This study provides the first evidence for the downregulation of gut expression of G6PC, GPT1, SLC6A19and PPARGC1A on CD. Glucose-6-phosphatase, the protein product of G6PC, plays an essential role in gluconeogenesis by converting glucose-6-phosphate, which cannot be transported out of the cell, into glucose, which can then be released into the bloodstream, making its downregulation a particularly important discovery. Decreased expression of PCK1, FBP1and solute carriers have previously been shown in adult patients with CD, but have so far not been placed in the context of IGN [19,20,21]. Decreased expression of GLS is consistent with our previous finding of its downregulation in the GENEX material [1]. G6PC3 and GOT1 showed no significant change in expression; however, G6PC and GPT1which catalyze the same reactions in IGN, are more critical for these respective functions [22, 23].

These data therefore imply that the ability of the small intestine to perform gluconeogenesis and release glucose from the intestinal enterocyte might be severely diminished in patients with untreated CD. Decreased expression of GLS, GPT1, PCK1, FBP1and G6PC suggest an alteration of the IGN pathway from the onset of glutamine utilization in gluconeogenesis to the release of glucose into the blood. If only GLS, GPT1and PCK1 were down-regulated, using glycerol, the second most important substrate in IGN [5] might still be possible since it enters gluconeogenesis in later stages, but since FBP1 and G6PC, whose protein products catalyze the crucial final steps of gluconeogenesis, are also downregulated, it stands to reason that the entire IGN pathway is impaired. We propose that the diminished expression of PPARGC1A could provide an explanation for this at the regulatory level since its protein has a key role in the regulation of hepatic gluconeogenesis. While it’s unclear if it has a similar role in the gut, it doesn’t seem entirely implausible. Decreased expression of SLC6A19 suggests that the ability to absorb glutamine, as well as other neutral amino acids transported by the protein SLC6A19 (also known as B0AT1), from the intestinal lumen is impaired. Lower expression of SLC5A1 (SGLT1) and SLC2A2 (GLUT2) indicate a decrease in glucose transport capacity.

The metabolic effects of altered IGN in humans are not entirely clear. Studies of IGN in animal models show that increased portal vein glucose provides signals that increase satiety and improve energy homeostasis. Induced high levels of IGN appear to offer protection against metabolic diseases, while the alteration leads to signs of dysregulated blood sugar control and fatty liver disease. [7, 10].

Patients with CD are at increased risk for NAFLD, with the highest risk seen in the first few years after diagnosis and the greatest increase in relative risk seen in patients with a normal BMI [24, 25]. We speculate that impaired IGN might provide an explanation for the increased risk of NAFLD in CD patients. Our study does not examine whether the expression of IGN-related genes returns to normal in CD patients treated with a gluten-free diet, but the correlation with Marsh scores suggests that a degree of inflammation lower could improve IGN. If IGN is normalized when CD is treated, this could perhaps partly explain why the risk of NAFLD is greatest during the first year after diagnosis of CD, when the gluconeogenic capacity of the gut may not have fully recovered. Such recovery might also be suggested by a 1968 study of glutaminase enzyme activity, which found lower levels in untreated CD patients who appeared to recover in patients under treatment with a gluten-free diet. [26]. Studying the expression of IGN-related genes in patients before and after treatment would be an important next step.

This study has several limitations. The expression of selected genes in CD cases was compared to disease controls, i.e., they were children referred for upper endoscopy studied for other bowel diseases affecting the ‘intestine. It cannot be excluded that disease controls may have had conditions that may affect the expression of selected genes. However, all disease controls had normal mucosal signs, and children with inflammatory bowel disease and Helicobacter pylori infections were excluded prior to analysis. Another limitation was that the cases and controls were not age and sex matched. Yet, after adjusting for age and gender, the results remained significant. The strength of the study is that the children were recruited from four sites by pediatric gastroenterologists with extensive clinical experience in the diagnosis and treatment of children with CD. Enrollment of study participants took place in or before 2012, for example, when intestinal biopsy was the gold standard for diagnosing CD, meaning that children with very high levels of IgA-tTG were also included in the cohort. Additionally, we had previously had all intestinal biopsies reviewed and histologically scored by a single pathologist blinded to clinical and serological data prior to analysis to reduce observational bias and the potential risk of mismatching classification of cases and controls between the sites.

The results of this study raise several questions. It is unclear whether downregulation of target genes is specific to CD or related to gut inflammation in general. The association between the region of the gene containing GLS and other autoimmune traits, many of which show an increased risk of metabolic disease, could suggest that downregulation of IGN may also be present in other inflammatory diseases. Thus, further studies of IGN in other diseases are warranted. Additionally, the study does not answer whether altered IGN is involved in the risk of developing the disease or whether it is a response to other disease-initiation mechanisms in CD. Furthermore, we did not explore whether changes in the microbiota could have an effect on gene expression or whether IGN expression is affected by body mass index and glucose levels. Moreover, while there is a significant correlation between the decrease in the expression of IGN genes and the degree of mucosal involvement, the study does not answer whether treatment with a gluten-free diet leading to wound healing of the intestinal mucosa restores the expression of genes involved in IGN. Furthermore, it might be interesting to explore whether these genes are negatively regulated in other diseases of the intestinal mucosa such as immunodeficiency disorders or autoimmune enteropathy.