58: GLP-2 modulated genes in adult patients with Short Bowel Syndrome (SBS) treated with Teduglutide (TED)

Introduction: TED, a GLP-2-analog, has proven efficacy reducing the need for Parenteral Nutrition (PN) in patients with SBS. However, there is some heterogeneity in the patients’ response to TED and the mechanisms of action of GLP-2 on intestinal cells are still poorly understood. The purpose of the study was to explore the mechanisms of response to treatment with TED. Methods: For this purpose, intestinal biopsies of 41 SBS patients treated with TED, collected before and after the treatment initiation, were selected and analyzed. The mRNAs were extracted from the biopsies and analyzed with RNA sequencing. Statistical analyses for differential expression of genes and pathways were performed using R software (DESeq2 and GSEA). A modification of gene expression was considered significant with abs (log2 Fold-Change) >1.5 and padj (p-value adjusted with False Discovery Rate method) <0.05. Response to TED is defined as the PN reduction reached, as a percentage of baseline volume. Results: Among the genes showing significant expression changes during treatment, this study focused on the two most significant upregulated genes in jejunum of treated patients, which are PAPPA2 (log2 Fold-change =2.4, padj=1.4e-13) and MMP1 (log2 Fold-change =3.4, padj=2.1e-05). These two genes encode for metallo-proteases (pappalysin-2 and matrix metalloproteinase-1) which are both responsible for the cleavage of Insulin-like Growth Factor Binding Proteins (IGFBPs), thus promoting Insulin-like Growth Factor (IGF) bioavailability, a known mediator of the trophic effect of GLP-2 on the intestinal mucosa. The signaling pathway of IGF transport and uptake is significantly enhanced after TED treatment (p-value=0.01), which confirms these observations. Furthermore, there was an inverse correlation between PAPPA2 expression in the jejunum before TED initiation and the response to treatment (r=-0.65, p=0.006). Indeed, patients with the better response to TED are those who present an important upregulation of PAPPA2 during treatment (p<0.0001), whereas there is no significant increase in this gene expression in those who respond the least (p=0.39). These results suggest that there could be an greater intestinal pre-adaptation in the poorer responders, potentially related to a higher level of endogenous GLP-2, leading to a lower sensitivity to TED treatment. This difference could be explained by the presence or the absence of colon, which is an important site of GLP-2 secretion. Conclusion: This study highlights in SBS patients the involvement of IGF-1 as a mediator in the response to treatment by GLP-2 analogs such as TED and identifies two new factors - PAPPA2 and MMP1 - involved in this response by their implication in modulating the IGF transport and uptake pathway. Moreover, this study suggests a possible explanation for the heterogeneity of response to TED treatment which may be related to pre-adaptation by endogenous GLP-2 leading to a poorer response to GLP-2 analogues.