Identification of Pappalysin-2 (PAPP-A2), a modulator of Insulin-like Growth Factor-1 pathway, as a potential marker of teduglutide efficacy in patients with short bowel syndrome.

Background: Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is indicated to treat short bowel syndrome (SBS) since 2015. It has been shown to reduce parenteral support (PS) in SBS patients, although patients' response is quite heterogeneous. The exact mechanisms of action of GLP-2 on intestinal cells are still poorly understood. The aim of this study was to explore the intestinal action of teduglutide to identify molecular mechanisms underlying response heterogeneity.

Methods: A retrospective study was conducted in 39 SBS patients treated with teduglutide for at least 6 months. Intestinal biopsy specimens collected before and after treatment initiation were selected and analyzed by RNA sequencing to identify genes differentially expressed and pathways regulated following teduglutide treatment.

Results: Of the 39 patients included in the study, 29 (74%) had a colon in continuity. The overall response to teduglutide was a reduction by 75% (interquartile range: 42-100) in PS volume. Among the genes differentially expressed in the small bowel during teduglutide treatment, the most significantly upregulated gene was PAPPA2 (q-value < 0.0001), encoding the metalloproteinase Pappalysin-2 (PAPPA-2) involved in Insulin-like Growth Factor (IGF) bioavailability. The best responders to teduglutide showed a lower PAPPA2 expression at baseline (p < 0.01). PAPPA2 expression at baseline also correlated positively with the percentage of remnant colon (p < 0.001).

Conclusion: We identified a new stakeholder, PAPPA-2, known to modulate IGF bioavailability, as playing a possible role in GLP-2 mechanism of action in human with SBS. We showed by association the existence of a greater spontaneous intestinal adaptation in SBS patients with a colon in continuity that could reduce sensitivity to teduglutide. Additionally, we suggest that initial PAPPA2 expression could serve as a predictive biomarker for teduglutide efficacy.