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

IF 6.6 2区医学 Q1 NUTRITION & DIETETICS

Clinical nutrition Pub Date : 2025-05-14 DOI:10.1016/j.clnu.2025.05.006

Brune de Dreuille , Rémy Nicolle , Jérôme Cros , Dominique Cazals-Hatem , Anaïs Chassac , Nicolas Poté , Johanne Le Beyec-Le Bihan , André Bado , Maude Le Gall , Francisca Joly

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引用次数: 0

Abstract

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.

查看原文本刊更多论文

胰岛素样生长因子-1通路调节剂Pappalysin-2 （PAPP-A2）作为特杜葡肽在短肠综合征患者疗效的潜在标志物的鉴定

teduglutide是胰高血糖素样肽-2 （GLP-2）类似物，自2015年以来被用于治疗短肠综合征（SBS）。它已被证明可以减少SBS患者的肠外支持（PS），尽管患者的反应是相当不均匀的。GLP-2作用于肠细胞的确切机制尚不清楚。本研究的目的是探讨特杜葡肽的肠道作用，以确定反应异质性的分子机制。方法对39例接受特杜葡肽治疗6个月以上的SBS患者进行回顾性研究。选择治疗开始前后收集的肠道活检标本，通过RNA测序进行分析，以确定特杜葡肽治疗后差异表达的基因和调节的途径。结果在纳入研究的39例患者中，29例（74%）具有连续性结肠。对teduglutide的总体反应是PS体积减少75%（四分位数范围：42-100）。在teduglutide治疗期间小肠差异表达的基因中，上调幅度最大的基因是PAPPA2 (q-value <；0.0001)，编码参与胰岛素样生长因子（IGF）生物利用度的金属蛋白酶Pappalysin-2 （PAPPA-2）。对特杜葡肽反应最好的患者在基线时PAPPA2表达较低(p <；0.01)。基线时的PAPPA2表达也与残结肠百分比呈正相关(p <；0.001)。结论我们发现了一个新的利益相关者，PAPPA-2，已知可以调节IGF的生物利用度，可能在GLP-2在SBS患者中的作用机制中发挥作用。我们通过关联表明，在结肠连续性的SBS患者中，存在更大的自发肠道适应，可以降低对特杜葡肽的敏感性。此外，我们建议初始PAPPA2表达可以作为teduglutide疗效的预测性生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical nutrition 医学-营养学

CiteScore

14.10

自引率

6.30%

发文量

356

审稿时长

28 days

期刊介绍： Clinical Nutrition, the official journal of ESPEN, The European Society for Clinical Nutrition and Metabolism, is an international journal providing essential scientific information on nutritional and metabolic care and the relationship between nutrition and disease both in the setting of basic science and clinical practice. Published bi-monthly, each issue combines original articles and reviews providing an invaluable reference for any specialist concerned with these fields.