成纤维细胞生长因子 19 在法尼醇 X 受体存在的情况下调节肠道微生物群和炎症。

Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor.

机构信息

Department of Interdisciplinary Medicine, "Aldo Moro" University, Piazza Giulio Cesare 11, 70124 Bari, Italy; National Institute for Biostructures and Biosystems, Via delle Medaglie d'Oro 135, 00136 Rome, Italy.

Department of Interdisciplinary Medicine, "Aldo Moro" University, Piazza Giulio Cesare 11, 70124 Bari, Italy.

出版信息

EBioMedicine. 2020 Apr;54:102719. doi: 10.1016/j.ebiom.2020.102719. Epub 2020 Apr 5.

DOI:10.1016/j.ebiom.2020.102719

PMID:32259714

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7136604/

Abstract

BACKGROUND

Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation.

METHODS

A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXR mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis.

FINDINGS

FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR) mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease.

INTERPRETATION

Reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis.

FUNDING

A. Moschetta is funded by MIUR-PRIN 2017 <- 2017J3E2W2; Italian Association for Cancer Research (AIRC, IG 23239); Interreg V-A Greece-Italy 2014-2020-SILVER WELLBEING, MIS5003627; HDHL-INTIMIC EuJPI-FATMAL; MIUR PON "R&I" 2014-2020-ARS01_01220. No money has been paid by NGM Biopharmaceuticals or any other agency to write this article.

摘要

背景

胆汁酸（BA）稳态的破坏在肠道炎症中起着关键作用。肠道-肝脏轴是通过核法尼醇 X 受体（FXR）和肠源细胞因子成纤维细胞生长因子 19（FGF19）的联合作用调节 BA 合成和 BA 库大小的主要部位。越来越多的证据表明，BA 代谢的紊乱与微生态失调和粘膜炎症有关。因此，在这里，我们旨在研究 FGF19 类似物对肠道微生物群和炎症的潜在作用。

方法

生成了 FGF19 蛋白的新型工程非致瘤变异体 M52-WO 2016/0168219。WT 和 FXR 小鼠注射 AAV-FGF19-M52 或对照 AAV-GFP，并接受硫酸钠诱导的结肠炎。

结果

FGF19-M52 降低了 BA 的合成和库大小，调节了其组成，并保护了小鼠免受肠道炎症的影响。这些事件伴随着肠上皮屏障完整性的保存、炎症免疫反应的抑制和微生物群组成的调节。有趣的是，FXR 小鼠中完全消除了 FGF19-M52 驱动的全身和局部抗炎活性，因此强调了 FXR 保证肠细胞活力并补充 FGF19 抗炎活性的必要性。为了提供一个转化的视角，我们还表明，克罗恩病患者的循环 FGF19 水平降低。

解释

在肠道炎症的小鼠模型中，FXR-FGF19 轴的再激活可以真正提供 BA 代谢的积极变化，从而减少肠道炎症和调节微生物群。这些结果表明 FGF19 在治疗肠道炎症伴 BA 稳态失调方面具有治疗潜力。

资金

A. Moschetta 由 MIUR-PRIN 2017-2017J3E2W2 资助；意大利癌症研究协会（AIRC，IG 23239）；希腊-意大利 2014-2020 年 Interreg V-A 银健康；MIS5003627；HDHL-INTIMIC EuJPI-FATMAL；MIUR PON“R&I”2014-2020-ARS01_01220。NGM Biopharmaceuticals 或任何其他机构都没有支付资金来撰写本文。