犬尿氨酸途径中的新陈代谢限制推动了 IBD 的粘膜炎症

Lina Welz, Danielle Harris, Na-Mi Kim, Abrar Alsaadi, Qcong Wu, Mhmd Oumari, Jan Taubenheim, Valery Volk, Graziella Credido, Eric Koncina, Pranab Mukherjee, Florian Tran, Laura Katharina Sievers, Polychronis Pavlidis, Nicholas Powell, Florian Rieder, Elisabeth Letellier, Silvio Waschina, Christoph Kaleta, Friedrich Feuerhake, Bram Verstockt, Melanie McReynolds, Philip Rosenstiel, Stefan Schreiber, Konrad Aden
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引用次数: 0

摘要

炎症性肠病(IBD)与必需氨基酸色氨酸(Trp)的代谢紊乱有关。Trp降解的增加是直接加剧了粘膜炎症,还是作为一种补偿性尝试,通过去神经烟酰胺腺嘌呤二核苷酸(NAD+)合成来恢复细胞能量水平,目前尚不清楚。通过对纵向 IBD 治疗干预队列和临床前 IBD 模型中的靶向筛选采用系统医学方法,我们发现治疗成功后 Trp 水平的稳定增加与犬尿氨酸途径 (KP) 中代谢过程的重构相吻合。详细而言,我们发现 IBD 中 Trp 的分解代谢在喹啉磷酸基转移酶(QPRT)水平上受到代谢限制,导致喹啉酸(Quin)的积累和 NAD+ 的增加。我们进一步证明,Trp沿着KP降解发生在发炎的肠粘膜局部,并严重依赖于janus激酶/信号转导和激活转录(JAK/STAT)信号。随后,QPRT 的敲除会引起 NAD+ 的耗竭和促炎症状态,而通过其他 NAD+ 前体绕过 QPRT 则可以在很大程度上挽救这种状态。因此,我们提出了一种 IBD 患者从 Trp 合成 NAD+ 的能力受损的模型。这些发现表明,补充 NAD+ 前体是治疗 IBD 的新途径。
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A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD
Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo nicotinamide adenine dinucleotide (NAD+) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail, we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a decrease of NAD+. We further demonstrate that Trp degradation along the KP occurs locally in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT invitro induces NAD+ depletion and a pro-inflammatory state, which can largely be rescued by bypassing QPRT via other NAD+ precursors. We hence propose a model of impaired de-novo NAD+ synthesis from Trp in IBD. These findings point towards the replenishment of NAD+ precursors as a novel therapeutic pathway in IBD.
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