Owe-Larsson Maja, Drobek Dominik, Iwaniak Paulina, Kloc Renata, Urbanska Ewa M, Chwil Mirosława
Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland.
Chair and Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland.
Molecules. 2025 Sep 5;30(17):3628. doi: 10.3390/molecules30173628.
In recent years, gut-brain axis signaling has been recognized as an essential factor modifying behavior, mood, cognition, and cellular viability under physiological and pathological conditions. Consequently, the intestinal microbiome has become a potential therapeutic target in neurological and psychiatric disorders. The microbiota-derived metabolite of tryptophan (Trp), indole-3-propionic acid (IPA), was discovered to target a number of molecular processes and to impact brain function. In this review, we outline the key mechanisms by which IPA may affect neuronal activity and survival and provide an update on the evidence supporting the neuroprotective action of the compound in various experimental paradigms. Accumulating data indicates that IPA is a free radical scavenger, a ligand of aryl hydrocarbon receptors (AhR) and pregnane X receptors (PXR), and an anti-inflammatory molecule. IPA decreases the synthesis of the proinflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and other cytokines, reduces the generation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and enhances the synthesis of neurotrophic factors. Furthermore, produced in the gut, or administered orally, IPA boosts the central levels of kynurenic acid (KYNA), a neuroprotective metabolite of Trp. IPA reduces the release of proinflammatory molecules in the gut, breaking the gut-inflammation-brain vicious cycle, which otherwise leads to neuronal loss. Moreover, as a molecule that easily enters central compartment, IPA may directly impact brain function and cellular survival. Overall, the gathered data confirms neuroprotective features of IPA, and supports its potential use in high-risk populations, in order to delay the onset and ameliorate the course of neurodegenerative disorders and cognitive impairment. Clinical trials evaluating IPA as a promising therapeutic add-on, able to slow down the progress of neurodegenerative disorders such as Alzheimer's or Parkinson's disease and to limit the morphological and behavioral consequences of ischemic stroke, are urgently needed.
近年来，肠-脑轴信号传导已被公认为是在生理和病理条件下改变行为、情绪、认知和细胞活力的重要因素。因此，肠道微生物群已成为神经和精神疾病的潜在治疗靶点。人们发现，微生物群衍生的色氨酸（Trp）代谢产物吲哚-3-丙酸（IPA）可作用于许多分子过程并影响脑功能。在本综述中，我们概述了IPA可能影响神经元活动和存活的关键机制，并更新了支持该化合物在各种实验范式中的神经保护作用的证据。越来越多的数据表明，IPA是一种自由基清除剂、芳烃受体（AhR）和孕烷X受体（PXR）的配体，也是一种抗炎分子。IPA可减少促炎的活化B细胞核因子κ轻链增强子（NF-κB）、肿瘤坏死因子-α（TNF-α）和其他细胞因子的合成，减少含NLR家族pyrin结构域3（NLRP3）炎性小体的生成，并增强神经营养因子的合成。此外，在肠道中产生或口服的IPA可提高犬尿氨酸（KYNA）的中枢水平，KYNA是Trp的一种神经保护代谢产物。IPA可减少肠道中促炎分子的释放，打破肠道-炎症-脑恶性循环，否则会导致神经元丢失。此外，作为一种容易进入中枢的分子，IPA可能直接影响脑功能和细胞存活。总体而言，收集到的数据证实了IPA的神经保护特性，并支持其在高危人群中的潜在应用，以延缓神经退行性疾病和认知障碍的发病并改善其病程。迫切需要进行临床试验，评估IPA作为一种有前景的治疗辅助药物，能够减缓阿尔茨海默病或帕金森病等神经退行性疾病的进展，并限制缺血性中风的形态和行为后果。
