Tanaka Masaru, Vécsei László
Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged, Tisza Lajos krt. 113, H-6725 Szeged, Hungary.
Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary.
Biomedicines. 2025 Aug 19;13(8):2020. doi: 10.3390/biomedicines13082020.
The kynurenine (KYN) metabolic pathway sits at the crossroads of immunity, metabolism, and neurobiology, yet its clinical translation remains fragmented. Emerging spatial omics, wearable chronobiology, and synthetic microbiota studies reveal that tryptophan (Trp) metabolism is regulated by distinct cellular "checkpoints" along the gut-brain axis, finely modulated by sex differences, circadian rhythms, and microbiome composition. However, current interventions tackle single levers in isolation, leaving a key gap in the precision control of Trp's fate. To address this, we drew upon an extensive body of the primary literature and databases, mapping enzyme expression across tissues at single-cell resolution and linking these profiles to clinical trials investigating dual indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO) inhibitors, engineered probiotics, and chrono-modulated dosing strategies. We then developed decision-tree algorithms that rank therapeutic combinations against biomarker feedback loops derived from real-time saliva, plasma, and stool metabolomics. This synthesis pinpoints microglial and endothelial KYN hotspots, quantifies sex-specific chronotherapeutic windows, and identifies engineered Bifidobacterium consortia and dual inhibitors as synergistic nodes capable of reducing immunosuppressive KYN while preserving neuroprotective kynurenic acid. Here, we highlight a framework that couples lifestyle levers, bio-engineered microbes, and adaptive pharmaco-regimens into closed-loop "smart protocols." By charting these intersections, this study offers a roadmap for biomarker-guided, multidisciplinary interventions that could recalibrate KYN metabolic activity across cancer, mood, neurodegeneration, and metabolic disorders, appealing to clinicians, bioengineers, and systems biologists alike.
犬尿氨酸（KYN）代谢途径处于免疫、代谢和神经生物学的交叉点，但其临床转化仍然零散。新兴的空间组学、可穿戴生物钟学和合成微生物群研究表明，色氨酸（Trp）代谢受沿肠-脑轴不同细胞“检查点”的调节，并受到性别差异、昼夜节律和微生物群组成的精细调控。然而，目前的干预措施孤立地处理单个环节，在Trp命运的精确控制方面留下了关键差距。为了解决这一问题，我们借鉴了大量的原始文献和数据库，以单细胞分辨率绘制了各组织中的酶表达图谱，并将这些图谱与研究双吲哚胺2,3-双加氧酶1（IDO1）/色氨酸2,3-双加氧酶（TDO）抑制剂、工程益生菌和时辰调制给药策略的临床试验联系起来。然后，我们开发了决策树算法，根据来自实时唾液、血浆和粪便代谢组学的生物标志物反馈回路对治疗组合进行排名。这种综合确定了小胶质细胞和内皮细胞的KYN热点，量化了性别特异性时辰治疗窗口，并确定工程双歧杆菌联合体和双重抑制剂是能够减少免疫抑制性KYN同时保留神经保护性犬尿酸的协同节点。在这里，我们强调了一个将生活方式环节、生物工程微生物和适应性药物治疗方案结合成闭环“智能方案”的框架。通过绘制这些交叉点，本研究为生物标志物引导的多学科干预提供了路线图，这些干预可以重新校准癌症、情绪、神经退行性疾病和代谢紊乱中的KYN代谢活性，对临床医生、生物工程师和系统生物学家都具有吸引力。
