Munteanu Constantin, Onose Gelu, Poștaru Mădălina, Turnea Marius, Rotariu Mariana, Galaction Anca Irina
Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy "Grigore T. Popa", 700454 Iasi, Romania.
Neuromuscular Rehabilitation Clinic Division, Clinical Emergency Hospital "Bagdasar-Arseni", 041915 Bucharest, Romania.
Pharmaceuticals (Basel). 2024 Nov 4;17(11):1480. doi: 10.3390/ph17111480.
The intricate relationship between hydrogen sulfide (HS), gut microbiota, and sirtuins (SIRTs) can be seen as a paradigm axis in maintaining cellular homeostasis, modulating oxidative stress, and promoting mitochondrial health, which together play a pivotal role in aging and neurodegenerative diseases. HS, a gasotransmitter synthesized endogenously and by specific gut microbiota, acts as a potent modulator of mitochondrial function and oxidative stress, protecting against cellular damage. Through sulfate-reducing bacteria, gut microbiota influences systemic HS levels, creating a link between gut health and metabolic processes. Dysbiosis, or an imbalance in microbial populations, can alter HS production, impair mitochondrial function, increase oxidative stress, and heighten inflammation, all contributing factors in neurodegenerative diseases such as Alzheimer's and Parkinson's. Sirtuins, particularly SIRT1 and SIRT3, are NAD-dependent deacetylases that regulate mitochondrial biogenesis, antioxidant defense, and inflammation. HS enhances sirtuin activity through post-translational modifications, such as sulfhydration, which activate sirtuin pathways essential for mitigating oxidative damage, reducing inflammation, and promoting cellular longevity. SIRT1, for example, deacetylates NF-κB, reducing pro-inflammatory cytokine expression, while SIRT3 modulates key mitochondrial enzymes to improve energy metabolism and detoxify reactive oxygen species (ROS). This synergy between HS and sirtuins is profoundly influenced by the gut microbiota, which modulates systemic HS levels and, in turn, impacts sirtuin activation. The gut microbiota-HS-sirtuin axis is also essential in regulating neuroinflammation, which plays a central role in the pathogenesis of neurodegenerative diseases. Pharmacological interventions, including HS donors and sirtuin-activating compounds (STACs), promise to improve these pathways synergistically, providing a novel therapeutic approach for neurodegenerative conditions. This suggests that maintaining gut microbiota diversity and promoting optimal HS levels can have far-reaching effects on brain health.
硫化氢（HS）、肠道微生物群和沉默调节蛋白（SIRTs）之间的复杂关系可被视为维持细胞稳态、调节氧化应激和促进线粒体健康的范式轴，它们共同在衰老和神经退行性疾病中起关键作用。HS是一种由内源性和特定肠道微生物群合成的气体信号分子，作为线粒体功能和氧化应激的有效调节剂，可防止细胞损伤。通过硫酸盐还原菌，肠道微生物群影响全身HS水平，在肠道健康和代谢过程之间建立联系。生态失调，即微生物种群失衡，可改变HS产生、损害线粒体功能、增加氧化应激并加剧炎症，这些都是阿尔茨海默病和帕金森病等神经退行性疾病的促成因素。沉默调节蛋白，特别是SIRT1和SIRT3，是依赖烟酰胺腺嘌呤二核苷酸（NAD）的脱乙酰酶，可调节线粒体生物合成、抗氧化防御和炎症。HS通过翻译后修饰增强沉默调节蛋白活性，如硫氢化作用，从而激活减轻氧化损伤、减少炎症和促进细胞长寿所必需的沉默调节蛋白途径。例如，SIRT1使核因子κB（NF-κB）去乙酰化，减少促炎细胞因子表达，而SIRT3调节关键线粒体酶以改善能量代谢并清除活性氧（ROS）。HS与沉默调节蛋白之间的这种协同作用受到肠道微生物群的深刻影响，肠道微生物群调节全身HS水平，进而影响沉默调节蛋白的激活。肠道微生物群-HS-沉默调节蛋白轴在调节神经炎症方面也至关重要，神经炎症在神经退行性疾病的发病机制中起核心作用。包括HS供体和沉默调节蛋白激活化合物（STACs）在内的药物干预有望协同改善这些途径，为神经退行性疾病提供一种新的治疗方法。这表明维持肠道微生物群多样性和促进最佳HS水平对大脑健康可能产生深远影响。
