当前睡眠障碍的一线药物与抗抑郁药物存在较多重合，且疗效有限，亟需从新的机制角度开发创新的治疗策略。本研究首先通过横断面研究发现，失眠患者血清中S-腺苷甲硫氨酸（S-adenosylmethionine，SAM）含量显著降低，提示SAM可作为睡眠障碍潜在的生化诊断指标和药物干预靶点。随后，从7个不同菌种的60株肠道菌株中筛选得到一株高产SAM的益生菌——瑞士乳杆菌（Lactobacillus helveticus）CCFM1320，证明其能够改善小鼠睡眠剥夺引起的认知和记忆行为异常；在机制上，CCFM1320通过提供SAM促进褪黑素合成前体N-乙酰色氨酸的甲基化，进一步使其调控的下游生物节律基因表达正常化。随后，一项为期4周的安慰剂对照临床试验结果显示，CCFM1320显著改善了睡眠障碍患者的睡眠质量，表现为匹兹堡睡眠质量指数（PSQI）评分降低、血清皮质醇水平下降以及肠道致病菌丰度的减少。益生菌治疗还显著升高了肠道菌群宏基因组中与SAM合成和代谢相关的酶编码基因丰度，这可能与高产SAM益生菌的引入以及SAM在肠道中的累积相关。综上，本研究为基于益生菌的睡眠障碍管理策略提供了新的思路，有望成为睡眠障碍的非药物治疗替代方案。

Current first-line medications for sleep disorders often overlap with antidepressants, yet their effectiveness remains suboptimal, highlighting the urgent need for novel therapeutic strategies based on new mechanisms. Our study initially identified a significant reduction in serum S-adenosylmethionine (SAM) levels in insomnia patients through a cross-sectional analysis, suggesting SAM as a potential biomarker and therapeutic target for sleep disorders. We then screened 60 gut strains across seven species and identified a high-SAM-producing probiotic, Lactobacillus helveticus CCFM1320, which improved cognitive and memory impairments caused by sleep deprivation in mice. Mechanistically, CCFM1320 enhances the methylation of N-acetylserotonin, a precursor of melatonin synthesis, normalizing the expression of downstream circadian rhythm genes. A subsequent four-week placebo-controlled clinical trial demonstrated that CCFM1320 significantly improved sleep quality in patients with sleep disorders, as evidenced by reduced Pittsburgh sleep quality index (PSQI) scores, lower serum cortisol levels, and decreased prevalence of pathogenic species in the gut. Probiotic treatment also elevated the abundance of SAM synthesis and metabolism-related enzyme genes in the gut microbiome, likely due to the introduction of high-SAM-producing probiotics and subsequent SAM accumulation. This study presents a promising probiotic-based strategy for managing sleep disorders, offering a potential non-pharmacological treatment alternative.