Lactiplantibacillus plantarum PS128 restores microbiota-driven polyamine homeostasis to alleviate autism-like behaviors in Fmr1 knockout mice

Background: Autism spectrum disorder (ASD) is biologically heterogeneous and has limited mechanism-informed interventions targeting core behavioral symptoms. Emerging evidence suggests that gut microbial metabolism shapes neurobehavioral outcomes, yet the specific metabolic pathways linking gut ecology to brain function remain incompletely understood. One candidate pathway is polyamine metabolism, which links microbial amino acid metabolism to host regulation and represents a plausible but underexplored contributor to ASD-related phenotypes. Notably, the psychobiotic Lactiplantibacillus plantarum PS128 has been reported to improve social behaviors in individuals with ASD, although the molecular basis for these effects is unclear. In this study, we used Fragile X mental retardation 1 knockout (Fmr1 KO) mice, a well-established ASD model, to investigate microbiota-dependent metabolic mechanisms underlying autism-like behaviors.
Results: We found that autism-like behaviors in Fmr1 KO mice were associated with gut dysbiosis, impaired intestinal barrier integrity, disruption of the arginine-ornithine-polyamine pathway, and elevated putrescine in the prefrontal cortex (PFC). Supplementation with PS128 remodeled the gut microbiota, reduced inflammation- and disease-associated taxa, improved intestinal structure and permeability, and restored polyamine homeostasis. Targeted metabolomics revealed an increased PFC-to-serum putrescine ratio in KO mice, which was normalized following PS128 intervention. This correction was accompanied by reduced expression of polyamine transporters in the PFC, including ATP13A family members. Causal experiments supported a functional role for putrescine, as peripheral elevation of putrescine induced autism-like behaviors in wild-type mice, whereas pharmacological inhibition of putrescine synthesis ameliorated behavioral deficits in Fmr1 KO mice.
Conclusions: These findings identify putrescine metabolic dysregulation as a key contributor to autism-like phenotypes and support the existence of an ASD subtype defined by disruption of the arginine-ornithine-polyamine axis. Integrated multi-omics and causal perturbation analyses support a model in which microbiota-targeted intervention rebalances systemic polyamine regulation along the gut-brain axis, thereby improving ASD-relevant behaviors. Our work provides mechanistic evidence linking microbial metabolism to neurochemical homeostasis and highlights the translational potential of metabolic stratification in ASD.

UHPLC-MS/MS analysis of murine blood serum are reported in this study
UHPLC-MS/MS analysis of murine brain tissues are reported in MTBLS13881
GC-MS analysis of murine brain tissues are reported in MTBLS13859

背景：自闭症谱系障碍（Autism spectrum disorder, ASD）具有生物学异质性，且针对核心行为症状的机制导向干预手段十分有限。越来越多的研究证据表明，肠道微生物代谢可调控神经行为结局，但连接肠道菌群生态与大脑功能的具体代谢通路仍未完全阐明。其中一个候选通路为多胺代谢通路，该通路可将微生物氨基酸代谢与宿主调控过程联系起来，是与自闭症相关表型相关但尚未被充分探索的潜在影响因素。值得注意的是，已有研究报道精神益生菌植物乳杆菌PS128（Lactiplantibacillus plantarum PS128）可改善自闭症患者的社交行为，但其发挥作用的分子机制尚不明确。本研究选用经典的自闭症模型——脆性X智力低下1基因敲除（Fmr1 KO）小鼠，探究自闭症样行为背后依赖于肠道菌群的代谢机制。
结果：我们发现，脆性X智力低下1基因敲除（Fmr1 KO）小鼠的自闭症样行为与肠道菌群失调、肠道屏障完整性受损、精氨酸-鸟氨酸-多胺通路紊乱以及前额叶皮层（PFC）内腐胺（putrescine）水平升高密切相关。补充植物乳杆菌PS128可重塑肠道菌群结构，减少与炎症及疾病相关的菌群分类群，改善肠道结构与通透性，并恢复多胺稳态。靶向代谢组学分析显示，基因敲除小鼠的前额叶皮层与血清腐胺比值升高，而经PS128干预后该比值可恢复至正常水平。这一恢复过程伴随前额叶皮层内多胺转运蛋白（包括ATP13A家族成员）表达水平的降低。因果性实验证实了腐胺的功能性作用：外周给予腐胺可诱导野生型小鼠出现自闭症样行为，而通过药理学手段抑制腐胺合成则可改善脆性X智力低下1基因敲除小鼠的行为缺陷。
结论：本研究结果证实，腐胺代谢紊乱是自闭症样表型的关键致病因素，并支持存在一类以精氨酸-鸟氨酸-多胺轴紊乱为特征的自闭症亚型。整合多组学与因果扰动分析的结果支持以下模型：靶向肠道菌群的干预措施可重新平衡肠脑轴沿线的系统性多胺调控，进而改善与自闭症相关的行为表现。本研究为微生物代谢与神经化学稳态之间的联系提供了机制层面的证据，并凸显了代谢分层策略在自闭症临床转化中的应用潜力。
本研究包含小鼠血清的超高效液相色谱-串联质谱（UHPLC-MS/MS）分析数据；小鼠脑组织的超高效液相色谱-串联质谱分析数据收录于MTBLS13881，其气相色谱-质谱（GC-MS）分析数据收录于MTBLS13859。