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

ABSTRACT:

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.

GC-MS analysis of murine brain tissues are reported in in this study

UHPLC-MS/MS analysis of murine brain tissues are reported in MTBLS13881

UHPLC-MS/MS analysis of murine blood serum are reported in MTBLS13862

INSTRUMENT(S): Gas Chromatography MS - positive

PROVIDER: MTBLS13859 | MetaboLights | 2026-02-06

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13859_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13859_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13859.txt	Txt

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Project description: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 brain tissues are reported in this studyGC-MS analysis of murine brain tissues are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13859' rel='noopener noreferrer' target='_blank'>MTBLS13859</a>UHPLC-MS/MS analysis of murine blood serum are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13862' rel='noopener noreferrer' target='_blank'>MTBLS13862</a>

Project description: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 studyUHPLC-MS/MS analysis of murine brain tissues are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13881' rel='noopener noreferrer' target='_blank'>MTBLS13881</a>GC-MS analysis of murine brain tissues are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13859' rel='noopener noreferrer' target='_blank'>MTBLS13859</a>

Project description:Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. To identify potential A2BP1-dependent differential splicing events in ASD brain, we performed high-throughput RNA sequencing (RNA-Seq) on three autism samples with significant downregulation of A2BP1 (average fold change by quantitative RT-PCR = 5.9) and three control samples with average A2BP1 levels. The list of potential A2BP1-depending differential splicing events in ASD is given in the Supplementary file linked at the foot of this record.

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

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