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Background <p>Gut dysbiosis is deeply implicated in the pathophysiology of autism spectrum disorder (ASD); however, the mechanisms by which fecal microbiota transplantation (FMT) regulates host systemic metabolic homeostasis remain incompletely understood. Specifically, this study aims to address three core objectives: (1) to characterize the paired fecal and urinary metabolic signatures of ASD; (2) to map the microbiota-metabolite interaction networks; and (3) to evaluate the longitudinal metabolic remodeling effects of FMT. Through these objectives, we seek to elucidate the pathological mechanisms from a systems biology perspective.</p> Methods <p>We employed a multi-omics strategy, integrating 16&#xa0;S rRNA sequencing with untargeted metabolomics on paired fecal and urinary samples from children with ASD (<i>n</i> = 33) and healthy controls (HCs) (<i>n</i> = 27). Furthermore, we conducted an exploratory longitudinal evaluation of the metabolic remodeling effects of FMT in a subset of patients (<i>n</i> = 7) using paired samples collected at baseline and 3 months post-treatment.</p> Results <p>We observed consistent metabolic dysregulation across both gut and peripheral matrices in children with ASD. These alterations were characterized by specific molecular signatures: impaired lipid metabolism (depletion of lysophosphatidylcholine [LPC] 18:2), downregulated cholinergic signaling (reduced methacholine), and the accumulation of neuroactive toxins (elevated tetraethylammonium [TEA]). Integrated multi-omics analysis correlated these metabolic deviations with a reduced abundance of beneficial commensals, such as <i>Faecalibacterium</i>. Preliminary data from the FMT intervention demonstrated a potential reversal of these metabolic phenotypes toward a healthy baseline, with trends indicating targeted restoration of core metabolic markers including LPC 18:2 and methacholine.</p> Conclusions <p>This study reveals that FMT may exert neuroprotective effects by ameliorating lipid metabolic defects and replenishing precursors of the cholinergic anti-inflammatory pathway (CAP). These findings delineate an ASD-specific gut-kidney metabolic axis, providing a preliminary theoretical basis for precision ASD treatment strategies targeting the microbiota-metabolism axis.</p>

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Integrated multi-matrix metabolomics reveals gut microbiota-driven systemic metabolic alterations and therapeutic remodeling by fecal microbiota transplantation in autism spectrum disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Rui Wu,
  • Xu Teng,
  • Yongxi Cai,
  • Yifan Liu,
  • Wen Zhang,
  • Zhiqiang Li,
  • Jingyi Fan

摘要

Background

Gut dysbiosis is deeply implicated in the pathophysiology of autism spectrum disorder (ASD); however, the mechanisms by which fecal microbiota transplantation (FMT) regulates host systemic metabolic homeostasis remain incompletely understood. Specifically, this study aims to address three core objectives: (1) to characterize the paired fecal and urinary metabolic signatures of ASD; (2) to map the microbiota-metabolite interaction networks; and (3) to evaluate the longitudinal metabolic remodeling effects of FMT. Through these objectives, we seek to elucidate the pathological mechanisms from a systems biology perspective.

Methods

We employed a multi-omics strategy, integrating 16 S rRNA sequencing with untargeted metabolomics on paired fecal and urinary samples from children with ASD (n = 33) and healthy controls (HCs) (n = 27). Furthermore, we conducted an exploratory longitudinal evaluation of the metabolic remodeling effects of FMT in a subset of patients (n = 7) using paired samples collected at baseline and 3 months post-treatment.

Results

We observed consistent metabolic dysregulation across both gut and peripheral matrices in children with ASD. These alterations were characterized by specific molecular signatures: impaired lipid metabolism (depletion of lysophosphatidylcholine [LPC] 18:2), downregulated cholinergic signaling (reduced methacholine), and the accumulation of neuroactive toxins (elevated tetraethylammonium [TEA]). Integrated multi-omics analysis correlated these metabolic deviations with a reduced abundance of beneficial commensals, such as Faecalibacterium. Preliminary data from the FMT intervention demonstrated a potential reversal of these metabolic phenotypes toward a healthy baseline, with trends indicating targeted restoration of core metabolic markers including LPC 18:2 and methacholine.

Conclusions

This study reveals that FMT may exert neuroprotective effects by ameliorating lipid metabolic defects and replenishing precursors of the cholinergic anti-inflammatory pathway (CAP). These findings delineate an ASD-specific gut-kidney metabolic axis, providing a preliminary theoretical basis for precision ASD treatment strategies targeting the microbiota-metabolism axis.