# Xiaoyao San ameliorates maternal inflammation-induced neurobehavioral deficits by modulating the microbiota-gut-brain axis in offspring

## TL;DR

Xiaoyao San improves neurobehavioral issues in offspring caused by maternal inflammation by affecting gut microbes and brain chemistry.

## Contribution

Xiaoyao San is shown to modulate the gut-brain axis and restore neurotransmitter balance in maternal inflammation-induced neurobehavioral deficits.

## Key findings

- Xiaoyao San improves social interaction and reduces repetitive behaviors in offspring of inflamed mothers.
- Xiaoyao San restores cerebral glutamate-GABA balance via the glutamine pathway.
- Bacteroides spp., especially B. uniformis, mediate Xiaoyao San's neurophysiological effects through metabolic regulation.

## Abstract

XiaoYao San (XYS), a classical Traditional Chinese Medicine (TCM), has demonstrated efficacy in alleviating stress-related neuropsychiatric disorders. However, its therapeutic potential against maternal immune activation (MIA)-induced neurobehavioral impairments remains unexplored. This study aims to investigate the neuroprotective effects of XYS on MIA-related behavioral dysfunctions and elucidate its underlying mechanisms.

Using a poly (I:C)-induced MIA mouse model, we demonstrated that XYS effectively ameliorates autism spectrum disorder (ASD) related behavioral phenotypes. Mechanistic investigations revealed that XYS exerts its therapeutic effects through: (1) Attenuation of core behavioral deficits including enhanced social interaction and reduced repetitive behaviors; (2) Downregulation of intestinal amino acid transporters; (3) Restoration of cerebral glutamate-GABA balance via modulation of glutamine pathway; (4) Structural remodeling of gut microbiota with specific enrichment of Bacteroides spp. Notably, B. uniformis was identified as a key microbial mediator capable of recapitulating XYS-mediated neurophysiological improvements through metabolic regulation.

This study elucidates XYS as a multi-target therapeutic agent that coordinately modulates gut microbial ecosystems, amino acid homeostasis, and neurotransmitter homeostasis. The findings provide novel insights into the gut-brain axis mechanisms of TCM formulations, offering a scientific foundation for developing microbiota-based intervention strategies for neurodevelopmental disorders.