# Gut microbial ammonia as a mediator of PFOS neurotoxicity and its remediation by the flavonoid Icaritin

## TL;DR

This study shows how gut microbes contribute to PFOS-related brain damage and how a flavonoid called Icaritin can help by restoring gut health and reducing ammonia.

## Contribution

The study identifies ammonia dysmetabolism as a novel mediator of PFOS neurotoxicity and demonstrates the therapeutic potential of Icaritin via microbiota modulation.

## Key findings

- Icaritin restored gut microbial balance by increasing beneficial bacteria and reducing ammonia producers.
- Ammonia dysregulation was identified as a key driver of PFOS-induced cognitive dysfunction.
- Modulating gut microbiota with Icaritin improved cognitive outcomes by reducing neuroinflammation and oxidative stress.

## Abstract

Perfluorooctane sulfonate (PFOS), a persistent environmental pollutant, is associated with cognitive dysfunction through mechanisms involving neuroinflammation, oxidative stress, and metabolic disruption. Icaritin, a bioactive flavonoid with antioxidant and anti-inflammatory properties, exhibits therapeutic potential, though its efficacy against PFOS-induced cognitive impairment remains unexplored. Herein, a mouse model of PFOS-induced cognitive dysfunction was established and treated with oral ICT. Integrated 16S rRNA sequencing and untargeted metabolomics revealed that ICT restored gut microbial homeostasis by enriching beneficial genera (e.g. Akkermansia, Lactobacillus) and reducing ammonia-producing bacteria (e.g. Proteus, Helicobacter, Escherichia), thereby improving gut barrier integrity. Metabolomic profiling identified significant perturbations in ammonia-related pathways, particularly arginine and proline metabolism, underscoring ammonia dysmetabolism as a pivotal mediator of PFOS neurotoxicity. These modifications attenuated systemic and cerebral ammonia accumulation, mitigated neuroinflammation and oxidative stress, and ultimately improved cognitive function. Our findings elucidate ammonia dysmetabolism as a central mechanism in PFOS-induced cognitive decline and highlight the microbiota–gut–brain axis as a promising therapeutic target. This study provides a mechanistic foundation for targeting microbial and metabolic pathways in environmental neurotoxicity.