Scientific reportsMar 4, 2026

Sex differences in gut-brain neuropeptide Y system problems in a mouse model of autism

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 5, 2026

Abstract

Sex-specific differences in the neuropeptide Y (NPY) system were observed in both the brain and intestinal tissues of juvenile Nf1mice.

The study focused on understanding the role of the NPY system in gut-brain communication related to autism spectrum disorder (ASD).
Distinct correlations between brain and intestinal NPY systems were identified in both sexes of wild-type and Nf1mice.
Lactobacillus abundance in stool samples exhibited sex-dependent alterations that correlated with the intestinal NPY system.
In mutant females, fluctuations in the estrous cycle were linked to changes in the NPY system.
The Y2 receptor showed sex-specific expression patterns in both the gut and brain of Nf1mice.
These findings suggest that the NPY system may be critical for gut-brain communication in ASD, highlighting the importance of considering sex differences.

Simplified

The microbiome-gut-brain axis has been increasingly recognized for its role in the pathophysiology of autism spectrum disorder (ASD), yet the underlying molecular mechanisms remain poorly understood. Neuropeptide Y (NPY), a key modulator of gut-brain communication, may play a pivotal role in this axis. This study investigated the sex-specific molecular profile of the NPY system in gut-brain communication via a genetic mouse model of ASD, the Nf1mice. Quantitative real-time PCR was performed to assess the expression of NPY and its receptor transcripts in the amygdala, hippocampus, prefrontal cortex and intestinal tissue of juvenile male and female Nf1mice. Additionally, gut microbiota analysis focused on Lactobacillus species in stool samples. Special emphasis was placed on sex differences, an area underexplored in ASD research. Sex-specific differences in NPY and its receptor expression were observed in both the brain and intestinal tissues of Nf1mice. In mutant females, estrous cycle fluctuations were partly associated with changes in the NPY system. Notably, distinct correlations between the brain and intestinal NPY systems were identified in both sexes of wild-type (WT) and Nf1mice. Microbiota analysis revealed sex-dependent alterations in Lactobacillus abundance, which correlated with the intestinal NPY system. Importantly, the Y2 receptor exhibited sex-specific expression patterns in both the gut and brain of Nf1mice. This study provides novel evidence that the NPY system may play a critical role in gut-brain communication in ASD, with sex-dependent alterations in both the brain and gut. The intestinal Y2 receptor has emerged as a potential molecular biomarker for ASD, underscoring the importance of incorporating sex as a biological variable in future ASD research. +/-+/-+/-+/-+/-

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Competing interests

Declarations. Competing interests: The authors declare no competing interests. Ethics approval: All animal procedures adhered to protocols approved by the ORBEA of the Institute of Nuclear Science Applied to Health (1/2017 and 8/2022).

PubMed

Sex differences in gut-brain neuropeptide Y system problems in a mouse model of autism

Abstract

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