# Gut dysbiosis in neurodevelopmental disorders: linking microbiota signatures to cognitive rigidity in autism spectrum disorder

## TL;DR

This review explores how gut microbiota imbalances may contribute to cognitive rigidity in autism spectrum disorder through the gut-brain axis.

## Contribution

The paper integrates preclinical and clinical evidence to link specific gut microbiota signatures to cognitive inflexibility in ASD.

## Key findings

- Microbial metabolites like short-chain fatty acids and tryptophan derivatives influence brain function in ASD.
- Gut dysbiosis is associated with altered excitatory-inhibitory balance and synaptic plasticity in ASD.
- Microbiota-targeted interventions show promise as therapeutic strategies for ASD-related cognitive rigidity.

## Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterised not only by social-communication difficulties but also by restricted interests, stereotyped behaviours, and marked cognitive rigidity. Over the past decade, converging lines of evidence have implicated gut dysbiosis, an imbalance in intestinal microbial composition and function, as a potentially important modulator of these behavioural phenotypes via the microbiota-gut-brain axis. In this narrative review, we integrate preclinical and clinical data to examine how specific microbial signatures, metabolic pathways, and immune and synaptic mechanisms may contribute to inflexible cognition in ASD. The manuscript outlines the organisation of the microbiota gut-brain axis in neurodevelopment and summarises reproducible microbial alterations reported in ASD cohorts. We then discuss how microbial metabolites, including short-chain fatty acids and tryptophan-derived neuroactive molecules, as well as immune mediators and neurotransmitter precursors, converge on pathways regulating excitatory-inhibitory balance, synaptic plasticity, and corticostriatal circuit function. Evidence from germ-free, genetic, and environmental rodent models provides causal support for microbiota-dependent modulation of repetitive and rigid behaviours, whilst clinical studies reveal associations between dysbiosis, metabolomic profiles, gastrointestinal symptoms, and ASD severity. Finally, we consider the translational landscape of microbiota-targeted interventions, probiotics, prebiotics, dietary strategies, and faecal microbiota transplantation and highlight key methodological and ethical challenges for moving toward precision microbiome-based therapies. Taken together, current data support gut dysbiosis as both a mechanistic contributor and a tractable therapeutic target for cognitive rigidity in ASD.

Conceptual model illustrating how gut dysbiosis contributes to cognitive rigidity in autism spectrum disorder (ASD). Individuals with ASD commonly exhibit difficulties in social communication, followed by restricted interests and stereotyped behaviours. These behavioural features intersect with alterations along the gut-brain axis. Gut dysbiosis, characterised by shifts in microbial composition and function, leads to abnormal production of microbial metabolites, including short-chain fatty acids and other neuroactive compounds. These metabolites influence the central nervous system through immune, metabolic, and neural pathways, resulting in altered neurotransmitter levels, disrupted excitatory-inhibitory balance, and impaired synaptic plasticity. Together, these processes contribute to increased cognitive rigidity, a core feature of ASD.Flowchart illustrating the relationship between autism spectrum disorders and the gut-brain axis. It shows difficulties in social communication, restricted interests, and stereotyped behaviors. The gut-brain axis is highlighted, involving gut dysbiosis and microbial metabolites, leading to altered neurotransmitters, defects in excitatory-inhibitory balance and synaptic plasticity, and cognitive rigidity.

Conceptual model illustrating how gut dysbiosis contributes to cognitive rigidity in autism spectrum disorder (ASD). Individuals with ASD commonly exhibit difficulties in social communication, followed by restricted interests and stereotyped behaviours. These behavioural features intersect with alterations along the gut-brain axis. Gut dysbiosis, characterised by shifts in microbial composition and function, leads to abnormal production of microbial metabolites, including short-chain fatty acids and other neuroactive compounds. These metabolites influence the central nervous system through immune, metabolic, and neural pathways, resulting in altered neurotransmitter levels, disrupted excitatory-inhibitory balance, and impaired synaptic plasticity. Together, these processes contribute to increased cognitive rigidity, a core feature of ASD.