Autism and the gut metabolome: Evidence for altered short-chain fatty acid profiles from a systematic review and meta-analysis

Growing evidence implicates gut microbiome dysbiosis and its metabolites, particularly short-chain fatty acids (SCFAs), in the pathophysiology of autism spectrum disorder (ASD). However, individual study findings are inconsistent. Objective: This systematic review and meta-analysis synthesized evidence comparing SCFA profiles between individuals with ASD and neurotypical controls. Methods: We comprehensively searched PubMed, EMBASE, Cochrane Library, Web of Science, and CNKI databases from inception to December 1, 2024. Observational studies reporting quantitative SCFA measurements were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using random-effects models. Results: Sixteen studies (473 ASD cases, 514 controls) were included. Meta-analysis revealed substantial heterogeneity across studies for most SCFAs. Despite this, levels of valeric acid (SMD = 0.76, 95% CI: 0.23 to 1.29) and hexanoic acid (SMD = 0.60, 95% CI: 0.05 to 1.16) were significantly elevated in individuals with ASD. Isobutyric acid also showed a positive association (SMD = 0.21, 95% CI: 0.03 to 0.46) with lower heterogeneity. No significant overall differences were found for acetic, propionic, or butyric acids, but subgroup analyses indicated crucial variations based on sample source (e.g., fecal, plasma, urine). Conclusion: This meta-analysis provides evidence for altered SCFA profiles in ASD, specifically elevated valeric and hexanoic acids and a consistent signal for isobutyric acid, suggesting gut microbial dysbiosis involving distinct metabolic pathways. The significant heterogeneity and sample-source-dependent effects highlight the complexity of the gut-brain axis in ASD and underscore the need for future research with standardized protocols and longitudinal designs to clarify the role of SCFAs.