Short-chain fatty acids, neuroinflammation, and autism spectrum disorders: A mechanistic systematic review

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits, repetitive behaviors, and cognitive alterations. Increasing evidence indicates that immune dysregulation, particularly neuroinflammation, is central to its pathophysiology. The gut-brain axis and microbial metabolites, especially short-chain fatty acids (SCFAs: butyrate, acetate, propionate), have emerged as potential modulators of these processes. SCFAs are absorbed from the gut and may modulate brain function via transporter-dependent mechanisms at the BBB, although evidence in ASD contexts remains limited, thereby allowing them to influence both peripheral and central immune responses. This qualitative systematic review included studies published between 2015 and 2025 addressing at least one of three links: (1) ASD and neuroinflammation, (2) ASD and SCFAs, and (3) SCFAs and neuroinflammation. Twenty studies met inclusion criteria and were analyzed. Findings indicate that SCFAs exert distinct effects: butyrate consistently shows neuroprotective and anti-inflammatory actions, acetate displays context-dependent dual effects, and propionate is mainly associated with detrimental outcomes, including social and cognitive impairments and elevated inflammatory markers. Overall, SCFAs may influence ASD pathophysiology through modulation of neuroinflammatory mechanisms, with effects depending on the specific SCFA, dosage, and context. Nutritional strategies that modulate SCFA production, such as dietary fiber enrichment, prebiotics, and probiotics, may offer feasible, non-invasive therapeutic approaches. However, clinical evidence remains limited and heterogeneous, highlighting the need for well-designed trials to determine optimal interventions targeting SCFAs in ASD.