Streptococcus mutans exacerbates gut microbiota dysbiosis in SHANK3 -/- autism model mice via the oral-gut axis

Background and objective Autism spectrum disorder (ASD) is associated with gut microbiota dysbiosis, yet the impact of oral pathobiont translocation via the oral–gut axis remains unclear. This study investigated how Streptococcus mutans (S. mutans), a primary cariogenic pathogen, influences gut microbial structure and function in an ASD mouse model.Methods SHANK3 knockout (SHANK3-/-) and wild-type (WT) mice were divided into four groups: WT control, WT S. mutans-gavaged (WT-S.m), SHANK3-/- control, and SHANK3-/- S. mutans-gavaged (SHANK3-S.m). Mice were gavaged with S. mutans UA159 twice weekly for five weeks, followed by fecal metagenomic sequencing (n = 6 per group).Results S. mutans translocated to the gut in both gavaged groups but did not achieve enhanced colonization in SHANK3-/- mice. S. mutans gavage significantly altered the gut microbiota structure in both WT and SHANK3-/- mice. In the ASD model, S. mutans gavage led to a significant enrichment of potential pathobionts (e.g. Duncaniella dubosii, Muribaculum gordoncarteri) and a decrease in beneficial bacteria (e.g. Bacteroides caecimuris, Bacteroides faecium). LEfSe analysis identified Parascardovia denticolens and Bacteroides heparinolyticus as specific biomarkers for the SHANK3-S.m group. Microbial networks showed reduced stability in SHANK3-S.m mice, with Enterocloster bolteae as a key node. Functional analysis revealed suppressed butanoate metabolism and enhanced neuroinflammation-related pathways.Conclusion Although S. mutans colonized only transiently, it provoked exacerbated ecological instability and pro-inflammatory metabolic alterations in ASD model mice, underscoring the role of the oral-gut-brain axis in ASD.