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Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of
Simone Zuffa1, Patrick Schimmel2, Ayoze Gonzalez-Santana3
1Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.
Insights
Infants with an elevated likelihood of autism spectrum disorder (ASD) show early gut microbiome differences, including lower Bifidobacterium and altered GABA levels, preceding behavioral changes. These gut changes may influence later neurodevelopment.
Area of Science:
- Neuroscience
- Microbiology
- Developmental Psychology
Background:
- The gut-brain axis and microbiota are increasingly implicated in autism spectrum disorder (ASD) neurobiology.
- Early life gut microbiome alterations may precede behavioral symptoms in ASD.
Purpose of the Study:
- To investigate the longitudinal fecal microbiota and metabolome profiles in infants with and without a family history of ASD.
- To correlate gut microbiome and metabolome data with early developmental assessments.
Main Methods:
- Prospective longitudinal study of infants (n=16 elevated-likelihood ASD, n=19 low-likelihood) from birth to 36 months.
- Fecal microbiota and untargeted metabolome profiling.
- Developmental evaluation using Mullen Scales of Early Learning (MSEL) and Autism Diagnostic Observation Schedule (ADOS-2).
Main Results:
- At 5 months, infants at elevated likelihood for ASD (EL) had reduced Bifidobacterium and increased Clostridium/Klebsiella compared to low-likelihood (LL) infants.
- LL infants showed higher fecal GABA at 5 months, which declined with age; EL infants had consistently low GABA.
- Microbiome-metabolome analysis revealed positive associations between GABA and Bifidobacterium, and negative associations with Clostridium.
Conclusions:
- Early life gut microbiota composition and function are altered in infants at elevated likelihood for ASD.
- These gut alterations occur before detectable behavioral impairments, suggesting a potential role in later neurodevelopmental variability.
Abstract:
Evidence from cross-sectional human studies, and preliminary microbial-based intervention studies, have implicated the microbiota-gut-brain axis in the neurobiology of autism spectrum disorder (ASD). Using a prospective longitudinal study design, we investigated the developmental profile of the fecal microbiota and metabolome in infants with (n = 16) and without (n = 19) a family history of ASD across the first 36 months of life. In addition, the general developmental levels of infants were evaluated using the Mullen Scales of Early Learning (MSEL) test at 5 and 36 months of age, and with ADOS-2 at 36 months of age. At 5 months of age, infants at elevated-likelihood of ASD (EL) harbored less Bifidobacterium and more Clostridium and Klebsiella species compared to the low-likelihood infants (LL). Untargeted metabolic profiling highlighted that LL infants excreted a greater amount of fecal γ-aminobutyric acid (GABA) at 5 months, which progressively declined with age. Similar age-dependent patterns were not observed in the EL group, with GABA being consistently low across all timepoints. Integrated microbiome-metabolome analysis showed a positive correlation between GABA and Bifidobacterium species and negative associations with Clostridium species. In vitro experiments supported these observations demonstrating that bifidobacteria can produce GABA while clostridia can consume it. At the behavioral level, there were no significant differences between the EL and LL groups at 5 months. However, at 36 months of age, the EL group had significantly lower MSEL and ADOS-2 scores compared to the LL group. Taken together, the present results reveal early life alterations in gut microbiota composition and functionality in infants at elevated-likelihood of ASD. These changes occur before any behavioral impairments can be detected, supporting a possible role for the gut microbiota in emerging behavioral variability later in life.
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