Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder

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.

Decreased wrist rotation imitation abilities in children with autism spectrum disorder

“…Fifth and finally, we used the Gesell, PEP-3, and CARS scales to measure developmental abilities, and ASD symptoms, respectively. In future studies, it will be recommended to use ADOS-2 ( 62 ) or ADI-R ( 63 ) for describing the core symptoms of ASD, and use the Griffiths ( 64 ) or Mullen Scales of Early Learning (MSEL) ( 65 ) for evaluating developmental abilities.…”

Gut microbiota and autism spectrum disorders: a bidirectional Mendelian randomization study

“…The absence of certain microorganisms has been linked to enduring effects on neurogenesis, synaptogenesis, axonal and dendritic growth, and the establishment of neural connections, all of which can influence the development of ASD ( Rogers et al., 2016 ). Research indicates that infants at higher risk of ASD suffer different gut microbiota composition during a crucial developmental period for the gut microbiota and brain ( Zuffa et al., 2023 ). This indicates that alterations in gut microbiota during early development may have persistent impacts on the formation of neuronal pathways.…”

Gamma-aminobutyric acid as a potential postbiotic mediator in the gut–brain axis

“…↑ Acinetobacter spp. ↑GABA degradation 98 Epilepsy ↓ Anaerotruncus ↓ Peptococcaceae ↓ Prevotellaceae Ga6A1 group ↓ Ruminococcus torques group ↓ Peptococcus y Ruminococcus gauvreauii group ↓ Pseudomonas graminis* ↓ Ruminococcaceae bacterium AM2 ↓GABA levels 102 ↓ Akkermansia muciniphila ↓ Parabacteroides ↓GABA/glutamate levels 105 Autism spectrum disorder ↑ Clostridium* ↑ Klebsiella ↓ Bifidobacterium* ↓ Prevotella copri ↓ Feacalibacterium prausnitzii ↓ Haemophilus parainfluenzae ↓GABA levels 108 , 109 ↑ Escherichia/Shigella* ↑ Lachnoclostridium ↑ Megamonas ↑ Megasphaera* ↑ Veillonella* ↓ Bacteroides ↓ Akkermansia ↓ Parabacteroide ↓ Rothia ↑GABA/glutamate levels 110 ↑ Dialister ↑ Escherichia/Shigella ↑ Bifidobacterium* ↓ Prevotella 9 ↑GABA precursor levels 111 Attention deficit hyperactivity disorder ↑ Bacteroides ↑ Dorea ↑ Erysipelotrichaceae ↑ Ruminococcaceae ↑ Dialister ↓ Lachnospiraceae ↓ Ruminococcus ↓ Bacteroides ↓ Lachnospiraceae ↓ Enterococcus ↓GABA levels (putative) 114 ↑ Bifidobacterium adolescentis ↑ Bifidobacterium animalis ↑ Bifidobacterium breve ↑ Bifidobacterium longum ↑ Bacteroides ovatus ↑ Bacteroides uniformis ↑ Fusobacterium ulcerans ↑ Enterocococcus avium ↑ Enterococcus gallinarumi ↓ Faecalibacterium prausnitzii ↑GABA levels (putative) …”

“…Specifically, 76–87% of beta2-toxin-producing Clostridium perfringens were significantly higher in children with ASD compared to control children, indicating that these opportunistic pathogens thrive in immature or compromised immune systems 107 . A recent study has shown that infants with increased-likelihood of ASD have a decreased abundance of Bifidobacterium but an increased abundance of Clostridium and Klebsiella compared to those with lower likelihood of ASD 108 . Moreover, fecal GABA levels of infants with increased likelihood of ASD were lower than those with lower likelihood of ASD, in which fecal GABA levels are positively correlated with Bifidobacterium , but negatively correlated with Clostridium 108 .…”

“…A recent study has shown that infants with increased-likelihood of ASD have a decreased abundance of Bifidobacterium but an increased abundance of Clostridium and Klebsiella compared to those with lower likelihood of ASD 108 . Moreover, fecal GABA levels of infants with increased likelihood of ASD were lower than those with lower likelihood of ASD, in which fecal GABA levels are positively correlated with Bifidobacterium , but negatively correlated with Clostridium 108 . A lower abundance of Prevotella copri , Feacalibacterium prausnitzii , and Haemophilus parainfluenzae and decreased concentrations of fecal GABA were found in children with ADS when compared to healthy children 109 .…”