Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder
Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder
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.
Humans, Infant, Autism Spectrum Disorder/microbiology, Gastrointestinal Microbiome, Longitudinal Studies, Prospective Studies, Cross-Sectional Studies
257
Zuffa, Simone
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Schimmel, Patrick
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Gonzalez-Santana, Ayoze
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Belzer, Clara
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Knol, Jan
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Bölte, Sven
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Falck-Ytter, Terje
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Forssberg, Hans
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Swann, Jonathan
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Diaz Heijtz, Rochellys
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13 July 2023
Zuffa, Simone
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Schimmel, Patrick
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Gonzalez-Santana, Ayoze
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Belzer, Clara
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Knol, Jan
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Bölte, Sven
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Falck-Ytter, Terje
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Forssberg, Hans
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Swann, Jonathan
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Diaz Heijtz, Rochellys
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Zuffa, Simone, Schimmel, Patrick, Gonzalez-Santana, Ayoze, Belzer, Clara, Knol, Jan, Bölte, Sven, Falck-Ytter, Terje, Forssberg, Hans, Swann, Jonathan and Diaz Heijtz, Rochellys
(2023)
Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder.
Translational Psychiatry, 13 (1), , [257].
(doi:10.1038/s41398-023-02556-6).
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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s41398-023-02556-6
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Accepted/In Press date: 30 June 2023
e-pub ahead of print date: 13 July 2023
Published date: 13 July 2023
Additional Information:
Funding Information:
PS and CB received funding from Danone Nutricia Research. JK is an employee of Danone Nutricia Research. Danone Nutricia Research was not involved in the design or funding of this research. SB discloses that he has in the last 5 years acted as an author, consultant, or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe and Liber. SB is a partner of Neuro Support Solutions International AB.
Funding Information:
This work was supported by the Swedish Research Council (2018-06232), Swedish Brain Foundation (FO2020-0088, FO2022-0199), Foundation Freemasons-Children’s house in Stockholm, and Foundation Olle Engkvists. J.R.S. is supported by the NIHR Southampton Biomedical Research Centre, Medical Research Council (MR/W003597/1), and BBSRC (BB/W00139X/1, BB/N005953/1). We thank the children and families who participated in this research.
Publisher Copyright:
© 2023, The Author(s).
Keywords:
Humans, Infant, Autism Spectrum Disorder/microbiology, Gastrointestinal Microbiome, Longitudinal Studies, Prospective Studies, Cross-Sectional Studies
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Local EPrints ID: 482439
URI: http://eprints.soton.ac.uk/id/eprint/482439
PURE UUID: 44375d08-90a3-423c-8665-182196116362
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Date deposited: 03 Oct 2023 16:43
Last modified: 18 Mar 2024 03:56
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Author:
Simone Zuffa
Author:
Patrick Schimmel
Author:
Ayoze Gonzalez-Santana
Author:
Clara Belzer
Author:
Jan Knol
Author:
Sven Bölte
Author:
Terje Falck-Ytter
Author:
Hans Forssberg
Author:
Rochellys Diaz Heijtz
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