Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins
Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins
Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins’ models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.
ADHD, Attention deficit hyperactivity disorder, Gut microbiota, Hippurate, Metabolomics, Microbial metabolites, Twin study
Swann, J. R.
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Diaz Heijtz, R.
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Mayneris-Perxachs, J.
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Arora, A.
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Isaksson, J.
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Bölte, S.
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Tammimies, K.
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15 August 2023
Swann, J. R.
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Diaz Heijtz, R.
9674f8f4-677c-4c5a-896b-db2ae01797ae
Mayneris-Perxachs, J.
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Arora, A.
f557b663-05bf-40ad-951b-9533cd84c403
Isaksson, J.
366b156f-0377-4cde-8ede-a021b23d2269
Bölte, S.
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Tammimies, K.
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Swann, J. R., Diaz Heijtz, R., Mayneris-Perxachs, J., Arora, A., Isaksson, J., Bölte, S. and Tammimies, K.
(2023)
Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins.
Neuropharmacology, 234 (8), [109562].
(doi:10.1016/j.neuropharm.2023.109562).
Abstract
Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins’ models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.
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Accepted/In Press date: 21 April 2023
Published date: 15 August 2023
Additional Information:
Funding Information: 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 ). R.D.H. is supported by the Swedish Research Council ( 2018–06232 ) and the Swedish Brain Foundation ( FO2022-0199 ). K.T. is supported by the Swedish Research Council ( 2017-01660 ), the Swedish Foundation for Strategic Research ( FFL18-0104 ), The Swedish Brain Foundation ( FO2021-0073 ).
Publisher Copyright:
© 2023 The Authors
Keywords:
ADHD, Attention deficit hyperactivity disorder, Gut microbiota, Hippurate, Metabolomics, Microbial metabolites, Twin study
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Local EPrints ID: 478442
URI: http://eprints.soton.ac.uk/id/eprint/478442
ISSN: 0028-3908
PURE UUID: baf7f5cc-dfb9-4e90-bca8-5dddb5fa478b
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Date deposited: 30 Jun 2023 16:54
Last modified: 18 Mar 2024 03:56
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Author:
R. Diaz Heijtz
Author:
J. Mayneris-Perxachs
Author:
A. Arora
Author:
J. Isaksson
Author:
S. Bölte
Author:
K. Tammimies
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