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Multi-omic analysis along the gut-brain axis points to a functional architecture of autism

View ORCID ProfileJames T. Morton, View ORCID ProfileDong-Min Jin, View ORCID ProfileRobert H. Mills, View ORCID ProfileYan Shao, View ORCID ProfileGibraan Rahman, View ORCID ProfileKirsten Berding, View ORCID ProfileBrittany D. Needham, View ORCID ProfileMaría Fernanda Zurita, View ORCID ProfileMaude David, View ORCID ProfileOlga V. Averina, View ORCID ProfileAlexey S. Kovtun, View ORCID ProfileAntonio Noto, View ORCID ProfileMichele Mussap, View ORCID ProfileMingbang Wang, View ORCID ProfileDaniel N. Frank, View ORCID ProfileEllen Li, View ORCID ProfileWenhao Zhou, View ORCID ProfileVassilios Fanos, View ORCID ProfileValery N. Danilenko, View ORCID ProfileDennis P. Wall, View ORCID ProfilePaúl Cárdenas, View ORCID ProfileManuel E. Baldeón, View ORCID ProfileRamnik J. Xavier, View ORCID ProfileSarkis K. Mazmanian, View ORCID ProfileRob Knight, View ORCID ProfileJack A. Gilbert, View ORCID ProfileSharon M. Donovan, View ORCID ProfileTrevor D. Lawley, View ORCID ProfileBob Carpenter, View ORCID ProfileRichard Bonneau, View ORCID ProfileGaspar Taroncher-Oldenburg
doi: https://doi.org/10.1101/2022.02.25.482050
James T. Morton
1Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
2The Simons Foundation Autism Research Initiative, Simons Foundation, New York, NY, USA
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  • For correspondence: gtaroncher-consultant@simonsfoundation.org
Dong-Min Jin
3Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
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Robert H. Mills
4Precidiag Inc, Watertown, MA, USA
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Yan Shao
5Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
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Gibraan Rahman
6Bioinformatics and Systems Biology Program, University of California San Diego, San Diego, CA, USA
7Department of Pediatrics, School of Medicine, University of California San Diego, San Diego, CA, USA
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Kirsten Berding
8Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
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Brittany D. Needham
9Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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María Fernanda Zurita
10Microbiology Institute and Health Science College, Universidad San Francisco de Quito, Quito, Ecuador
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Maude David
11Departments of Microbiology & Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA
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Olga V. Averina
12Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
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Alexey S. Kovtun
12Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
13Skolkovo Institute of Science and Technology, Skolkovo, Russia
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Antonio Noto
14Department of Biomedical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy
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Michele Mussap
15Laboratory Medicine, Department of Surgical Sciences, School of Medicine, University of Cagliari, Italy
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Mingbang Wang
16Children’s Hospital of Fudan University, National Center for Children’s Health, Shanghai, China
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Daniel N. Frank
17Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Ellen Li
18Department of Medicine, Division of Gastroenterology and Hepatology, Stony Brook University, Stony Brook, NY, USA
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Wenhao Zhou
16Children’s Hospital of Fudan University, National Center for Children’s Health, Shanghai, China
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Vassilios Fanos
19Neonatal Intensive Care Unit and Neonatal Pathology, Department of Surgical Sciences, School of Medicine, University of Cagliari, Italy
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Valery N. Danilenko
12Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
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Dennis P. Wall
20Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
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Paúl Cárdenas
21Institute of Microbiology, COCIBA, Universidad San Francisco de Quito, Quito, Ecuador
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Manuel E. Baldeón
22Facultad de Ciencias Médicas, de la Salud y la Vida, Universidad Internacional del Ecuador, Quito, Ecuador
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Ramnik J. Xavier
23Broad Institute of MIT and Harvard, Cambridge, MA, USA
24Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
25Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
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Sarkis K. Mazmanian
9Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Rob Knight
7Department of Pediatrics, School of Medicine, University of California San Diego, San Diego, CA, USA
26Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA
27Department of Bioengineering, University of California San Diego, La Jolla, California, USA
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Jack A. Gilbert
7Department of Pediatrics, School of Medicine, University of California San Diego, San Diego, CA, USA
28Scripps Institution of Oceanography, UC San Diego, La Jolla, CA, USA
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Sharon M. Donovan
8Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
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Trevor D. Lawley
5Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
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Bob Carpenter
1Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
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Richard Bonneau
1Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
3Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
29Prescient Design, a Genentech Accelerator, New York, NY, USA
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Gaspar Taroncher-Oldenburg
2The Simons Foundation Autism Research Initiative, Simons Foundation, New York, NY, USA
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  • ORCID record for Gaspar Taroncher-Oldenburg
  • For correspondence: gtaroncher-consultant@simonsfoundation.org
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Abstract

Autism is a highly heritable neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in autism, with dozens of cross-sectional microbiome and other omic studies revealing autism-specific profiles along the GBA albeit with little agreement in composition or magnitude. To explore the functional architecture of autism, we developed an age and sex-matched Bayesian differential ranking algorithm that identified autism-specific profiles across 10 cross-sectional microbiome datasets and 15 other omic datasets, including dietary patterns, metabolomics, cytokine profiles, and human brain expression profiles. The analysis uncovered a highly significant, functional architecture along the GBA that encapsulated the overall heterogeneity of autism phenotypes. This architecture was determined by autism-specific amino acid, carbohydrate and lipid metabolism profiles predominantly encoded by microbial species in the genera Prevotella, Enterococcus, Bifidobacterium, and Desulfovibrio, and was mirrored in brain-associated gene expression profiles and restrictive dietary patterns in individuals with autism. Pro-inflammatory cytokine profiling and virome association analysis further supported the existence of an autism-specific architecture associated with particular microbial genera. Re-analysis of a longitudinal intervention study in autism recapitulated the cross-sectional profiles, and showed a strong association between temporal changes in microbiome composition and autism symptoms. Further elucidation of the functional architecture of autism, including of the role the microbiome plays in it, will require deep, multi-omic longitudinal intervention studies on well-defined stratified cohorts to support causal and mechanistic inference.

Competing Interest Statement

R.H.M. is Scientific Director at Precidiag Inc.; T.D.L. is co-founder and Chief Scientific Officer of Microbiotica; S.K.M. is a co-founder and has equity in Axial Therapeutics; R.B is currently Executive Director of Prescient Design, a Genentech Accelerator; G.T.-O. is a Consultant-in-Residence at the Simons Foundation.

Footnotes

  • Conflict of Interest R.H.M. is Scientific Director at Precidiag Inc.; T.D.L. is co-founder and Chief Scientific Officer of Microbiotica; S.K.M. is a co-founder and has equity in Axial Therapeutics; R.B is currently Executive Director of Prescient Design, a Genentech Accelerator; G.T.-O. is a Consultant-in-Residence at the Simons Foundation.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 26, 2022.
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Multi-omic analysis along the gut-brain axis points to a functional architecture of autism
James T. Morton, Dong-Min Jin, Robert H. Mills, Yan Shao, Gibraan Rahman, Kirsten Berding, Brittany D. Needham, María Fernanda Zurita, Maude David, Olga V. Averina, Alexey S. Kovtun, Antonio Noto, Michele Mussap, Mingbang Wang, Daniel N. Frank, Ellen Li, Wenhao Zhou, Vassilios Fanos, Valery N. Danilenko, Dennis P. Wall, Paúl Cárdenas, Manuel E. Baldeón, Ramnik J. Xavier, Sarkis K. Mazmanian, Rob Knight, Jack A. Gilbert, Sharon M. Donovan, Trevor D. Lawley, Bob Carpenter, Richard Bonneau, Gaspar Taroncher-Oldenburg
bioRxiv 2022.02.25.482050; doi: https://doi.org/10.1101/2022.02.25.482050
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Multi-omic analysis along the gut-brain axis points to a functional architecture of autism
James T. Morton, Dong-Min Jin, Robert H. Mills, Yan Shao, Gibraan Rahman, Kirsten Berding, Brittany D. Needham, María Fernanda Zurita, Maude David, Olga V. Averina, Alexey S. Kovtun, Antonio Noto, Michele Mussap, Mingbang Wang, Daniel N. Frank, Ellen Li, Wenhao Zhou, Vassilios Fanos, Valery N. Danilenko, Dennis P. Wall, Paúl Cárdenas, Manuel E. Baldeón, Ramnik J. Xavier, Sarkis K. Mazmanian, Rob Knight, Jack A. Gilbert, Sharon M. Donovan, Trevor D. Lawley, Bob Carpenter, Richard Bonneau, Gaspar Taroncher-Oldenburg
bioRxiv 2022.02.25.482050; doi: https://doi.org/10.1101/2022.02.25.482050

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