Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles
Nat Neurosci. 2023 Jul;26(7):1208-1217.
doi: 10.1038/s41593-023-01361-0. Epub 2023 Jun 26.
James T Morton 1 2 , Dong-Min Jin 3 , Robert H Mills 4 , Yan Shao 5 , Gibraan Rahman 6 7 , Daniel McDonald 7 , Qiyun Zhu 8 9 , Metin Balaban 6 , Yueyu Jiang 10 , Kalen Cantrell 7 11 , Antonio Gonzalez 7 , Julie Carmel 12 , Linoy Mia Frankiensztajn 12 , Sandra Martin-Brevet 13 , Kirsten Berding 14 , Brittany D Needham 15 16 , María Fernanda Zurita 17 , Maude David 18 , Olga V Averina 19 , Alexey S Kovtun 19 20 , Antonio Noto 21 , Michele Mussap 22 , Mingbang Wang 23 24 , Daniel N Frank 25 , Ellen Li 26 , Wenhao Zhou 23 , Vassilios Fanos 27 , Valery N Danilenko 19 , Dennis P Wall 28 , Paúl Cárdenas 29 , Manuel E Baldeón 30 , Sébastien Jacquemont 31 32 , Omry Koren 12 , Evan Elliott 12 33 , Ramnik J Xavier 34 35 36 , Sarkis K Mazmanian 37 , Rob Knight 7 11 38 39 , Jack A Gilbert 7 39 40 , Sharon M Donovan 14 , Trevor D Lawley 5 , Bob Carpenter 1 , Richard Bonneau 1 3 41 , Gaspar Taroncher-Oldenburg # 42 43
Affiliations
1 Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA.
2 Biostatistics & Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
3 Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA.
4 Precidiag, Inc., Watertown, MA, USA.
5 Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK.
6 Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
7 Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
8 School of Life Sciences, Arizona State University, Tempe, AZ, USA.
9 Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, USA.
10 Department of Electrical and Computer Engineering, University of California, San Diego, La Jolla, CA, USA.
11 Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA, USA.
12 Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
13 Laboratory for Research in Neuroimaging, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
14 Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA.
15 Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
16 Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
17 Microbiology Institute and Health Science College, Universidad San Francisco de Quito, Quito, Ecuador.
18 Departments of Microbiology & Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA.
19 Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia.
20 Skolkovo Institute of Science and Technology, Skolkovo, Russia.
21 Department of Biomedical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy.
22 Laboratory Medicine, Department of Surgical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy.
23 Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children’s Hospital of Fudan University, National Center for Children’s Health, Shanghai, China.
24 Microbiome Therapy Center, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, China.
25 Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
26 Department of Medicine, Division of Gastroenterology and Hepatology, Stony Brook University, Stony Brook, NY, USA.
27 Neonatal Intensive Care Unit and Neonatal Pathology, Department of Surgical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy.
28 Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
29 Institute of Microbiology, COCIBA, Universidad San Francisco de Quito, Quito, Ecuador.
30 Facultad de Ciencias Médicas, de la Salud y la Vida, Universidad Internacional del Ecuador, Quito, Ecuador.
31 Sainte Justine Hospital Research Center, Montréal, QC, Canada.
32 Department of Pediatrics, Université de Montréal, Montréal, QC, Canada.
33 The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel.
34 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
35 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
36 Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA.
37 Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
38 Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
39 Center for Microbiome Innovation, University of California, San Diego, La Jolla, California, USA.
40 Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA.
41 Prescient Design, a Genentech Accelerator, New York, NY, USA.
42 Gaspar Taroncher Consulting, Philadelphia, PA, USA. gtaroncher@gmail.com.
43 Simons Foundation Autism Research Initiative, Simons Foundation, New York, NY, USA. gtaroncher@gmail.com.
PMID: 37365313 PMCID: PMC10322709 DOI: 10.1038/s41593-023-01361-0
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.
