Microbiome-Specific Statistical Modeling Identifies Interplay Between Gastrointestinal Microbiome and Neurobehavioral Outcomes in Patients With Autism: A Case Control Study.

Minshi Huang,Michelle Fong,Christoph Budjan,Jierong Chen,Kevin Liu,Ruiyi Tian,Patrick Zhuang,Bryan Wang,Xue-Jun Kong,Guobin Wan,Zhe Feng,Jun Liu,Yuyu Wu,Zhen Wei

doi:10.3389/fpsyt.2021.682454

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear mechanisms of pathogenesis. Gastrointestinal microbiome alterations were found to correlate with ASD core symptoms, but its specific role in ASD pathogenesis has not been determined. In this study, we used a case-control strategy that simultaneously compared the ASD gastrointestinal microbiome with that from age-sex matched controls and first-degree relative controls, using a statistical framework accounting for confounders such as age. Enterobacteriaceae (including Escherichia/Shigella) and Phyllobacterium were significantly enriched in the ASD group, with their relative abundances all following a pattern of ASD > first degree relative control > healthy control, consistent with our hypothesis of living environment and shared microbial and immunological exposures as key drivers of ASD gastrointestinal microbiome dysbiosis. Using multivariable omnibus testing, we identified clinical factors including ADOS scores, dietary habits, and gastrointestinal symptoms that covary with overall microbiome structure within the ASD cohort. A microbiome-specific multivariate modeling approach (MaAsLin2) demonstrated microbial taxa, such as Lachnoclostridium and Tyzzerella, are significantly associated with ASD core symptoms measured by ADOS. Finally, we identified alterations in predicted biological functions, including tryptophan and tyrosine biosynthesis/metabolism potentially relevant to the pathophysiology of the gut-brain-axis. Overall, our results identified gastrointestinal microbiome signature changes in patients with ASD, highlighted associations between gastrointestinal microbiome and clinical characteristics related to the gut-brain axis and identified contributors to the heterogeneity of gastrointestinal microbiome within the ASD population.

Highlights

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder [1]
Using MaAsLin2 mixed linear modeling adjusting for age as a covariate, we found that the relative abundance of Akkermansia was significantly lower in ASD compared to first-degree relative controls (Figure 1D, Q = 0.04117), and Phyllobacterium, Enterobacteriaceae, and Escherichia/Shigella are increased in the ASD group as compared to healthy controls (Figures 1E–G, Q = 0.1503, 0.06485, and 0.06950, respectively)
We found that the relative abundances of the taxa Akkermansia, Escherichia/Shigella, Phyllobacterium, and Enterobacteriaceae were significantly different in patients with ASD as compared to first-degree relative controls or healthy controls

Summary

Introduction

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder [1]. the etiology of ASD is unclear and likely multifactorial, it likely involves an interplay between genetic and environmental factors [2,3,4]. The clinical presentation of ASD is highly heterogeneous, and current research points to the existence of multiple subtypes, potentially caused by different routes of pathophysiology and each with diverse comorbid psychiatric and medical conditions (e.g., gastrointestinal symptoms, allergies, sleep disorders). This heterogeneity is not addressed by the conventional DSM5-based behavioral diagnostic criteria. There has been a recent explosion of literature on the roles of inflammation and immune regulation on ASD pathogenesis and symptoms presentations Both clinical studies and ASD mouse models demonstrated aberrations in important immune pathways such as interleukin level, chemokine receptor signaling, and TIM-3 signaling [14,15,16]

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