Browsing by Author "Mazmanian, Sarkis K."

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    Global Metabolic Profiles in a Non-human Primate model of Maternal Immune Activation: Implications for Neurodevelopmental Disorders
    (Springer Nature, 2022) Boktor, Joseph C.; Adame, Mark D.; Rose, Destanie R.; Schumann, Cynthia M.; Murray, Karl D.; Bauman, Melissa D.; Careaga, Milo; Mazmanian, Sarkis K.; Ashwood, Paul; Needham, Brittany D.; Anatomy, Cell Biology and Physiology, School of Medicine
    Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.
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    Multi-level analysis of the gut–brain axis shows autism spectrum disorder-associated molecular and microbial profiles
    (Springer Nature, 2023) Morton, James T.; Jin, Dong-Min; Mills, Robert H.; Shao, Yan; Rahman, Gibraan; McDonald, Daniel; Zhu, Qiyun; Balaban, Metin; Jiang, Yueyu; Cantrell, Kalen; Gonzalez, Antonio; Carmel, Julie; Frankiensztajn, Linoy Mia; Martin-Brevet, Sandra; Berding, Kirsten; Needham, Brittany D.; Zurita, María Fernanda; David, Maude; Averina, Olga V.; Kovtun, Alexey S.; Noto, Antonio; Mussap, Michele; Wang, Mingbang; Frank, Daniel N.; Li, Ellen; Zhou, Wenhao; Fanos, Vassilios; Danilenko, Valery N.; Wall, Dennis P.; Cárdenas, Paúl; Baldeón, Manuel E.; Jacquemont, Sébastien; Koren, Omry; Elliott, Evan; Xavier, Ramnik J.; Mazmanian, Sarkis K.; Knight, Rob; Gilbert, Jack A.; Donovan, Sharon M.; Lawley, Trevor D.; Carpenter, Bob; Bonneau, Richard; Taroncher-Oldenburg, Gaspar; Anatomy, Cell Biology and Physiology, School of Medicine
    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.
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    Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder
    (Elsevier, 2021) Needham, Brittany D.; Adame, Mark D.; Serena, Gloria; Rose, Destanie R.; Preston, Gregory M.; Conrad, Mary C.; Campbell, A. Stewart; Donabedian, David H.; Fasano, Alessio; Ashwood, Paul; Mazmanian, Sarkis K.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal dysfunction, and altered gut microbiome compositions. Methods: We sought to better understand nonbehavioral features of ASD by determining molecular signatures in peripheral tissues through mass spectrometry methods (ultrahigh performance liquid chromatography-tandem mass spectrometry) with broad panels of identified metabolites. Herein, we compared the global metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing control children. Results: Differences in amino acid, lipid, and xenobiotic metabolism distinguished ASD and typically developing samples. Our results implicated oxidative stress and mitochondrial dysfunction, hormone level elevations, lipid profile changes, and altered levels of phenolic microbial metabolites. We also revealed correlations between specific metabolite profiles and clinical behavior scores. Furthermore, a summary of metabolites modestly associated with gastrointestinal dysfunction in ASD is provided, and a pilot study of metabolites that can be transferred via fecal microbial transplant into mice is identified. Conclusions: These findings support a connection between metabolism, gastrointestinal physiology, and complex behavioral traits and may advance discovery and development of molecular biomarkers for ASD.