Tightening the Case for Gut Microbiota in Autism-Spectrum Disorder (2017)

Autism-spectrum disorder (ASD) is a developmental behavioral disorder often accompanied and aggravated by a range of gastrointestinal and cognitive dysfunction. The concern for ASD reflects its increasing incidence and the disproportionate burden of this and other cognitive disorders on those affected and the family and community around them. Is there a role for us to help from the distant fields of gastroenterology and hepatology? The etiology of ASD probably occurs during gestation, with evidence that maternal diet and inflammatory events result in systemic products that alter central nervous system neurodevelopment of regions critical to the cognition of social interaction.1Buffington S.A. Di Prisco G.V. Auchtung T.A. et al.Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring.Cell. 2016; 165: 1762-1775Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar Emerging candidates for such products include the cytokines interleukin 6 and interleukin 17A and certain bioactive amines, notably serotonin.2Choi G.B. Yim Y.S. Wong H. et al.The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring.Science. 2016; 351: 933-939Crossref PubMed Scopus (613) Google Scholar, 3Hsiao E.Y. McBride S.W. Hsien S. et al.Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.Cell. 2013; 155: 1451-1463Abstract Full Text Full Text PDF PubMed Scopus (2056) Google Scholar, 4Masi A. Quintana D.S. Glozier N. et al.Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis.Mol Psychiatry. 2015; 20: 440-446Crossref PubMed Scopus (286) Google Scholar, 5Muller C.L. Anacker A.M. Veenstra-VanderWeele J. The serotonin system in autism spectrum disorder: from biomarker to animal models.Neuroscience. 2016; 321: 24-41Crossref PubMed Scopus (263) Google Scholar Because select intestinal commensal microbiota can induce or attenuate production of these molecules, the intestinal mucosa and microbiome may be a modifier of ASD penetrance. Mouse models of ASD indeed provide some precedents for this idea, although this is early and incomplete evidence, and the outlook for addressing this concept in at-risk human mothers is experimentally and ethically fraught. In children with ASD, an important question is whether these or other processes modify disease progression or phenotype. Because functional gastrointestinal disorders are a common and probably increased comorbidity in ASD, these patients may provide clues to such processes because distinct cytokines, bioactive amines, and microbiome constituents are biomarkers and probable modifiers of certain adult functional gastrointestinal disorders. Studies of ASD patients with gastrointestinal dysfunction have been small scale to date, but have associated this patient subset with increased levels of serotonin and certain microbial taxa, although the latter findings have been inconsistent among studies. The study by Luna et al6Luna R.A. Oezguen N. Balderas M. et al.Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder.Cell Mol Gastroenterol Hepatol. 2017; 3: 218-230Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar in this issue of Cellular and Molecular Gastroenterology and Hepatology tightens the case for a microbial hub and serotonin and cytokine spokes in the gastrointestinal dysfunction of ASD. Compared with ASD-unaffected children, children with ASD and gastrointestinal dysfunction had increased mucosal tissue levels of select microbial taxa, mainly members of the genus Clostridium. Notably, several of these taxa were associated with ASD patients in cross-sectional case–control studies. In the Luna et al6Luna R.A. Oezguen N. Balderas M. et al.Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder.Cell Mol Gastroenterol Hepatol. 2017; 3: 218-230Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar study, mucosal production of cytokines and serotonin-pathway bioamines also were measured. Bioinformatic analysis established a layered network of relationships between these microbial taxa, serotonin pathway metabolites, and several inflammatory cytokines. Again, these same metabolites and cytokines predominate with those associated with the ASD disease state in prior cross-sectional studies. In these frontier times of microbiome science, several strengths in design and analysis distinguish this study. First, its care in patient phenotypic selection (gastrointestinal dysfunction and stratification of the pain subset) and biospecimen choice (mucosal biopsy vs fecal) ensure that the collected data are closest to the clinical state and biologic site in question. Second, deep 16S metagenomic sequencing and optimized pre-analytic bioinformatics permit deeper resolution of microbial taxa. Third and most exciting is the simultaneous assessment of the mucosal ecosystem in single biopsy specimens, including microbial composition and bioamine and cytokine production. Such simultaneous measurement permits the follow-through with powerful bioinformatic analyses to construct potential functional relationships between microbiota and clinical relevant properties of the mucosal site.7Jacobs J.P. Goudarzi M. Singh N. et al.A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients.Cell Mol Gastroenterol Hepatol. 2016; 2: 750-766Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Important and challenging questions loom as this pathogenic ecologic network is advanced from association to causation. What are the direct mucosal cell types and functions targeted of this network for the microbiota, and via what microbial products? For example, perhaps certain microbiota act on local enteroendocrine cells for serotonin production, or by direct microbial metabolism of enteral tryptophan. Or, others may elicit epithelial or mucosal hematopoietic cell cytokine production that may in turn elicit mucosal bioamine secretion.8Li X. LeBlanc J. Elashoff D. et al.Microgeographic proteomic networks of the human colonic mucosa and their association with inflammatory bowel disease.Cell Mol Gastroenterol Hepatol. 2016; 2: 567-583Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Conversely, levels of some microbiota may instead be altered secondarily by the altered ecologic state of the dysfunctional intestine, and not involved causally in the functional biology. However, no worries, this is life as usual in frontier times. The exciting study by Luna et al6Luna R.A. Oezguen N. Balderas M. et al.Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder.Cell Mol Gastroenterol Hepatol. 2017; 3: 218-230Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar increases confidence for this path ahead, and its promise for clarifying ASD pathogenesis and uncovering targetable elements for intervention. Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum DisorderCellular and Molecular Gastroenterology and HepatologyVol. 3Issue 2PreviewEmerging data on the gut microbiome in autism spectrum disorder (ASD) suggest that altered host–microbe interactions may contribute to disease symptoms. Although gut microbial communities in children with ASD are reported to differ from individuals with neurotypical development, it is not known whether these bacteria induce pathogenic neuroimmune signals. Full-Text PDF Open Access