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      Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder

      1 , 2 , , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 4 , 5 , 1 , 2 , 6

      Cellular and Molecular Gastroenterology and Hepatology

      Elsevier

      Microbiome, Microbiome–Gut–Brain Axis, Gastrointestinal Disorders, Mucosa, Serotonin, ASD, autism spectrum disorder, 5-HIAA, 5-hydroxyindoleacetic acid, 5-HT, serotonin, FGID, functional gastrointestinal disorder, GI, gastrointestinal, GM-CSF, granulocyte-macrophage colony-stimulating factor, GROα, growth-related oncogene alpha, IBS, irritable bowel syndrome, IFN, interferon, IL, interleukin, IP, interferon gamma-induced protein, MCP-1, monocyte chemoattractant protein, MIP, macrophage inflammatory protein, NT, neurotypical, OTU, operational taxonomic unit, QPGS-RIII, Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III, TNF, tumor necrosis factor, VEGF, vascular endothelial growth factor

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          Abstract

          Background & Aims

          Emerging 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.

          Methods

          Because commensal clostridia interactions with the intestinal mucosa can regulate disease-associated cytokine and serotonergic pathways in animal models, we evaluated whether microbiome-neuroimmune profiles (from rectal biopsy specimens and blood) differed in ASD children with functional gastrointestinal disorders (ASD-FGID, n = 14) compared with neurotypical (NT) children with FGID (NT-FGID, n = 15) and without abdominal pain (NT, n = 6). Microbial 16S ribosomal DNA community signatures, cytokines, and serotonergic metabolites were quantified and correlated with gastrointestinal symptoms.

          Results

          A significant increase in several mucosa-associated Clostridiales was observed in ASD-FGID, whereas marked decreases in Dorea and Blautia, as well as Sutterella, were evident. Stratification by abdominal pain showed multiple organisms in ASD-FGID that correlated significantly with cytokines (interleukin [IL]6, IL1, IL17A, and interferon-γ). Group comparisons showed that IL6 and tryptophan release by mucosal biopsy specimens was highest in ASD children with abdominal pain, whereas serotonergic metabolites generally were increased in children with FGIDs. Furthermore, proinflammatory cytokines correlated significantly with several Clostridiales previously reported to associate with ASD, as did tryptophan and serotonin.

          Conclusions

          Our findings identify distinctive mucosal microbial signatures in ASD children with FGID that correlate with cytokine and tryptophan homeostasis. Future studies are needed to establish whether these disease-associated Clostridiales species confer early pathogenic signals in children with ASD and FGID.

          Graphical Abstract

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          Most cited references 36

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          Pyrosequencing study of fecal microflora of autistic and control children.

          There is evidence of genetic predisposition to autism, but the percent of autistic subjects with this background is unknown. It is clear that other factors, such as environmental influences, may play a role in this disease. In the present study, we have examined the fecal microbial flora of 33 subjects with various severities of autism with gastrointestinal symptoms, 7 siblings not showing autistic symptoms (sibling controls) and eight non-sibling control subjects, using the bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP) procedure. The results provide us with information on the microflora of stools of young children and a compelling picture of unique fecal microflora of children with autism with gastrointestinal symptomatology. Differences based upon maximum observed and maximum predicted operational taxonomic units were statistically significant when comparing autistic and control subjects with p-values ranging from <0.001 to 0.009 using both parametric and non-parametric estimators. At the phylum level, Bacteroidetes and Firmicutes showed the most difference between groups of varying severities of autism. Bacteroidetes was found at high levels in the severely autistic group, while Firmicutes were more predominant in the control group. Smaller, but significant, differences also occurred in the Actinobacterium and Proteobacterium phyla. Desulfovibrio species and Bacteroides vulgatus are present in significantly higher numbers in stools of severely autistic children than in controls. If the unique microbial flora is found to be a causative or consequent factor in this type of autism, it may have implications with regard to a specific diagnostic test, its epidemiology, and for treatment and prevention. Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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            Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.

            The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.
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              Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.

              Children with autistic spectrum disorders (ASDs) tend to suffer from severe gastrointestinal problems. Such symptoms may be due to a disruption of the indigenous gut flora promoting the overgrowth of potentially pathogenic micro-organisms. The faecal flora of patients with ASDs was studied and compared with those of two control groups (healthy siblings and unrelated healthy children). Faecal bacterial populations were assessed through the use of a culture-independent technique, fluorescence in situ hybridization, using oligonucleotide probes targeting predominant components of the gut flora. The faecal flora of ASD patients contained a higher incidence of the Clostridium histolyticum group (Clostridium clusters I and II) of bacteria than that of healthy children. However, the non-autistic sibling group had an intermediate level of the C. histolyticum group, which was not significantly different from either of the other subject groups. Members of the C. histolyticum group are recognized toxin-producers and may contribute towards gut dysfunction, with their metabolic products also exerting systemic effects. Strategies to reduce clostridial population levels harboured by ASD patients or to improve their gut microflora profile through dietary modulation may help to alleviate gut disorders common in such patients.
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                Author and article information

                Contributors
                Journal
                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                Elsevier
                2352-345X
                March 2017
                11 December 2016
                : 3
                : 2
                : 218-230
                Affiliations
                [1 ]Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Houston, Texas
                [2 ]Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
                [3 ]Department of Psychiatry, Columbia University, New York, New York
                [4 ]Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut
                [5 ]Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
                [6 ]Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, Columbus, Ohio
                Author notes
                [] Correspondence Address correspondence to: Ruth Ann Luna, PhD, Texas Children’s Microbiome Center, Department of Pathology, Texas Children’s Hospital, Feigin Tower, 1102 Bates Street, FC830, Houston, Texas 77030. fax: (832) 825-1211.Texas Children’s Microbiome CenterDepartment of PathologyTexas Children’s HospitalFeigin Tower1102 Bates StreetFC830HoustonTexas 77030 raluna@ 123456bcm.edu
                Article
                S2352-345X(16)30136-9
                10.1016/j.jcmgh.2016.11.008
                5331780
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Original Research

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