Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Istituto Clinico Humanitas | OTHER |
Not provided
Not provided
Not provided
Not provided
Recent research links gut microbiota alterations to Autism Spectrum Disorders (ASD), a neurobiological condition with multifactorial bases. In some ASD patients, altered gut flora and increased intestinal permeability are observed, influencing the central nervous system's development and function. Chronic gastrointestinal (GI) symptoms are commonly associated with ASD and correlate with its severity. This non-pharmacological interventional clinical study aims to investigate the role of gut microbiota on ASD and the effectiveness of postbiotic-based dietary supplements in children aged 3-8 years old. Gastrointestinal symptoms, behavioral profile and analysis of intestinal metagenomic and metabolomic profiles will be assessed before and after one-month treatment. The results of the study could enhance understanding of non-pharmacological therapeutic approaches in ASD and improve clinical management strategies and the behavioural functioning for children with ASD.
Modulating the microbiota could be an effective way to improve gastrointestinal issues and related behavioral symptoms in children with ASD, offering new treatment avenues. There is particular interest in alternatives to fecal microbiota transplantation, such as postbiotic supplements, which contain molecules naturally released during microbiota metabolism.
These molecules can regulate intestinal homeostasis and microbe-host interactions generating health benefits, possess anti-inflammatory and immunomodulatory activities, and contribute to the barrier activity of the intestinal epithelium. In line with findings for other nutraceutical therapies, dietary supplementation with postbiotics could resolve bowel problems in children with ASD and have positive consequences on behavioral regulation; however, the data collected in the literature is still scarce and limited to studies on mouse models of ASD.
This non-pharmacological clinical study, part of a collaboration between Fondazione IRCCS Istituto Neurologico Carlo Besta (FINCB) and Istituto Clinico Humanitas (ICH), evaluates postbiotic-based supplements' impact on gut microbiota's role in ASD.
Stool samples will be collected from patients at FINCB and FDG, and transported to ICH for analysis of the intestinal bacterial community and intestinal permeability. Participants will then receive a postbiotic-based dietary supplement. After treatment, changes in bowel habits, intestinal bacteria characteristics, intestinal permeability, and any behavioral changes will be evaluated.
Existing literature highlights the protective effects of postbiotics derived from Lactobacillus paracasei CNCM I-5220 on the intestine, specifically contributing to the maintenance of intestinal barrier integrity and protection against leaky gut syndrome.
Unlike probiotics, it provides immediate benefits without live bacteria risks, offering a safe alternative for fragile populations. PostbiotiX Comfort®, which includes the same fermented FOS by L. paracasei found in various infant food supplements (such as Smart D3 Matrix, Polivit Immuno Matrix, and Idra Matrix), will be utilized in this study. These products have been safely used in other formulations without any recorded safety concerns and have demonstrated an excellent toxicological profile.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 (ASD with gastrointestinal symptoms): | Other | 30 patients with Autism Spectrum Disorder and coexisting gastrointestinal disorders, aged 3 to 8 years (male or female) |
|
| Group 2 (ASD without gastrointestinal symptoms) | Other | 30 participants with Autism Spectrum Disorder without gastrointestinal disorders, aged 3 to 8 years (male or female) |
|
| Group 3 (Typically developing) | Other | 30 participants with typical neurodevelopment and no gastrointestinal symptoms, aged 3 to 8 years (male or female) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PostbiotiX Comfort® | Dietary Supplement | Treatment with a postbiotic dietary supplement, PostbiotiX Comfort®, administered for 1 month in participants from Group 1 and Group 2. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Modulation of Gastrointestinal Symptoms in ASD with Postbiotic Supplement | The presence of gastrointestinal symptoms will be assessed at recruitment (T0) using the GI Severity Index. Subjects recruited will be treated with the postbiotic-based dietary supplement, PostbiotiX Comfort®, once daily for 1 month. The GI Severity Index will be repeated within one week after the end of the treatment (T1) to quantify changes in bowel regulation and one month after the end of the treatment (T2) to assess the stability of the observed changes. | 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Effects of postbiotics on sleep regulation | Standardized behavioral assessments will be conducted through parents/caregivers reported questionnaires to evaluate the effects of postbiotic supplementation on sleep regulation. Sleep disturbances will be assessed through validated instruments designed to investigate difficulties related to sleep onset and maintenance, respiratory sleep disturbances, disorder of arousal, wake-sleep transition, excessive daytime sleepiness, and nocturnal hyperhidrosis. Sleep regulation will be assessed using the italian version of the Sleep Disturbance Scale for Children. The scale consists of 26 items rated on a 5-point Likert scale (1 = never; 2 = occasionally; 3 = sometimes; 4 = often; 5 = always). The total raw score ranges from 26 to 130, with higher scores indicating greater severity of sleep disturbances. Assessments will be conducted at three time points: baseline (T0), at enrollment in the interventional study; post-treatment (T1), within one week after the end of treatment; and follow-up (T |
Not provided
Inclusion Criteria:
Inclusion criteria
Group 3 Inclusion criteria
Exclusion Criteria:
Group 1 and 2
Group 3 exclusion criteria
- Participants with gastrointestinal problems requiring immediate (life-threatening) treatment, or with gastrointestinal symptoms such as chronic irregular bowel movements (constipation, diarrhea), encopresis, recurrent abdominal bloating and pain, gastroesophageal reflux and vomiting, or food aversion.
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Stefano D'Arrigo, MD | Contact | + 39 02.2394 | stefano.darrigo@istituto-besta.it | |
| Sara Bulgheroni | Contact | sara.bulgheroni@istituto-besta.it |
| Name | Affiliation | Role |
|---|---|---|
| Stefano D'Arrigo, MD | Fondazione IRCCS Istituto Neurologico Carlo Besta | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fondazione IRCCS Istituto Neurologico Carlo Besta | Recruiting | Milan | MI | 20133 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7814313 | Background | Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994 Oct;24(5):659-85. doi: 10.1007/BF02172145. | |
| 20410722 | Background | Althoff RR. Dysregulated children reconsidered. J Am Acad Child Adolesc Psychiatry. 2010 Apr;49(4):302-5. No abstract available. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D001321 | Autistic Disorder |
| D000067877 | Autism Spectrum Disorder |
| ID | Term |
|---|---|
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
A total of 90 subjects will be enrolled in the study, including 60 children diagnosed with Autism Spectrum Disorder (ASD) and 30 typically developing children, aged 3 to 8 years. The 60 ASD patient with diagnosis of ASD will be devided into two groups (n= 30 per group) based on the presence or absence of gastrointestinal symptoms. Only participants in the ASD groups will receive the treatment with pstbiotic. The postbiotic, derived from the fermentation of Lactobacillus paracasei CNCM I-5220 and contained in PostbiotiX Comfort®, is a safe product that does not contain live or dead microorganisms, or any parts of them, but only the metabolic products of the microorganisms. The postbiotic supplement, PostbiotiX Comfort®, has a safety profile and is already available on the Italian market. Each participant will receive one sachet (4 g) of PostbiotiX Comfort® per day for a period of 30 consecutive days.
Not provided
Not provided
Not provided
Not provided
| Control | Other | Participants in Group 3 do not receive any treatment. |
|
| 24 months |
| Effects of postbiotics on behavioral regulation | Standardized behavioral assessments will be conducted through parents/caregivers reported questionnaires to evaluate the effects of postbiotic supplementation on behavioral regulation. Emotional and behavioral regulation will be assessed through validated instruments designed to investigate the presence and severity of emotional and behavioral problems, including internalizing and externalizing symptoms. Behavioral and emotional problems will be assessed using the Italian versions of the Child Behavior Checklist (CBCL) according to age. The instrument consists of items rated on a 3-point Likert scale (0 = not true; 1 = somewhat or sometimes true; 2 = very true or often true). Higher scores indicate greater severity of emotional and behavioral problems. Raw scores will be converted into standardized T-scores (mean = 50, standard deviation = 10). Assessments will be performed at three time points: baseline (T0), at enrollment in the interventional study; post-treatment (T1) | 24 months |
| Effects of postbiotics on sensory profile | Standardized behavioral assessments will be conducted through parents/caregivers reported questionnaires to evaluate the effects of postbiotic supplementation on sensory profile. The sensory profile will be assessed using the Sensory Profile-2 (Italian version), completed by parents/caregivers for children aged 3-8 years. The questionnaire evaluates sensory functioning, self-regulation behavioral responses and the frequency of behavioral responses to environmental sensory stimuli. Raw scores are calculated for each sensory domain; higher scores indicate greater deviation from typical sensory processing patterns. Assessments will be performed at three time points: baseline (T0), at enrollment in the interventional study; post-treatment (T1), within one week after the end of treatment; and follow-up (T2), within one month after the end of treatment to assess the stability of the observed changes. All questionnaires completed by the parents/caregivers will subsequently be discussed with | 24 months |
| Metagenomic analyses in typically developing children and in ASD before and after postbiotic treatment | Fecal samples obtained from control subjects and children with ASD with and without gastrointestinal symptoms. For the latter group, samples will be collected both prior to the initiation of supplement therapy (T0) and after treatment (T1). Taxonomic and functional profiling of the fecal microbiota will be performed using shallow shotgun metagenomic sequencing. Total bacterial DNA will be extracted from fecal samples and sequenced using Illumina platforms. Taxonomic analyses will be performed at Species-level Genome Bin (SGB) resolution (8th taxonomic rank). Functional analyses will be based on destratified gene family and metabolic pathway abundances, with pathway annotation performed against the MetaCyc database. Differential abundance analyses (DAAs) will be performed on taxonomic profiles expressed as relative abundances and on gene family and pathway profiles normalized to copies per million (CPM) Unit of measure: Relative abundance of bacterial taxa (%) | 24 months |
| Metabolomic analyses in typically developing children and in ASD before and after postbiotic treatment | The following laboratory tests will be performed on fecal samples obtained from control subjects and children with ASD with and without gastrointestinal symptoms. For the latter group, samples will be collected both prior to the initiation of supplement therapy (T0) and after treatment (T1). Untargeted metabolomic analysis will be performed on fecal samples to identify metabolites of bacterial origin. Metabolites will be detected and quantified using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS), followed by bioinformatic analysis. Unit of measure: • Relative or absolute metabolite abundance (normalized peak intensity/concentration) | 24 months |
| Intestinal permeability analyses in typically developing children and in ASD before and after postbiotic treatment | The following laboratory tests will be performed on fecal samples obtained from control subjects and children with ASD with and without gastrointestinal symptoms. For the latter group, samples will be collected both prior to the initiation of supplement therapy (T0) and after treatment (T1). Intestinal permeability will be assessed by quantifying fecal levels of zonulin and albumin using commercially available enzyme-linked immunosorbent assays (ELISA). Increased fecal zonulin levels will be interpreted as indicative of tight junction disassembly and increased epithelial permeability. Elevated fecal albumin concentrations will be interpreted as a marker of intestinal barrier dysfunction associated with inflammatory leakage across the intestinal mucosa . Both biomarkers will be analyzed as indicators of altered intestinal permeability and gut barrier integrity. Unit of measure:
| 24 months |
| Investigation of the relationships between metagenomic/metabolomic profiles and behavioral/GI outcomes in children with ASD | Correlation analyses will be performed to investigate the relationships between metagenomic and metabolomic profiles and behavioral and gastrointestinal outcomes in children with ASD. This initial analysis will enable the identification of significant associations between microbial diversity, metabolite abundance, and clinical measures potentially modulated by postbiotic treatment. Metagenomic, metabolomic, and intestinal permeability data will then be integrated with behavioral outcomes using advanced computational multi-omics approaches. Following data normalization and harmonization through standardized pipelines, metagenomic and metabolomic datasets will be combined using network-based integration strategies and multivariate methods, including Canonical Correlation Analysis (CCA), sparse Partial Least Squares (sPLS), and Multi-Omics Factor Analysis (MOFA), to identify shared functional signatures, key microbial-metabolic interactions, and convergent pathways across datasets. Cross | 24 months |
| IRCCS Humanitas Reasearch Hospital (ICH) Laboratory of Microbiota and Mucosal Immunology | Recruiting | Milan | Italy |
|
| 9065877 | Background | Bruni O, Ottaviano S, Guidetti V, Romoli M, Innocenzi M, Cortesi F, Giannotti F. The Sleep Disturbance Scale for Children (SDSC). Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. J Sleep Res. 1996 Dec;5(4):251-61. doi: 10.1111/j.1365-2869.1996.00251.x. |
| 24193577 | Background | Chaidez V, Hansen RL, Hertz-Picciotto I. Gastrointestinal problems in children with autism, developmental delays or typical development. J Autism Dev Disord. 2014 May;44(5):1117-27. doi: 10.1007/s10803-013-1973-x. |
| 24520333 | Background | Zagato E, Mileti E, Massimiliano L, Fasano F, Budelli A, Penna G, Rescigno M. Lactobacillus paracasei CBA L74 metabolic products and fermented milk for infant formula have anti-inflammatory activity on dendritic cells in vitro and protective effects against colitis and an enteric pathogen in vivo. PLoS One. 2014 Feb 10;9(2):e87615. doi: 10.1371/journal.pone.0087615. eCollection 2014. |
| 23271068 | Background | Tsilingiri K, Rescigno M. Postbiotics: what else? Benef Microbes. 2013 Mar 1;4(1):101-7. doi: 10.3920/BM2012.0046. |
| 22713266 | Background | Tsilingiri K, Rescigno M. Should probiotics be tested on ex vivo organ culture models? Gut Microbes. 2012 Sep-Oct;3(5):442-8. doi: 10.4161/gmic.20885. Epub 2012 Jun 20. |
| 22301383 | Background | Tsilingiri K, Barbosa T, Penna G, Caprioli F, Sonzogni A, Viale G, Rescigno M. Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model. Gut. 2012 Jul;61(7):1007-15. doi: 10.1136/gutjnl-2011-300971. Epub 2012 Feb 1. |
| 19756155 | Background | Mileti E, Matteoli G, Iliev ID, Rescigno M. Comparison of the immunomodulatory properties of three probiotic strains of Lactobacilli using complex culture systems: prediction for in vivo efficacy. PLoS One. 2009 Sep 16;4(9):e7056. doi: 10.1371/journal.pone.0007056. |
| 17198973 | Background | Pardridge WM. Blood-brain barrier delivery. Drug Discov Today. 2007 Jan;12(1-2):54-61. doi: 10.1016/j.drudis.2006.10.013. Epub 2006 Nov 13. |
| 25411471 | Background | Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, Korecka A, Bakocevic N, Ng LG, Kundu P, Gulyas B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, Pettersson S. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014 Nov 19;6(263):263ra158. doi: 10.1126/scitranslmed.3009759. |
| 33798472 | Background | Bertocchi A, Carloni S, Ravenda PS, Bertalot G, Spadoni I, Lo Cascio A, Gandini S, Lizier M, Braga D, Asnicar F, Segata N, Klaver C, Brescia P, Rossi E, Anselmo A, Guglietta S, Maroli A, Spaggiari P, Tarazona N, Cervantes A, Marsoni S, Lazzari L, Jodice MG, Luise C, Erreni M, Pece S, Di Fiore PP, Viale G, Spinelli A, Pozzi C, Penna G, Rescigno M. Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Cancer Cell. 2021 May 10;39(5):708-724.e11. doi: 10.1016/j.ccell.2021.03.004. Epub 2021 Apr 1. |
| 33382359 | Background | Grander C, Grabherr F, Spadoni I, Enrich B, Oberhuber G, Rescigno M, Tilg H. The role of gut vascular barrier in experimental alcoholic liver disease and A. muciniphila supplementation. Gut Microbes. 2020 Nov 9;12(1):1851986. doi: 10.1080/19490976.2020.1851986. |
| 31295531 | Background | Sorribas M, Jakob MO, Yilmaz B, Li H, Stutz D, Noser Y, de Gottardi A, Moghadamrad S, Hassan M, Albillos A, Frances R, Juanola O, Spadoni I, Rescigno M, Wiest R. FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. J Hepatol. 2019 Dec;71(6):1126-1140. doi: 10.1016/j.jhep.2019.06.017. Epub 2019 Jul 8. |
| 31419514 | Background | Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, Mileti E, Galbiati M, Invernizzi P, Adorini L, Penna G, Rescigno M. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol. 2019 Dec;71(6):1216-1228. doi: 10.1016/j.jhep.2019.08.005. Epub 2019 Aug 13. |
| 26564856 | Background | Spadoni I, Zagato E, Bertocchi A, Paolinelli R, Hot E, Di Sabatino A, Caprioli F, Bottiglieri L, Oldani A, Viale G, Penna G, Dejana E, Rescigno M. A gut-vascular barrier controls the systemic dissemination of bacteria. Science. 2015 Nov 13;350(6262):830-4. doi: 10.1126/science.aad0135. |
| 28869253 | Background | Spadoni I, Fornasa G, Rescigno M. Organ-specific protection mediated by cooperation between vascular and epithelial barriers. Nat Rev Immunol. 2017 Dec;17(12):761-773. doi: 10.1038/nri.2017.100. Epub 2017 Sep 4. |
| 27957319 | Background | Fiorentino M, Sapone A, Senger S, Camhi SS, Kadzielski SM, Buie TM, Kelly DL, Cascella N, Fasano A. Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism. 2016 Nov 29;7:49. doi: 10.1186/s13229-016-0110-z. eCollection 2016. |
| 21248165 | Background | Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011 Jan;91(1):151-75. doi: 10.1152/physrev.00003.2008. |
| 12455944 | Background | Croonenberghs J, Wauters A, Devreese K, Verkerk R, Scharpe S, Bosmans E, Egyed B, Deboutte D, Maes M. Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med. 2002 Nov;32(8):1457-63. doi: 10.1017/s0033291702006037. |
| 28502607 | Background | Esnafoglu E, Cirrik S, Ayyildiz SN, Erdil A, Erturk EY, Dagli A, Noyan T. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. J Pediatr. 2017 Sep;188:240-244. doi: 10.1016/j.jpeds.2017.04.004. Epub 2017 May 11. |
| 25262969 | Background | Julio-Pieper M, Bravo JA, Aliaga E, Gotteland M. Review article: intestinal barrier dysfunction and central nervous system disorders--a controversial association. Aliment Pharmacol Ther. 2014 Nov;40(10):1187-201. doi: 10.1111/apt.12950. Epub 2014 Sep 28. |
| 31150625 | Background | Sharon G, Cruz NJ, Kang DW, Gandal MJ, Wang B, Kim YM, Zink EM, Casey CP, Taylor BC, Lane CJ, Bramer LM, Isern NG, Hoyt DW, Noecker C, Sweredoski MJ, Moradian A, Borenstein E, Jansson JK, Knight R, Metz TO, Lois C, Geschwind DH, Krajmalnik-Brown R, Mazmanian SK. Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice. Cell. 2019 May 30;177(6):1600-1618.e17. doi: 10.1016/j.cell.2019.05.004. |
| 27315483 | Background | Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016 Jun 16;165(7):1762-1775. doi: 10.1016/j.cell.2016.06.001. |
| 28122648 | Background | Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Lipson KS, Sullivan MB, Caporaso JG, Krajmalnik-Brown R. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017 Jan 23;5(1):10. doi: 10.1186/s40168-016-0225-7. |
| 30967657 | Background | Kang DW, Adams JB, Coleman DM, Pollard EL, Maldonado J, McDonough-Means S, Caporaso JG, Krajmalnik-Brown R. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Sci Rep. 2019 Apr 9;9(1):5821. doi: 10.1038/s41598-019-42183-0. |
| 27882443 | Background | Ding HT, Taur Y, Walkup JT. Gut Microbiota and Autism: Key Concepts and Findings. J Autism Dev Disord. 2017 Feb;47(2):480-489. doi: 10.1007/s10803-016-2960-9. |
| 27655151 | Background | Iovene MR, Bombace F, Maresca R, Sapone A, Iardino P, Picardi A, Marotta R, Schiraldi C, Siniscalco D, Serra N, de Magistris L, Bravaccio C. Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders. Mycopathologia. 2017 Apr;182(3-4):349-363. doi: 10.1007/s11046-016-0068-6. Epub 2016 Sep 21. |
| 26748423 | Background | Fulceri F, Morelli M, Santocchi E, Cena H, Del Bianco T, Narzisi A, Calderoni S, Muratori F. Gastrointestinal symptoms and behavioral problems in preschoolers with Autism Spectrum Disorder. Dig Liver Dis. 2016 Mar;48(3):248-54. doi: 10.1016/j.dld.2015.11.026. Epub 2015 Dec 11. |
| 25145752 | Background | Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays. 2014 Oct;36(10):933-9. doi: 10.1002/bies.201400075. Epub 2014 Aug 22. |
| 14523189 | Background | Afzal N, Murch S, Thirrupathy K, Berger L, Fagbemi A, Heuschkel R. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42. doi: 10.1542/peds.112.4.939. |
| 29388597 | Background | Wasilewska J, Klukowski M. Gastrointestinal symptoms and autism spectrum disorder: links and risks - a possible new overlap syndrome. Pediatric Health Med Ther. 2015 Sep 28;6:153-166. doi: 10.2147/PHMT.S85717. eCollection 2015. |
| 16685178 | Background | Niehus R, Lord C. Early medical history of children with autism spectrum disorders. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S120-7. doi: 10.1097/00004703-200604002-00010. |
| 24777214 | Background | McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 2014 May;133(5):872-83. doi: 10.1542/peds.2013-3995. |
| 27773355 | Background | Vuong HE, Hsiao EY. Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder. Biol Psychiatry. 2017 Mar 1;81(5):411-423. doi: 10.1016/j.biopsych.2016.08.024. Epub 2016 Aug 26. |
| 21358411 | Background | Miles JH. Autism spectrum disorders--a genetics review. Genet Med. 2011 Apr;13(4):278-94. doi: 10.1097/GIM.0b013e3181ff67ba. |
| 19218885 | Background | Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009 Jun;65(6):591-8. doi: 10.1203/PDR.0b013e31819e7203. |