Role of the Gut Vascular Barrier and Microbiota in Autism Spectrum Disorders

Official title

Role of the Gut Vascular Barrier and Microbiota in Autism Spectrum Disorders: Evaluation of Efficacy of Postbiotic-based Nutraceutical Treatment

Overview

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.

Detailed description

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.

Interventions

• Dietary supplement PostbiotiX Comfort®
  Treatment with a postbiotic dietary supplement, PostbiotiX Comfort®, administered for 1 month in participants from Group 1 and Group 2.
• Other Control
  Participants in Group 3 do not receive any treatment.

Primary outcome measures

• Modulation of Gastrointestinal Symptoms in ASD with Postbiotic Supplement [Time frame: 24 months]

Secondary outcome measures (7)

• Effects of postbiotics on sleep regulation [Time frame: 24 months]
• Effects of postbiotics on behavioral regulation [Time frame: 24 months]
• Effects of postbiotics on sensory profile [Time frame: 24 months]
• Metagenomic analyses in typically developing children and in ASD before and after postbiotic treatment [Time frame: 24 months]
• Metabolomic analyses in typically developing children and in ASD before and after postbiotic treatment [Time frame: 24 months]
• Intestinal permeability analyses in typically developing children and in ASD before and after postbiotic treatment [Time frame: 24 months]
• Investigation of the relationships between metagenomic/metabolomic profiles and behavioral/GI outcomes in children with ASD [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• Group 1 and 2:

Inclusion criteria

• Diagnosis of ASD according to DSM-5 diagnostic criteria;
• Clinical neurological evaluation by child neurologist and neuropsychologist with administration of standardized instruments such as Autism Diagnostic Observation Schedule-2 (ADOS-2) and/or Autism Diagnostic Interview-Revised (ADI-R) to support diagnosis;
• Assessment of psychomotor or intellectual development (Griffiths Scales, Wechsler Scales, Leiter Scale)
• Assessment of the following symptoms in the past three months: constipation, diarrhea, abnormal stool consistency, abnormal stool smell, flatulence, abdominal pain, unexplained daytime irritability, and nighttime awakening, and abdominal tenderness. The degree of gastrointestinal disturbances will be quantified before recruitment using an Italian version of the GI Severity Index. A score of at least 2 in a single item of gastrointestinal symptoms (item 1-6) was required for entry into the symptomatic group.
• Signed informed consent for analysis of intestinal microbiota and metabolome and administration of nutraceutical therapy with PostbiotiX Comfort ®.

Group 3 Inclusion criteria

• Males or females aged between 3 and 8 years whit typical development and absence of gastrointestinal symtomps
• Signed informed consent for analysis of intestinal microbiota and metabolome

Exclusion criteria

Group 1 and 2

• Exclusion Criteria
• Children with syndromic ASD or defined genetic diseases;
• Subjects with significant health problems requiring surgical treatment or continuous medical; treatment;
• Severe gastrointestinal problems requiring immediate (life-threatening) treatment;
• Severely underweight/malnourished children;
• Use of medications that may affect biomarkers assessed, for example: antibiotics and/or pre-, probiotics within 1 month prior to enrollment.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 2 centers

• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan
• IRCCS Humanitas Reasearch Hospital (ICH) Laboratory of Microbiota and Mucosal Immunology — Milan

Publications

• 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. PMID 7814313
• Althoff RR. Dysregulated children reconsidered. J Am Acad Child Adolesc Psychiatry. 2010 Apr;49(4):302-5. No abstract available. PMID 20410722
• 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. PMID 9065877
• 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. PMID 24193577
• 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. PMID 24520333
• Tsilingiri K, Rescigno M. Postbiotics: what else? Benef Microbes. 2013 Mar 1;4(1):101-7. doi: 10.3920/BM2012.0046. PMID 23271068
• 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. PMID 22713266
• 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. PMID 22301383

Identifiers

NCT: NCT07450443 · DSA/GVB

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗