Gut to Brain Interaction in Autism. Role of Probiotics on Clinical, Biochemical and Neurophysiological Parameters

Overview

The purpose of this study is to assess the effects of a 6-months supplementation with probiotic Vivomixx® on inflammatory and gastrointestinal (GI) biomarkers, gastrointestinal disturbances, behavioral and developmental profiles, and neurophysiological features in preschoolers with Autism Spectrum Disorders (ASD) with or without GI symptoms.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: August 2018

Detailed Description

Autism Spectrum Disorders (ASD) are most likely multifactorial diseases in which the combination of genetic and environmental factors might have a role in the expression of the phenotype. A high incidence of gastrointestinal (GI) symptoms is reported in ASD. GI disturbances and altered gut microflora could make a child with a genetic predisposition for ASD more prone to express the ASD phenotype or increase the severity of his behavioral symptoms. The exploitation of strategies which can reduce the gut production and absorption of toxins or restore normal gut microbiota, such as probiotics may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this study is to determine effects of probiotics supplementation with Vivomixx® in ASD children on specific GI symptoms, ASD core deficits, cognitive and language development, on inflammatory and gastrointestinal (GI) biomarkers and on Quantitative Electroencephalographic measures (QEEG). Vivomixx® is a probiotic mixture of 8 probiotic strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus and Streptococcus thermophilus). An additional aim of the study is to determine the environmental exposure to phthalates (chemical pollutant) in ASD children, and the possible effects of probiotic supplementation on their urinary concentrations. A group of 100 unselected preschoolers with ASD will be classified as belonging to the Gastro Intestinal (GI) group or to the Not Gastro Intestinal (NGI) group on the basis of the presence of significant GI symptoms at GI severity Index. Subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotic Vivomixx® or with placebo for 6 months. All the participants will be assessed at the baseline, after three months and after six months from the baseline in order to evaluate the possible changes in GI symptoms, in ASD symptomatology, in other affective and behavioral comorbid symptoms, in plasmatic, urinary and fecal biomarkers related to abnormal intestinal function and in the electrophysiological patterns. The effects of treatments with probiotics on children with ASD need to be confirmed by rigorous controlled trials. Aiming to examine the impact of this treatment not only on clinical but also on neurophysiological patterns this trial sets out to provide new insights into the gut-brain connection in autism. Moreover, this study's results could add new data on the relationship between the presence of phthalates, clinical features and neurophysiological patterns in ASD.

Interventions

  • Dietary Supplement: Vivomixx®
    • Two packets (900 billions bacteria) per os (P.O.) daily x 1 month and one packet (450 billions bacteria) P.O. daily x 5 months
  • Dietary Supplement: Placebo
    • Two packets (4,4 grams of maltose and silicon dioxide x 2) P.O. daily x 1 month and one packet (4,4 grams of maltose and silicon dioxide) P.O. daily x 5 months

Arms, Groups and Cohorts

  • Active Comparator: GI Vivomixx®
    • 25 children with GI symptoms
  • Placebo Comparator: GI Placebo
    • 25 children with GI symptoms
  • Active Comparator: NGI Vivomixx®
    • 25 children without GI symptoms
  • Placebo Comparator: NGI placebo
    • 25 children without GI symptoms

Clinical Trial Outcome Measures

Primary Measures

  • Changes in severity level of ASD symptomatology
    • Time Frame: 6 months
    • Delta of scores at Autism Diagnostic Observation Schedule-2

Secondary Measures

  • Changes in GI symptomatology
    • Time Frame: 3 months and 6 months
    • Delta of scores at GI Severity Index
  • Changes in Electroencephalogram (EEG) power
    • Time Frame: 6 months
    • Registration with a 128-channels digital EEG: power will be assessed within each frequency band
  • Changes in EEG coherence
    • Time Frame: 6 months
    • Registration with a 128-channels digital EEG: coherence will be assessed within each frequency band
  • Changes in EEG asymmetry
    • Time Frame: 6 months
    • Registration with a 128-channels digital EEG: asymmetry will be assessed within each frequency band
  • Changes in levels of serum Lipopolysaccharide
    • Time Frame: 6 months
    • Delta of values of serum Lipopolysaccharide
  • Changes in levels of serum Leptin
    • Time Frame: 6 months
    • Delta of values of serum Leptin
  • Changes in levels of serum Resistin
    • Time Frame: 6 months
    • Delta of values of serum Resistin
  • Changes in levels of serum Tumor Necrosis Factor – alfa
    • Time Frame: 6 months
    • Delta of values of serum Tumor Necrosis Factor – alfa
  • Changes in levels of serum Interleukin-6 (IL-6)
    • Time Frame: 6 months
    • Delta of values of serum Interleukin-6 (IL-6)
  • Changes in levels of serum Plasminogen Activator Inhibitor-1 (PAI-1)
    • Time Frame: 6 months
    • Delta of values of serum Plasminogen Activator Inhibitor-1 (PAI-1)
  • Changes in levels of fecal calprotectin
    • Time Frame: 3 months and 6 months
    • Delta of values of fecal calprotectin
  • Changes in global ASD symptomatology assessed by Childhood Autism Rating Scale
    • Time Frame: 6 months
    • Delta of scores at Childhood Autism Rating Scale
  • Changes in ASD symptomatology: repetitive behaviors
    • Time Frame: 3 months and 6 months
    • Delta of scores at Repetitive Behavior Scale
  • Changes in ASD symptomatology: sensory profiles
    • Time Frame: 3 months and 6 months
    • Delta of scores at Sensory Profile
  • Changes in global ASD symptomatology assessed by Social Communication Questionnaire
    • Time Frame: 3 months and 6 months
    • Delta of scores at Social Communication Questionnaire
  • Changes in Developmental Quotient
    • Time Frame: 6 months
    • Delta of score at Griffiths Mental Developmental Scale
  • Changes in Adaptive Functioning
    • Time Frame: 6 months
    • Delta of scores at Vineland Adaptive Behavior Scale-II
  • Changes in Behavioral Profiles
    • Time Frame: 3 months and 6 months
    • Delta of scores at Child Behavior Checklist 1.5-5
  • Changes in Parental Stress
    • Time Frame: 3 months and 6 months
    • Delta of scores at Parenting Stress Index

Participating in This Clinical Trial

Inclusion Criteria

  • age-range: 18-72 months – ASD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria Exclusion Criteria:

  • brain anomalies detected by Magnetic Resonance Imaging (MRI) – neurological syndromes or focal neurological signs – anamnesis of birth asphyxia, severe premature birth (≤ 28 gestational weeks) or perinatal injuries – epilepsy – significant sensory impairment – diagnosis of organic GI Disorder (i.e. gastroesophageal reflux, food allergies, Inflammatory Bowel Disease) – diagnosis of Coeliac Disease – special diet (i.e. gluten-free diet, casein-free diet, high-protein diet, ketogenic diet)

Gender Eligibility: All

Minimum Age: 18 Months

Maximum Age: 72 Months

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • IRCCS Fondazione Stella Maris
  • Collaborator
    • Ministry of Health, Italy
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Elisa Santocchi, MD, PhD, Principal Investigator, IRCCS Stella Maris Foundation

References

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.

Santocchi E, Guiducci L, Fulceri F, Billeci L, Buzzigoli E, Apicella F, Calderoni S, Grossi E, Morales MA, Muratori F. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016 Jun 4;16:183. doi: 10.1186/s12888-016-0887-5.

Calderoni S, Santocchi E, Del Bianco T, Brunori E, Caponi L, Paolicchi A, Fulceri F, Prosperi M, Narzisi A, Cosenza A, Tancredi R, Muratori F. Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder. Ital J Pediatr. 2016 Nov 16;42(1):98. doi: 10.1186/s13052-016-0308-x.

Prosperi M, Santocchi E, Balboni G, Narzisi A, Bozza M, Fulceri F, Apicella F, Igliozzi R, Cosenza A, Tancredi R, Calderoni S, Muratori F. Behavioral Phenotype of ASD Preschoolers with Gastrointestinal Symptoms or Food Selectivity. J Autism Dev Disord. 2017 Nov;47(11):3574-3588. doi: 10.1007/s10803-017-3271-5.

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