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

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 Overview

• Status: Completed
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Dietary supplement: Vivomixx®; Dietary supplement: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Pisa
    • Calambrone, Pisa, Italy, 56128
      • IRCCS Stella Maris Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GI Vivomixx®; 25 children with GI symptoms	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
Placebo Comparator: GI Placebo; 25 children with GI symptoms	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
Active Comparator: NGI Vivomixx®; 25 children without GI symptoms	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
Placebo Comparator: NGI placebo; 25 children without GI symptoms	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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: IRCCS Fondazione Stella Maris
• Collaborators: Ministry of Health, Italy; Istituto di Fisiologia Clinica CNR
• Investigators: Principal Investigator: Elisa Santocchi, MD, PhD, IRCCS Stella Maris Foundation

Publications and helpful links

General Publications

• 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.
• Santocchi E, Guiducci L, Prosperi M, Calderoni S, Gaggini M, Apicella F, Tancredi R, Billeci L, Mastromarino P, Grossi E, Gastaldelli A, Morales MA, Muratori F. Effects of Probiotic Supplementation on Gastrointestinal, Sensory and Core Symptoms in Autism Spectrum Disorders: A Randomized Controlled Trial. Front Psychiatry. 2020 Sep 25;11:550593. doi: 10.3389/fpsyt.2020.550593. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: March 4, 2016
• First Submitted That Met QC Criteria: March 9, 2016
• First Posted (Estimate): March 15, 2016

Study Record Updates

• Last Update Posted (Actual): February 18, 2019
• Last Update Submitted That Met QC Criteria: February 15, 2019
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Autism Spectrum Disorder; Gastrointestinal Symptoms; Probiotic Vivomixx®; Gut-Brain Axis; Endophenotypes
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autistic Disorder; Autism Spectrum Disorder
• Other Study ID Numbers: GR-2011-02348280

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No