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BMC Psychiatry
Published in: BMC Psychiatry 1/2016

Open Access 01-12-2016 | Study protocol

Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters

Authors: Elisa Santocchi, Letizia Guiducci, Francesca Fulceri, Lucia Billeci, Emma Buzzigoli, Fabio Apicella, Sara Calderoni, Enzo Grossi, Maria Aurora Morales, Filippo Muratori

Published in: BMC Psychiatry | Issue 1/2016

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Abstract

Background

A high prevalence of a variety of gastrointestinal (GI) symptoms is frequently reported in patients with Autism Spectrum Disorders (ASD). The GI disturbances in ASD might be linked to gut dysbiosis representing the observable phenotype of a “gut-brain axis” disruption. The exploitation of strategies which can restore normal gut microbiota and reduce the gut production and absorption of toxins, such as probiotics addition/supplementation in a diet, may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this randomized controlled trial is to determine the effects of supplementation with a probiotic mixture (Vivomixx®) in ASD children not only on specific GI symptoms, but also on the core deficits of the disorder, on cognitive and language development, and on brain function and connectivity. An ancillary aim is to evaluate possible effects of probiotic supplementation on urinary concentrations of phthalates (chemical pollutants) which have been previously linked to ASD.

Methods

A group of 100 preschoolers with ASD will be classified as belonging to a GI group or to a Non-GI (NGI) group on the basis of a symptom severity index specific to GI disorders. In order to obtain four arms, subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotics or with placebo for 6 months. All participants will be assessed at baseline, after three months and after six months from baseline in order to evaluate the possible changes in: (1) GI symptoms; (2) autism symptoms severity; (3) affective and behavioral comorbid symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal function; (5) neurophysiological patterns.

Discussion

The effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trials. Examining the impact of probiotics not only on clinical but also on neurophysiological patterns, the current trial sets out to provide new insights into the gut-brain connection in ASD patients. Moreover, results could add information to the relationship between phthalates levels, clinical features and neurophysiological patterns in ASD.

Trial registration

ClinicalTrials.gov Identifier: NCT02708901. Retrospectively registered: March 4, 2016.
Literature
1.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington DC: American Psychiatric Association; 2013.CrossRef
2.
Goodwin MS, Cowen MA, Goodwin TC. Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophr. 1971;1:48–62.CrossRefPubMed
3.
Klukowski M, Wasilewska J, Lebensztejn D. Sleep and gastrointestinal disturbances in autism spectrum disorder in children. Dev Period Med. 2015;19:157–61.PubMed
4.
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;48:248–54.CrossRefPubMed
5.
Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays. 2014;36:933–9.CrossRefPubMed
6.
Bresnahan M, Hornig M, Schultz AF, Gunnes N, Hirtz D, Lie KK, Magnus P, Reichborn-Kjennerud T, Roth C, Schjølberg S, Stoltenberg C, Surén P, Susser E, Lipkin WI. Association of maternal report of infant and toddler gastrointestinal symptoms with autism: evidence from a prospective birth cohort. JAMA Psychiatry. 2015;72:466–74.CrossRefPubMedPubMedCentral
7.
Buie T, Campbell DB, Fuchs 3rd GJ, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125 Suppl 1:S1–18.CrossRefPubMed
8.
Coury DL, Ashwood P, Fasano A, Fuchs G, Geraghty M, Kaul A, Mawe G, Patterson P, Jones NE. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics. 2012;130 Suppl 2:S160–168.CrossRefPubMed
9.
Kohane IS, McMurry A, Weber G, MacFadden D, Rappaport L, Kunkel L, Bickel J, Wattanasin N, Spence S, Murphy S, Churchill S. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7, e33224.CrossRefPubMedPubMedCentral
10.
McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 2014;133:872–83.CrossRefPubMed
11.
Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002;14:583–7.CrossRefPubMed
12.
White JF. Intestinal pathophysiology in autism. Exp Biol Med (Maywood). 2003;228(6):639–49.
13.
Levy SE, Souders MC, Ittenbach RF, Giarelli E, Mulberg AE, Pinto-Martin JA. Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders. Biol Psychiatry. 2007;61:492–7.CrossRefPubMed
14.
Mazefsky CA, Schreiber DR, Olino TM, Minshew NJ. The association between emotional and behavioral problems and gastrointestinal symptoms among children with high-functioning autism. Autism. 2014;18:493–501.CrossRefPubMed
15.
De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M, Francavilla R. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013;8, e76993.CrossRefPubMedPubMedCentral
16.
Parracho HM, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005;54(Pt 10):987–91.CrossRefPubMed
17.
Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, Youn E, Summanen PH, Granpeesheh D, Dixon D, Liu M, Molitoris DR, Green JA 3rd. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16:444–53.CrossRefPubMed
18.
19.
Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013;4:42.CrossRefPubMedPubMedCentral
20.
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009;136:2003–14.CrossRefPubMed
21.
Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 2009;6:306–14.CrossRefPubMed
22.
Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701–12.CrossRefPubMed
23.
Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S. Normal gut microbiota modulates brain development and behaviour. Proc Natl Acad Sci U S A. 2011;108:3047–52.CrossRefPubMed
24.
Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res. 2015;63:1–9.CrossRefPubMed
25.
Bercik P, Collins SM. The effects of inflammation, infection and antibiotics on the microbiota-gut-brain axis. Adv Exp Med Biol. 2014;817:279–89.CrossRefPubMed
26.
Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. Microbiota is essential for social development in the mouse. Mol Psychiatry. 2014;19:146–8.CrossRefPubMed
27.
Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr. 2013;167:374–9.CrossRefPubMed
28.
Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144:1394–401.CrossRefPubMed
29.
de Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J, Garssen J, Kraneveld AD, Oozeer R. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun. 2014;37:197–206.CrossRefPubMed
30.
Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90:859–904.CrossRefPubMed
31.
Borre YE, Moloney RD, Clarke G, Dinan TG, Cryan JF. The impact of microbiota on brain and behavior: mechanisms and therapeutic potential. Adv Exp Med Biol. 2014;817:373–403.CrossRefPubMed
32.
Fond G, Boukouaci W, Chevalier G, Regnault A, Eberl G, Hamdani N, Dickerson F, Macgregor A, Boyer L, Dargel A, Oliveira J, Tamouza R, Leboyer M. The "psychomicrobiotic": Targeting microbiota in major psychiatric disorders: A systematic review. Pathol Biol (Paris). 2015;63:35–42.CrossRef
33.
Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, Krajmalnik-Brown R. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One. 2013;8, e68322.CrossRefPubMedPubMedCentral
34.
Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA. Gastrointestinal flora and gastrointestinal status in children with autism--comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011;11:22.CrossRefPubMedPubMedCentral
35.
Borre YE, O'Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014;20:509–18.CrossRefPubMed
36.
37.
Rodrigues DH, Rocha NP, Sousa LF, Barbosa IG, Kummer A, Teixeira AL. Changes in adipokine levels in autism spectrum disorders. Neuropsychobiology. 2014;69:6–10.CrossRefPubMed
38.
de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, Bravaccio C. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51:418–24.CrossRefPubMed
39.
Vissers ME, Cohen MX, Geurts HM. Brain connectivity and high functioning autism: a promising path of research that needs refined models, methodological convergence, and stronger behavioral links. Neurosci Biobehav Rev. 2012;36:604–25.CrossRefPubMed
40.
Uddin LQ, Supekar K, Menon V. Reconceptualizing functional brain connectivity in autism from a developmental perspective. Front Hum Neurosci. 2013;7:458.CrossRefPubMedPubMedCentral
41.
Billeci L, Sicca F, Maharatna K, Apicella F, Narzisi A, Campatelli G, Calderoni S, Pioggia G, Muratori F. On the application of quantitative EEG for characterizing autistic brain: a systematic review. Front Hum Neurosci. 2013;7:442–7.CrossRefPubMedPubMedCentral
42.
de Theije CG, Wu J, da Silva SL, Kamphuis PJ, Garssen J, Korte SM, Kraneveld AD. Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol. 2011;668:S70–80.CrossRefPubMed
43.
Critchfield JW, van Hemert S, Ash M, Mulder L, Ashwood P. The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterol Res Pract. 2011;2011:1–8.CrossRef
44.
Caselli M, Cassol F, Calò G, Holton J, Zuliani G, Gasbarrini A. Actual concept of "probiotics": is it more functional to science or business? World J Gastroenterol. 2013;19:1527–40.CrossRefPubMedPubMedCentral
45.
Bevilacqua L, Ovidi M, Di Mattia E, Trovatelli LD, Canganella F. Screening of Bifidobacterium strains isolated from human faeces for antagonistic activities against potentially bacterial pathogens. Microbiol Res. 2003;158:179–85.CrossRefPubMed
46.
Surawicz CM. Role of probiotics in antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, and recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2008;2:S64–70.CrossRef
47.
McFarland LV. Evidence-based review of probiotics for antibiotic-associated diarrhea and Clostridium difficile infections. Anaerobe. 2009;15:274–80.CrossRefPubMed
48.
Rohde CL, Bartolini V, Jones N. The use of probiotics in the prevention and treatment of antibiotic-associated diarrhea with special interest in Clostridium difficile-associated diarrhea. Nutr Clin Pract. 2009;24:33–40.CrossRefPubMed
49.
Folkers BL, Schuring C, Essmann M, Larsen B. Quantitative real time PCR detection of Clostridium difficile growth inhibition by probiotic organisms. N Am J Med Sci. 2010;2:5–10.PubMedPubMedCentral
50.
51.
Sealey LA, Hughes BW, Sriskanda AN, Guest JR, Gibson AD, Johnson-Williams L, Pace DG, Bagasra O. Environmental factors in the development of autism spectrum disorders. Environ Int. 2016;88:288–98.CrossRefPubMed
52.
Testa C, Nuti F, Hayek J, De Felice C, Chelli M, Rovero P, Latini G, Papini AM. Di-(2-ethylhexyl) phthalate and autism spectrum disorders. ASN Neuro. 2012;4:223–9.CrossRefPubMed
53.
54.
Parracho HMRT, Gibson GR, Knott F, Bosscher D, Kleerebezem M, McCartney AL. A double blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders. International Journal of Probiotics and Prebiotics. 2010;5:69–74.
55.
Kaluzna-Czaplinska J, Blaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012;28:124–6.CrossRefPubMed
56.
Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, Ostatnikova D. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. 2015;138:179–87.CrossRefPubMed
57.
Srinivasjois R, Rao S, Patole S. Probiotic supplementation in children with autism spectrum disorder. Arch Dis Child. 2015;100:505–6.CrossRefPubMed
58.
Liu X, Cao S, Zhang X. Modulation of Gut Microbiota-Brain Axis by Probiotics, Prebiotics, and Diet. J Agric Food Chem. 2015;63:7885–95.CrossRefPubMed
59.
McPheeters ML, Weitlauf A, Vehorn A, Taylor C, Sathe NA, Krishnaswami S, Fonnesbeck C, Warren ZE. Screening for Autism Spectrum Disorder in Young Children: A Systematic Evidence Review for the U.S. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016. Report No.: 13-05185-EF-1.
60.
Schneider CK, Melmed RD, Barstow LE, Enriquez FJ, Ranger-Moore J, Ostrem JA. Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. J Autism Dev Disord. 2006;36:1053–64.CrossRefPubMed
61.
Lord C, Rutter M, Di Lavore PC, Risi S, Gotham K, Bishop SL. Autism and Diagnostic Observation Schedule, Second Edition (ADOS-2) Manual (Part I): Modules 1–4. Torrance, CA: Western Psychological Services; 2012.
62.
Rutter M, Le Couteur A, Lord C. ADI-R: The autism diagnostic interview-revised. Los Angeles, CA: Western Psychological Services; 2003.
63.
Lord C, Rutter M, DiLavore P, Risi S. ADOS Autism Diagnostic Observation Schedule. Los Angeles: Western Psychological Services; 2001.
64.
Green J, Charman T, McConachie H, Aldred C, Slonims V, Howlin P, Le Couteur A, Leadbitter H, Byford S, Barrett B, Temple K, Macdonald W, Pickles A. The PACT Consortium: Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial. Lancet. 2010;375:2152–60.CrossRefPubMedPubMedCentral
65.
Aldred C, Green J, Adams C. A new social communication intervention for children with autism: pilot randomised controlled treatment study suggesting effectiveness. J Child Psychol Psyc. 2004;45:1420–30.CrossRef
66.
Owley T, McMahon W, Cook EH, Laulhere T, South M, Mays LZ, Shernoff ES, Lainhart J, Modahl CB, Corsello C, Ozonoff S, Risi S, Lord C, Leventhal BL, Filipek PA. Multisite, double-blind, placebo-controlled trial of porcine secretin in autism. J Am Acad Child Psy. 2001;40:1293–9.CrossRef
67.
Byford S, Cary M, Barrett B, Aldred CR, Charman T, Howlin P, Hudry K, Leadbitter K, Le Couteur A, McConachie H, Pickles A, Slonims V, Temple KJ, Green J. PACT Consortium. Cost-effectiveness analysis of a communication-focused therapy for pre-school children with autism: results from a randomised controlled trial. BMC Psychiatry. 2015;15:316–29.CrossRefPubMedPubMedCentral
68.
Gotham K, Pickles A, Lord C. Standardizing ADOS scores for a measure of severity in autism spectrum disorders. J Autism Dev Disord. 2009;39:693–705.CrossRefPubMed
69.
Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330:1841–5.CrossRefPubMed
70.
Schopler E, Reichler RJ, Renner BR. The Childhood Autism Rating Scale. Los Angeles: Western Psychological Services; 1988.
71.
Rutter M, Bailey A, Lord C. Social communication questionnaire (SCQ). Los Angeles: Western Psychological Services; 2003.
72.
Achenbach TM, Rescorla A. Manual for the ASEBA preschool forms and profiles. Burlington, VT: University of Vermont Department of Psychiatry; 2000.
73.
Dunn W. Performance of typical children on the Sensory Profile: An item analysis. Am J Occup Ther. 1994;48:967–74.CrossRefPubMed
74.
Bodfish JW, Symons FJ, Parker DE, Lewis MH. Varieties of repetitive behavior in autism: Comparisons to mental retardation. J Autism Dev Disord. 2000;30:237–43.CrossRefPubMed
75.
Fulceri F, Narzisi A, Apicella F, Balboni G, Baldini S, Brocchini J, Domenici I, Cerullo S, Igliozzi R, Cosenza A, Tancredi R, Muratori F, Calderoni S. Application of the Repetitive Behavior Scale-Revised -Italian version- in preschoolers with autism spectrum disorder. Res Dev Disabil. 2016;48:43–52.CrossRefPubMed
76.
Abidin RR. Parenting Stress Index - Short Form (3rd edition). Odessa, FL: Psychological Assessment Resources Inc; 1995.
77.
Sparrow SS, Cicchetti VD, Balla AD. Vineland Adaptive Behavior Scales, 2nd edition. Circle Pines, MN: American Guidance Service; 2005.
78.
Griffiths R. The Griffiths mental development scales, revision. UK: Association for Research in Infant and Child Development, the Test Agency; 1996.
79.
Fenson L, Dale PS, Reznick JS, Thal D, Bates E, Hartung JP, Pethick S, Reilly JS. MacArthur Communicative Development Inventories: User’s guide and technical manual. San Diego, CA: Singular Press; 1993.
80.
Narzisi A, Muratori F, Buscema M, Calderoni S, Grossi E. Outcome predictors in autism spectrum disorders preschoolers undergoing treatment as usual: insights from an observational study using artificial neural networks. Neuropsychiatr Dis Treat. 2015;11:1587–99.CrossRefPubMedPubMedCentral
Metadata
Title
Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters
Authors
Elisa Santocchi
Letizia Guiducci
Francesca Fulceri
Lucia Billeci
Emma Buzzigoli
Fabio Apicella
Sara Calderoni
Enzo Grossi
Maria Aurora Morales
Filippo Muratori
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Psychiatry / Issue 1/2016
Electronic ISSN: 1471-244X
DOI
https://doi.org/10.1186/s12888-016-0887-5

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