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Autism and neuro-immune-gut link

  • Recent evidences sustain the hypothesis that host-bacteria interactions play a critical role in regulating tissue and body homeostasis. Gut microbiota and the brain are strongly interconnected and share communication pathways. Modifications in gut bacteria compositions are correlated to changes in behaviors. Indeed, autism spectrum disorders (ASD) are linked to dysfunctions of the gut bacteria-brain axis. Possible therapeutic strategies in ASD management will aim to restore dysbiosis and gut bacteria imbalance.

    Citation: Dario Siniscalco, Anna Lisa Brigida, Nicola Antonucci. Autism and neuro-immune-gut link[J]. AIMS Molecular Science, 2018, 5(2): 166-172. doi: 10.3934/molsci.2018.2.166

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  • Recent evidences sustain the hypothesis that host-bacteria interactions play a critical role in regulating tissue and body homeostasis. Gut microbiota and the brain are strongly interconnected and share communication pathways. Modifications in gut bacteria compositions are correlated to changes in behaviors. Indeed, autism spectrum disorders (ASD) are linked to dysfunctions of the gut bacteria-brain axis. Possible therapeutic strategies in ASD management will aim to restore dysbiosis and gut bacteria imbalance.


    1. Introduction

    The risk of cerebral palsy (CP) is inversely correlated with gestational age at birth [1]. CP is accompanied with life-long consequences for the child, its family and society as a whole.Meta-analyses haveindicated that magnesium sulphate may be neuroprotective for the preterm infant, when the drug is given to women at high risk of preterm birth [2,3]. However, this was recently questioned by a trial sequential analysis (TSA), a statistical method which adjusts for risk of random errors [4]. The TSA demonstrated that additional data are needed before accepting magnesium sulphateas evidence-based therapy for women in preterm labour.

    Our aim is toinvestigate if antenatal magnesium sulphate administrated to women at risk of preterm birth can protect their children against CP.

    2. Materials and methodology:

    This trial is ongoing and is performed as a double-blinded, randomized, controlled, multicenter clinical trial. A study population consisting of 500 women, who are at risk of preterm birth at 24 to 32 weeks of gestation, are randomized to receive either intravenous magnesium sulphate or placebo with saline. The women are recruited from 14 obstetrics departments in Denmark. The children are followed up after 18 months of age by a questionnaire (The Ages & Stages Questionnaire), which is a standardized, validated questionnaire containing questions that can reveal signs of CP [5]. The trial is approved by the Scientific Ethics Committee of the Capital Region of Denmark (H-4-2011-024), the Danish Data Protection Agency (HVH-2011-41-6007) and is registered at ClinicalTrials.gov (no. NCT01492608).

    Inclusion criteria are: maternal age ≥ 18 years, gestational age 24+0 to 31+6 weeks, singleton or twin pregnancy, preterm rupture of membranes at 24+0 to 31+6 weeks with contractions and expected birth within 2-24 hours, or preterm contractions and expected birth within 2-24 hours and finally anticipated delivery within 2-24 hours of other reasons (for example fetal growth restriction).

    Exclusion criteria are major fetal abnormalities, maternal contraindication to magnesium sulphate (e.g. allergy, myasthenia gravis, kidney failure and heart disease), magnesium sulphate administrated for other reasons (e.g. for prevention of eclampsia) and lack of the ability to understand and speak Danish.

    2.1. Administration of magnesium sulphate:

    Magnesium sulphate is administrated as a loading dose of five grams infused for 20-30 minutes, followed by a maintenance dose of one gram per hour. Placebo is given in identical appearing doses. The maintenance infusion will be continued until delivery appears, or for 24 hours if delivery does not occur or no longer is considered imminent. The doses that are used in this project are similar to those used in Denmark for prevention of eclampsia. Blood pressure, pulse rate, respiration rate and reflexes are being controlled throughout the period. Also the fetal heart is monitored closely.

    2.2. Follow-up of the children:

    The children are followed up after 18 months of age. A questionnaire will be sent to the parents. If signs of CP are revealed from the questionnaire, the children will be examined neurologically by a pediatrician. The effect will be assessed blinded to the treatment.

    3. Power calculation:

    A total sample size of 500 patients would allow us to detect or reject a difference in CP of 25% or more with a 5% type 1 error risk. The present trial will with a power of only 13%, not in itself have the power to detect a significant difference between magnesium and placebo treatment. Instead, when the trial is completed, the results will be added to the existing data in a cumulative meta-analysis, in order to ‘close the gap of evidence’ in a TSA, and determine whether magnesium sulphate has an effect. The power of the new meta-analysis will be 63%. We used a one-sided test as a harmful effect of magnesium sulphate on CP seems unlikely according to previous data.

    4. Current status and future perspectives:

    To date more than 380 women have been included in the trial. We expect the inclusion period to end in December 2016. Positive results of this trial will support a change of the clinical guidelines concerning the treatment of women with threatening preterm birth.

    Conflict of Interest

    No conflict of interests.

    [1] Blikslager AT, Moeser AJ, Gookin JL, et al. (2007) Restoration of barrier function in injured intestinal mucosa. Physiol Rev 87: 545. doi: 10.1152/physrev.00012.2006
    [2] Podolsky DK (1999) V. Innate mechanisms of mucosal defense and repair: The best offense is a good defense. Am J Physiol 277: G495–G499.
    [3] Kunzelmann K, Mall M (2002) Electrolyte transport in the mammalian colon: Mechanisms and Implications for disease. Physiol Rev 82: 245–289. doi: 10.1152/physrev.00026.2001
    [4] Ferraris RP, Diamond J (1997) Regulation of intestinal sugar transport. Physiol Rev 77: 257–302. doi: 10.1152/physrev.1997.77.1.257
    [5] Groschwitz KR, Hogan SP (2009) Intestinal barrier function: Molecular regulation and disease pathogenesis. J Allergy Clin Immunol 124: 3–22. doi: 10.1016/j.jaci.2009.05.038
    [6] Bischoff S, Barbara G, Buurman W, et al. (2014) Intestinal permeability-A new target for disease prevention and therapy. BMC Gastroenterol 14: 189–214. doi: 10.1186/s12876-014-0189-7
    [7] Van Itallie CM, Holmes J, Bridges A, et al. (2008) The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J Cell Sci 121: 298–305. doi: 10.1242/jcs.021485
    [8] Ulluwishewa D, Anderson RC, Mcnabb WC, et al. (2011) Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr 141: 769–776. doi: 10.3945/jn.110.135657
    [9] De Magistris L, Picardi A, Sapone A, et al. (2014) Intestinal barrier in autism, In: Patel VB (ed.), Comprehensive guide to autism, New York: Springer, 123.
    [10] Catassi C, Fasano A (2008) Celiac disease. Curr Opin Gastroenterol 24: 687–691. doi: 10.1097/MOG.0b013e32830edc1e
    [11] Bjarnason I, Macpherson A, Hollander D (1995) Intestinal permeability: An overview. Gastroenterology 108: 1566–1581. doi: 10.1016/0016-5085(95)90708-4
    [12] Fasano A (2011) Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity and cancer. Physiol Rev 91: 151–175. doi: 10.1152/physrev.00003.2008
    [13] Lerner A, Matthias T (2015) Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmun Rev 14: 479–489. doi: 10.1016/j.autrev.2015.01.009
    [14] Siniscalco D, Cirillo A, Bradstreet JJ, et al. (2013) Epigenetic findings in autism: New perspectives for therapy. Int J Environ Res Public Health 10: 4261–4273. doi: 10.3390/ijerph10094261
    [15] Siniscalco D, Antonucci N (2013) Possible use of Trichuris suis ova in autism spectrum disorders therapy. Med Hypotheses 81: 1–4. doi: 10.1016/j.mehy.2013.03.024
    [16] Wakefield AJ (2002) The gut-brain axis in childhood developmental disorders. J Pediatr Gastroenterol Nutr 34: S14–S17. doi: 10.1097/00005176-200205001-00004
    [17] Siniscalco D (2014) Gut bacteria-brain axis in autism. Autism 4: e124.
    [18] Siniscalco D, Antonucci N (2013) Involvement of dietary bioactive proteins and peptides in autism spectrum disorders. Curr Protein Pept Sci 14: 674–679.
    [19] Trivedi MS, Shah JS, Al-Mughairy S, et al. (2014) Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences. J Nutr Biochem 25: 1011–1018. doi: 10.1016/j.jnutbio.2014.05.004
    [20] Frustaci A, Neri M, Cesario A, et al. (2012) Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radic Biol Med 52: 2128–2141. doi: 10.1016/j.freeradbiomed.2012.03.011
    [21] Melnyk S, Fuchs GJ, Schulz E, et al. (2012) Metabolic imbalance associated with methylation dys-regulation and oxidative damage in children with autism. J Autism Dev Disord 42: 367–377. doi: 10.1007/s10803-011-1260-7
    [22] Shattock P, Whiteley P (2002) Biochemical aspects in autism spectrum disorders: Updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets 6: 175–183. doi: 10.1517/14728222.6.2.175
    [23] Siniscalco D, Sapone A, Giordano C, et al. (2013) Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord 43: 2686–2695. doi: 10.1007/s10803-013-1824-9
    [24] Siniscalco D, Bradstreet JJ, Cirillo A, et al. (2014) The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. J Neuroinflammation 11: 78. doi: 10.1186/1742-2094-11-78
    [25] Fiorentino M, Sapone A, Senger S, et al. (2016) Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism 7: 49. doi: 10.1186/s13229-016-0110-z
    [26] Rose DR, Yang H, Serena G, et al. (2018) Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun 70: 354–368. doi: 10.1016/j.bbi.2018.03.025
    [27] Lionetti E, Leonardi S, Franzonello C, et al. (2015) Gluten psychosis: Confirmation of a new clinical entity. Nutrients 7: 5532–5539. doi: 10.3390/nu7075235
    [28] O'Mahony SM, Clarke G, Borre YE, et al. (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277: 32–48. doi: 10.1016/j.bbr.2014.07.027
    [29] Theije CGMD, Koelink PJ, Korte-Bouws GA, et al. (2014) Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun 37: 240–247. doi: 10.1016/j.bbi.2013.12.004
    [30] Baganz NL, Blakely RD (2013) A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci 4: 48–63. doi: 10.1021/cn300186b
    [31] Van Elst K, Bruining H, Birtoli B, et al. (2014) Food for thought: Dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. Neurosci Biobehav Rev 45: 369–738. doi: 10.1016/j.neubiorev.2014.07.004
    [32] Halliwell B (2006) Oxidative stress and neurodegeneration: Where are we now? J Neurochem 97: 1634–1658. doi: 10.1111/j.1471-4159.2006.03907.x
    [33] Cartocci V, Catallo M, Tempestilli M, et al. (2018) Altered brain cholesterol/isoprenoid metabolism in a rat model of autism spectrum disorders. Neuroscience 372: 27–37. doi: 10.1016/j.neuroscience.2017.12.053
    [34] Brigida AL, Schultz S, Cascone M, et al. (2017) Endocannabinod signal dysregulation in autism spectrum disorders: A correlation link between inflammatory state and neuro-immune alterations. Int J Mol Sci 18: 1425. doi: 10.3390/ijms18071425
    [35] Acharya N, Penukonda S, Shcheglova T, et al. (2017) Endocannabinoid system acts as a regulator of immune homeostasis in the gut. Proc Natl Acad Sci USA 114: 5005–5010. doi: 10.1073/pnas.1612177114
    [36] Gyires K, Zádori ZS (2016) Role of cannabinoids in gastrointestinal mucosal defense and inflammation. Curr Neuropharmacol 14: 935–951. doi: 10.2174/1570159X14666160303110150
    [37] Maríbauset S, Llopisgonzález A, Zazpe I, et al. (2016) Nutritional Impact of a Gluten-Free Casein-Free Diet in Children with Autism Spectrum Disorder. J Autism Dev Disord 46: 673–684. doi: 10.1007/s10803-015-2582-7
    [38] Iovene MR, Bombace F, Maresca R, et al. (2017) Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders. Mycopathologia 182: 349–363. doi: 10.1007/s11046-016-0068-6
    [39] Siniscalco D, Mijatovic T, Bosmans E, et al. (2016) Decreased Numbers of CD57 + CD3- Cells Identify Potential Innate Immune Differences in Patients with Autism Spectrum Disorder. Vivo 30: 83–89.
    [40] de Theije CG, Wopereis H, Ramadan M, et al. (2014) Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun 37: 197–206. doi: 10.1016/j.bbi.2013.12.005
    [41] Needham BD, Tang W, Wu WL (2018) Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder. Dev Neurobiol 78: 474–499. doi: 10.1002/dneu.22581
    [42] Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20: 145–155. doi: 10.1038/nn.4476
    [43] Santocchi E, Guiducci L, Fulceri F, et al. (2016) 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 16: 183. doi: 10.1186/s12888-016-0887-5
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