Zinc in Gut-Brain Interaction in Autism and Neurological Disorders

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.

[1]  H. Zoghbi,et al.  Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. , 2005, Genes & development.

[2]  J. Roman,et al.  Matrix metalloproteinase-9 regulates MUC-2 expression through its effect on goblet cell differentiation. , 2007, Gastroenterology.

[3]  B. Metzler-Zebeli,et al.  Supplementation of diets for lactating sows with zinc amino acid complex and gastric nutriment-intubation of suckling pigs with zinc methionine on mineral status, intestinal morphology and bacterial translocation in lipopolysaccharide-challenged weaned pigs. , 2009, Journal of animal physiology and animal nutrition.

[4]  J. Quarterman,et al.  The effect of zinc deficiency on sheep intestinal mucin. , 1976, Life sciences.

[5]  A. Russo Anti-metallothionein IgG and levels of metallothionein in autistic families. , 2008, Swiss medical weekly.

[6]  Emeran A. Mayer,et al.  Gut feelings: the emerging biology of gut–brain communication , 2011, Nature Reviews Neuroscience.

[7]  I. Johnson,et al.  Hexose transport and mucosal morphology in the small intestine of the zinc-deficient rat , 1984, British Journal of Nutrition.

[8]  R. Wood,et al.  High dietary calcium intakes reduce zinc absorption and balance in humans. , 1997, The American journal of clinical nutrition.

[9]  R. Stoltzfus,et al.  Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials. , 2005, The American journal of clinical nutrition.

[10]  K. Hambidge,et al.  Zinc correction of defective chemotaxis in acrodermatitis enteropathica. , 1977, Archives of dermatology.

[11]  R. Ettarh,et al.  Crypt Cell Production Rate in the Small Intestine of the Zinc-Supplemented Mouse , 2002, Cells Tissues Organs.

[12]  W. Katon,et al.  Psychiatric illness and irritable bowel syndrome: a comparison with inflammatory bowel disease. , 1990, The American journal of psychiatry.

[13]  D. Siniscalco,et al.  Intestinal Barrier in Autism , 2014 .

[14]  S. Brookes,et al.  Anatomy and physiology of the enteric nervous system , 2000, Gut.

[15]  G. Chrousos,et al.  Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Andrews,et al.  The transcriptional repressor Blimp1/Prdm1 regulates postnatal reprogramming of intestinal enterocytes , 2011, Proceedings of the National Academy of Sciences.

[17]  M. Surette,et al.  The interplay between the intestinal microbiota and the brain , 2012, Nature Reviews Microbiology.

[18]  Andreas M. Grabrucker,et al.  Environmental Factors in Autism , 2013, Front. Psychiatry.

[19]  E. Courchesne,et al.  Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism , 2010, Biological Psychiatry.

[20]  S. Koo,et al.  Effect of zinc deficiency on the ultrastructure of the pancreatic acinar cell and intestinal epithelium in the rat. , 1977, The Journal of nutrition.

[21]  R. Cousins Gastrointestinal factors influencing zinc absorption and homeostasis. , 2010, International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition.

[22]  A. Jaiswal,et al.  Zinc stabilizes adenomatous polyposis coli (APC) protein levels and induces cell cycle arrest in colon cancer cells , 2004, Journal of cellular biochemistry.

[23]  R. Shivdasani,et al.  Regulation of Mammalian Epithelial Differentiation and Intestine Development by Class I Histone Deacetylases , 2004, Molecular and Cellular Biology.

[24]  C. Keen,et al.  Developmental consequences of trace mineral deficiencies in rodents: acute and long-term effects. , 2003, The Journal of nutrition.

[25]  Kyu Shik Lee,et al.  Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway. , 2007, Cancer letters.

[26]  L. Magruder,et al.  Suppression of Antibody Response by Excess Dietary Zinc Exposure during Certain Stages of Ontogeny , 1985, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[27]  S. Genuis,et al.  Gluten Sensitivity Presenting as a Neuropsychiatric Disorder , 2014, Gastroenterology research and practice.

[28]  J. Bassaganya-Riera,et al.  Zinc deficiency alters host response and pathogen virulence in a mouse model of enteroaggregative escherichia coli-induced diarrhea , 2014, Gut microbes.

[29]  V. Rumjanek,et al.  Synergistic Effect Between Ouabain and Glucocorticoids for the Induction of Thymic Atrophy , 2006, Bioscience reports.

[30]  M. Manary,et al.  Diagnosis and treatment of severely malnourished children with diarrhoea , 2014, Journal of paediatrics and child health.

[31]  Carmela Bravaccio,et al.  Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree Relatives , 2010, Journal of pediatric gastroenterology and nutrition.

[32]  M. Elmes Apoptosis in the small intestine of zincdeficient and fasted rats , 1977, The Journal of pathology.

[33]  B. Şimşek,et al.  Prevalence of zinc deficiency and immune response in short-term hemodialysis. , 2005, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[34]  M. Harada,et al.  Wilson disease , 2002, Medical Electron Microscopy.

[35]  Geir Bjorklund,et al.  Serum copper and zinc levels in individuals with autism spectrum disorders , 2014, Neuroreport.

[36]  Z. Kovács,et al.  Depressive and Anxiety Symptoms, Dysfunctional Attitudes and Social Aspects in Irritable Bowel Syndrome and Inflammatory Bowel Disease , 2007, International journal of psychiatry in medicine.

[37]  T. Boeckers,et al.  Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. , 2014, Brain : a journal of neurology.

[38]  T. Pysher,et al.  Zinc Deficiency Acts as a Co-Teratogen with Alcohol in Fetal Alcohol Syndrome , 1985, Pediatric Research.

[39]  M. Will,et al.  Zinc transport proteins in plasma , 1981, British Journal of Nutrition.

[40]  S. Duncan,et al.  GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice. , 2011, Gastroenterology.

[41]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[42]  T. Schacker,et al.  Clinical and Epidemiologic Features of Primary HIV Infection , 1996, Annals of Internal Medicine.

[43]  R. Black,et al.  Zinc Supplementation Reduces the Incidence of Acute Lower Respiratory Infections in Infants and Preschool Children: A Double-blind, Controlled Trial , 1998, Pediatrics.

[44]  S. Samman,et al.  The effect of calcium carbonate and calcium citrate on the absorption of zinc in healthy female subjects. , 1994, European journal of clinical nutrition.

[45]  A. Grabrucker A Role for Synaptic Zinc in ProSAP/Shank PSD Scaffold Malformation in Autism Spectrum Disorders , 2013, Developmental neurobiology.

[46]  Richard M Bigega,et al.  Plasma Copper and Zinc Concentration in Individuals with Autism Correlate with Selected Symptom Severity , 2012, Nutrition and metabolic insights.

[47]  W. Katon,et al.  Comorbidity of gastrointestinal complaints, depression, and anxiety in the Epidemiologic Catchment Area (ECA) Study. , 1992, The American journal of medicine.

[48]  Aletta D Kraneveld,et al.  Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. , 2011, European journal of pharmacology.

[49]  K. Reichelt,et al.  Can the Pathophysiology of Autism be Explained by the Nature of the Discovered Urine Peptides? , 2003 .

[50]  R. Mooney,et al.  Plasma Amino Acids Profiles in Children with Autism: Potential Risk of Nutritional Deficiencies , 2003, Journal of autism and developmental disorders.

[51]  B. Metzler-Zebeli,et al.  Supplementation of diets for gestating sows with zinc amino acid complex and gastric intubation of suckling pigs with zinc-methionine on mineral status, intestinal morphology and bacterial translocation in lipopolysaccharide-challenged early-weaned pigs. , 2009, Research in veterinary science.

[52]  D. O’Carroll,et al.  Blimp1 regulates the transition of neonatal to adult intestinal epithelium , 2011, Nature communications.

[53]  D. Tancredi,et al.  The Prevalence of Gastrointestinal Problems in Children Across the United States With Autism Spectrum Disorders From Families With Multiple Affected Members , 2011, Journal of developmental and behavioral pediatrics : JDBP.

[54]  D. Baker,et al.  Methodology for assessing zinc bioavailability: efficacy estimates for zinc-methionine, zinc sulfate, and zinc oxide. , 1992, Journal of animal science.

[55]  R. P. Thompson,et al.  Are iron-folate supplements harmful? , 1987, The American journal of clinical nutrition.

[56]  J. Smythies,et al.  Microbiota, the immune system, black moods and the brain—melancholia updated , 2014, Front. Hum. Neurosci..

[57]  S. Naser,et al.  Pathophysiology of autism spectrum disorders: revisiting gastrointestinal involvement and immune imbalance. , 2014, World journal of gastroenterology.

[58]  William Gaffield,et al.  Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation , 2004, Nature Genetics.

[59]  D. Coury,et al.  Gastrointestinal Conditions in Children With Autism Spectrum Disorder , 2012 .

[60]  David Quig,et al.  Effect of a vitamin/mineral supplement on children and adults with autism , 2011, BMC pediatrics.

[61]  David Padua,et al.  Altered brain‐gut axis in autism: Comorbidity or causative mechanisms? , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[62]  K. S. Barone,et al.  Characterization and mechanisms of thymic atrophy in protein-malnourished mice: role of corticosterone. , 1993, Cellular immunology.

[63]  S. Janušonis,et al.  Serotonergic paradoxes of autism replicated in a simple mathematical model. , 2005, Medical hypotheses.

[64]  K. Sharkey,et al.  Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study , 2008, Journal of autism and developmental disorders.

[65]  A. Kraneveld,et al.  Altered gut microbiota and activity in a murine model of autism spectrum disorders , 2014, Brain, Behavior, and Immunity.

[66]  R. Black,et al.  Zinc supplementation reduces the incidence of persistent diarrhea and dysentery among low socioeconomic children in India. , 1996, The Journal of nutrition.

[67]  D. Theriaque,et al.  The Gluten-Free, Casein-Free Diet In Autism: Results of A Preliminary Double Blind Clinical Trial , 2006, Journal of autism and developmental disorders.

[68]  S. J. James,et al.  Redox metabolism abnormalities in autistic children associated with mitochondrial disease , 2013, Translational Psychiatry.

[69]  N. Krebs,et al.  Zinc deficiency in infants and children: a review of its complex and synergistic interactions , 2014, Paediatrics and international child health.

[70]  Andreas Trumpp,et al.  c-Myc Is Required for the Formation of Intestinal Crypts but Dispensable for Homeostasis of the Adult Intestinal Epithelium , 2005, Molecular and Cellular Biology.

[71]  James B. Adams,et al.  Gastrointestinal flora and gastrointestinal status in children with autism -- comparisons to typical children and correlation with autism severity , 2011, BMC gastroenterology.

[72]  L. Caulfield,et al.  Prenatal iron supplements impair zinc absorption in pregnant Peruvian women. , 2000, The Journal of nutrition.

[73]  Fiona Powrie,et al.  Microbiota, Disease, and Back to Health: A Metastable Journey , 2012, Science Translational Medicine.

[74]  T. Strand,et al.  Oral zinc and common childhood infections--An update. , 2015, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[75]  R. Black,et al.  Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea--a community-based, double-blind, controlled trial. , 1997, The American journal of clinical nutrition.

[76]  P. Fraker,et al.  Possible roles for glucocorticoids and apoptosis in the suppression of lymphopoiesis during zinc deficiency: a review. , 1995, Journal of the American College of Nutrition.

[77]  A. Alanazi The role of nutraceuticals in the management of autism. , 2013, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[78]  E. Mazzon,et al.  Effect of zinc supplementation on intestinal permeability in experimental colitis. , 2002, The Journal of laboratory and clinical medicine.

[79]  M. Gareau,et al.  Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis , 2012, BMC Microbiology.

[80]  R Day,et al.  Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism , 2002, Molecular Psychiatry.

[81]  C. F. Mills Dietary interactions involving the trace elements. , 1985, Annual review of nutrition.

[82]  J. A. Laurence,et al.  Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects , 2008, The Cerebellum.

[83]  T. Bale,et al.  A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment , 2014, Neurobiology of Stress.

[84]  Min Jung Park,et al.  Homeodomain transcription factor CDX1 is required for the transcriptional induction of PPARγ in intestinal cell differentiation , 2009, FEBS letters.

[85]  C. Bernstein Treatment of IBD: Where We Are and Where We Are Going , 2015, The American Journal of Gastroenterology.

[86]  Karoly Horvath,et al.  Autistic disorder and gastrointestinal disease , 2002, Current opinion in pediatrics.

[87]  B. Naliboff,et al.  Consumption of fermented milk product with probiotic modulates brain activity. , 2013, Gastroenterology.

[88]  David Wallinga,et al.  A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States , 2012, Clinical Epigenetics.

[89]  Andreas M Grabrucker,et al.  Characterization of biometal profiles in neurological disorders. , 2014, Metallomics : integrated biometal science.

[90]  H. Greene,et al.  Intestinal transport of zinc and folic acid: a mutual inhibitory effect. , 1986, The American journal of clinical nutrition.

[91]  L. Rink,et al.  T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions. , 2009, Endocrine, metabolic & immune disorders drug targets.

[92]  R. Black,et al.  Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes , 2010, International journal of epidemiology.

[93]  H. Rockman,et al.  GATA4 and the two sides of gene expression reprogramming. , 2006, Circulation research.

[94]  T. Imir,et al.  Decreased natural killer (NK) cell activity in zinc-deficient rats. , 1994, General pharmacology.

[95]  A. Grabrucker,et al.  Behavioral impairments in animal models for zinc deficiency , 2015, Front. Behav. Neurosci..

[96]  C. Tran,et al.  Dietary zinc and metallothionein on small intestinal disaccharidases activity in mice. , 2011, World journal of gastroenterology.

[97]  Nathalie Perreault,et al.  The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. , 2002, Development.

[98]  N. Darmon,et al.  Intestinal paracellular permeability during malnutrition in guinea pigs: effect of high dietary zinc. , 1996, Gut.

[99]  Micah O. Mazurek,et al.  Anxiety, Sensory Over-Responsivity, and Gastrointestinal Problems in Children with Autism Spectrum Disorders , 2013, Journal of abnormal child psychology.

[100]  Sangita B. Patil,et al.  Elevated immune response in the brain of autistic patients , 2009, Journal of Neuroimmunology.

[101]  F. Nobili,et al.  Involvement of interleukin-1beta in zinc deficiency-induced intestinal damage and beneficial effect of cyclosporine A. , 1997, Life sciences.

[102]  A. Kraneveld,et al.  The neuro-immune axis: prospect for novel treatments for mental disorders. , 2014, Basic & clinical pharmacology & toxicology.

[103]  Wiedenmann,et al.  Effects of exogenous zinc supplementation on intestinal epithelial repair in vitro , 2000, European journal of clinical investigation.

[104]  Rob Knight,et al.  Toward Effective Probiotics for Autism and Other Neurodevelopmental Disorders , 2013, Cell.

[105]  S. Genuis,et al.  Celiac Disease Presenting as Autism , 2010, Journal of child neurology.

[106]  W. Pu,et al.  Gata4 Is Essential for the Maintenance of Jejunal-Ileal Identities in the Adult Mouse Small Intestine , 2006, Molecular and Cellular Biology.

[107]  Jeroen Visser,et al.  Tight Junctions, Intestinal Permeability, and Autoimmunity , 2009, Annals of the New York Academy of Sciences.

[108]  C. H. Hill,et al.  Chemical parameters in the study of in vivo and in vitro interactions of transition elements. , 1970, Federation proceedings.

[109]  N. Shroyer,et al.  Intestinal development and differentiation. , 2011, Experimental cell research.

[110]  C. Bernstein,et al.  Depression and anxiety in inflammatory bowel disease: A review of comorbidity and management , 2009, Inflammatory bowel diseases.

[111]  J. F. White,et al.  Intestinal Pathophysiology in Autism , 2003, Experimental biology and medicine.

[112]  A. Prasad Impact of the Discovery of Human Zinc Deficiency on Health , 2009, Journal of the American College of Nutrition.

[113]  P. Louis Does the Human Gut Microbiota Contribute to the Etiology of Autism Spectrum Disorders? , 2012, Digestive Diseases and Sciences.

[114]  P. Pasricha,et al.  Transient Gastric Irritation in the Neonatal Rats Leads to Changes in Hypothalamic CRF Expression, Depression- and Anxiety-Like Behavior as Adults , 2011, PloS one.

[115]  A. Prasad,et al.  Zinc absorption in human small intestine. , 1989, The American journal of physiology.

[116]  T. Bosse,et al.  Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during development. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[117]  A. Takeda,et al.  Susceptibility to stress in young rats after 2-week zinc deprivation , 2010, Neurochemistry International.

[118]  A S Prasad,et al.  Zinc: an overview. , 1995, Nutrition.

[119]  Hiroshi Yasuda,et al.  Assessment of Infantile Mineral Imbalances in Autism Spectrum Disorders (ASDs) , 2013, International journal of environmental research and public health.

[120]  D. Leahy,et al.  All Mammalian Hedgehog Proteins Interact with Cell Adhesion Molecule, Down-regulated by Oncogenes (CDO) and Brother of CDO (BOC) in a Conserved Manner* , 2010, The Journal of Biological Chemistry.

[121]  A. Zimmerman,et al.  Neuroglial activation and neuroinflammation in the brain of patients with autism , 2005, Annals of neurology.

[122]  S. Roy,et al.  Impact of Zinc Supplementation on Intestinal Permeability in Bangladeshi Children with Acute Diarrhoea and Persistent Diarrhoea Syndrome , 1992, Journal of pediatric gastroenterology and nutrition.

[123]  Anne L McCartney,et al.  Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. , 2005, Journal of medical microbiology.

[124]  K. Moberg,et al.  Isolation of a novel cDNA encoding a zinc-finger protein that binds to two sites within the c-myc promoter. , 1992, Biochemistry.

[125]  Geir Bjorklund,et al.  The role of zinc and copper in autism spectrum disorders. , 2013, Acta neurobiologiae experimentalis.

[126]  A. Favier,et al.  Zinc nutritional status during pregnancy: a longitudinal study. , 1983, The American journal of clinical nutrition.

[127]  C. Hogstrand,et al.  Zinc uptake across the apical membrane of freshwater rainbow trout intestine is mediated by high affinity, low affinity, and histidine-facilitated pathways. , 2003, Biochimica et biophysica acta.

[128]  M. Katoh,et al.  Notch signaling in gastrointestinal tract (review). , 2007, International journal of oncology.

[129]  F. A. Costa-Pinto,et al.  Neural and behavioral correlates of food allergy. , 2012, Chemical immunology and allergy.

[130]  M. Ferriter,et al.  Gluten- and casein-free diets for autistic spectrum disorder. , 2019, The Cochrane database of systematic reviews.

[131]  S. Abd El-Nabi,et al.  The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders , 2017 .

[132]  Kazuya Yoshida,et al.  Infantile zinc deficiency: Association with autism spectrum disorders , 2011, Scientific reports.

[133]  Toshio Tanaka,et al.  Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[134]  S. Seppä,et al.  Polymorphonuclear leukocyte chemotaxis induced by zinc, copper and nickel in vitro. , 1995, Biochimica et biophysica acta.

[135]  Y. Taché,et al.  Role of corticotropin releasing factor receptor subtype 1 in stress-related functional colonic alterations: implications in irritable bowel syndrome. , 2002, The European journal of surgery. Supplement. : = Acta chirurgica. Supplement.

[136]  A. Prasad Discovery of human zinc deficiency: 50 years later. , 2012, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[137]  Marco Gobbetti,et al.  Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified , 2013, PloS one.

[138]  I Marshall,et al.  Zinc for the common cold. , 1999, The Cochrane database of systematic reviews.

[139]  L. Hurley,et al.  Teratogenic effects of short-term and transitory zinc deficiency in rats† , 1971 .

[140]  A. Wakefield The Gut–Brain Axis in Childhood Developmental Disorders , 2002, Journal of pediatric gastroenterology and nutrition.

[141]  N. Krebs,et al.  Overview of zinc absorption and excretion in the human gastrointestinal tract. , 2000, The Journal of nutrition.

[142]  Benjamin J Bondow,et al.  GATA4 is essential for jejunal function in mice. , 2008, Gastroenterology.

[143]  Ross Pelton Drug-Induced Nutrient Depletion Handbook , 1999 .

[144]  G. Livesey,et al.  Intestinal cellular proliferation and protein synthesis in zinc-deficient rats , 1985, British Journal of Nutrition.

[145]  P. D'eufemia,et al.  Food allergy and infantile autism. , 1995, Panminerva medica.

[146]  R. Wood,et al.  Adverse effects of high-calcium diets in humans. , 2009, Nutrition reviews.

[147]  Pierre Laurent-Puig,et al.  Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine , 2005, Development.

[148]  Eunseog Youn,et al.  Pyrosequencing study of fecal microflora of autistic and control children. , 2010, Anaerobe.

[149]  J. Warkany,et al.  Congenital malformations of the central nervous system in rats produced by maternal zinc deficiency. , 1972, Teratology.

[150]  K. Reichelt,et al.  Can the pathophysiology of autism be explained by the nature of the discovered urine peptides and dietary antigens? , 2016, European Psychiatry.

[151]  P. Rakic,et al.  Ontogeny of brain and blood serotonin levels in 5‐HT1A receptor knockout mice: potential relevance to the neurobiology of autism , 2006, Journal of neurochemistry.

[152]  Brian A Williams,et al.  Microglia in the Cerebral Cortex in Autism , 2012, Journal of Autism and Developmental Disorders.

[153]  J. Papadimitriou,et al.  Gastrointestinal abnormalities in children with autistic disorder. , 1999, The Journal of pediatrics.

[154]  Pat Levitt,et al.  Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report , 2010, Pediatrics.

[155]  K. Munir,et al.  Prenatal stress and risk for autism , 2008, Neuroscience & Biobehavioral Reviews.

[156]  T. Dinan,et al.  Mind-altering Microorganisms: the Impact of the Gut Microbiota on Brain and Behaviour , 2022 .

[157]  P. Whiteley,et al.  The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders , 2010, Nutritional neuroscience.

[158]  G. Davidson,et al.  Reversible intestinal mucosal abnormality in acrodermatitis enteropathica. , 1976, Archives of Disease in Childhood.

[159]  J. King Determinants of maternal zinc status during pregnancy. , 2000, The American journal of clinical nutrition.

[160]  T. Evans,et al.  Gata4 regulates the formation of multiple organs , 2005, Development.

[161]  J. King,et al.  Zinc and pregnancy outcome. , 1987, The American journal of clinical nutrition.

[162]  W. Khan,et al.  The role of serotonin and its receptors in activation of immune responses and inflammation , 2015, Acta physiologica.

[163]  James C. Cronk,et al.  Wild type microglia arrest pathology in a mouse model of Rett syndrome , 2012, Nature.

[164]  S. Finegold,et al.  Real-Time PCR Quantitation of Clostridia in Feces of Autistic Children , 2004, Applied and Environmental Microbiology.

[165]  C. McClain,et al.  The effect of severe zinc deficiency on activity of intestinal disaccharidases and 3-hydroxy-3-methylglutaryl coenzyme A reductase in the rat. , 1983, The Journal of nutrition.

[166]  Yuan-Yuan Zheng,et al.  Psychological Stress-Induced Lower Serum Zinc and Zinc Redistribution in Rats , 2013, Biological Trace Element Research.

[167]  Haroun Shah,et al.  Gastrointestinal microflora studies in late-onset autism. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[168]  C. Winter,et al.  Gut Vagal Afferents Differentially Modulate Innate Anxiety and Learned Fear , 2014, The Journal of Neuroscience.

[169]  M. Washington,et al.  Mtgr1 Is a Transcriptional Corepressor That Is Required for Maintenance of the Secretory Cell Lineage in the Small Intestine , 2005, Molecular and Cellular Biology.

[170]  A. C. Hall,et al.  Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. , 1979, Journal of inorganic biochemistry.

[171]  K. Schreck,et al.  Food preferences and factors influencing food selectivity for children with autism spectrum disorders. , 2006, Research in developmental disabilities.

[172]  P. Garg,et al.  Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. , 2013, American journal of physiology. Gastrointestinal and liver physiology.

[173]  A. Gasbarrini,et al.  Therapeutic modulation of gut microbiota: current clinical applications and future perspectives. , 2014, Current drug targets.

[174]  Pat Levitt,et al.  Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, and Associated Factors , 2012, Autism research : official journal of the International Society for Autism Research.

[175]  P. Aggett,et al.  A defect in zinc uptake by jejunal biopsies in acrodermatitis enteropathica. , 1979, Clinical science.

[176]  P. D'eufemia,et al.  Abnormal intestinal permeability in children with autism , 1996, Acta paediatrica.

[177]  C. McClain,et al.  Severe zinc deficiency in humans: association with a reversible T-lymphocyte dysfunction. , 1981, Annals of internal medicine.

[178]  B. Lönnerdal,et al.  Dietary factors influencing zinc absorption. , 2000, The Journal of nutrition.