PATHOPHYSIOLOGY
Common features of pathophysiology, including inflammation, oxidative stress, toxicity, endocrine disruptions, immune dysregulation, microbiome perturbations, cellular toxicity, among other irregularities are seen across diagnostic categories. Many of these pathophysiological features can be addressed, significantly improved or reversed through diet and lifestyle modifications, and personalized therapeutics or interventions that are available today. The key is to integrate these interventions, using a multimodal and integrative approach.
Following is a selection of literature that highlights the presence of these common underlying features and points to opportunities for treatment.
Aguilera M, Cerda-Cuellar M, Martinez V. Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice. Gut Microbes. 2015;6(1):10-23.
Alabdali A, Al-Ayadhi L, El-Ansary A. A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders. Behav Brain Funct. 2014;10:14.
Aroniadis OC, Brandt LJ. Fecal microbiota transplantation: past, present and future. Curr Opin Gastroenterol. 2013;29(1):79-84.
Assa A, Vong L, Pinnell LJ, Avitzur N, Johnson-Henry KC, Sherman PM. Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation. J Infect Dis. 2014;210(8):1296-305.
Bazar KA, Yun AJ, Lee PY, Daniel SM, Doux JD. Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders. Med Hypotheses. 2006;66(2):263-9.
Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.
Brown CM, Austin DW, Busija L. Observable essential fatty acid deficiency markers and autism spectrum disorder. Breastfeed Rev. 2014;22(2):21-6.
Brown SD, Baxter KM, Stephenson ST, Esper AM, Brown LA, Fitzpatrick AM. Airway TGFbeta1 and oxidant stress in children with severe asthma: association with airflow limitation. Allergy Clin Immunol. 2012;129(2):388-96, 96 e1-8.
Buccigrossi V, Nicastro E, Guarino A. Functions of intestinal microflora in children. Curr Opin Gastroenterol. 2013;29(1):31-8.
Caramia G. [Childhood feeding, chronic-degenerative disease in adults, and nutrigenomics]. Pediatr Med Chir. 2007;29(6):309-20.
Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis. 2015;26:26191.
Cortese S, Angriman M. Attention-deficit/hyperactivity disorder, iron deficiency, and obesity: is there a link? Postgrad Med. 2014;126(4):155-70.
Costello EJ, Foley DL, Angold A. 10-year research update review: the epidemiology of child and adolescent psychiatric disorders: II. Developmental epidemiology. J Am Acad Child Adolesc Psychiatry. 2006 Jan;45(1):8–25.
Cubala-Kucharska M. The review of most frequently occurring medical disorders related to aetiology of autism and the methods of treatment. Acta Neurobiol Exp (Wars). 2010;70(2):141-6.
Cucchiara S, Stronati L, Aloi M. Interactions between intestinal microbiota and innate immune system in pediatric inflammatory bowel disease. J Clin Gastroenterol. 2012;46 Suppl:S64-6.
de Goffau MC, Luopajarvi K, Knip M, Ilonen J, Ruohtula T, Harkonen T, et al. Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes. 2013;62(4):1238-44.
de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51(4):418-24.
Edwards CA, Parrett AM. Intestinal flora during the first months of life: new perspectives. Br J Nutr. 2002;88 Suppl 1:S11-8.
Elamin NE, Al-Ayadhi LY. Brain autoantibodies in autism spectrum disorder. Biomark Med. 2014;8(3):345-52.
El-Ansary A, Al-Ayadhi L. Neuroinflammation in autism spectrum disorders. J Neuroinflammation. 2012;9:265.
Faber S, Zinn GM, Boggess A, Fahrenholz T, Kern JC 2nd, Kingston HM. A cleanroom sleeping environment’s impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders. BMC Complement Altern Med. 2015;15:71.
Frye RE, James SJ. Metabolic pathology of autism in relation to redox metabolism. Biomark Med. 2014;8(3):321-30.
Galland L. The gut microbiome and the brain. J Med Food. 2014;17(12):1261-72.
Gu F, Chauhan V, Chauhan A. Glutathione redox imbalance in brain disorders. Curr Opin Clin Nutr Metab Care. 2015;18(1):89-95.
Guney E, Fatih Ceylan M, Tektas A, Alisik M, Ergin M, Goker Z, et al. Oxidative stress in children and adolescents with anxiety disorders. J Affect Disord. 2014;156:62-6.
Hammons AL, Summers CM, Woodside JV, McNulty H, Strain JJ, Young IS, et al. Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1. Clin Immunol. 2009;133(1):132-7.
Hansel TT, Johnston SL, Openshaw PJ. Microbes and mucosal immune responses in asthma. Lancet. 2013;381(9869):861-73.
He C, Shan Y, Song W. Targeting gut microbiota as a possible therapy for diabetes. Nutr Res. 2015.
Hepgul N, Cattaneo A, Zunszain PA, Pariante CM. Depression pathogenesis and treatment: what can we learn from blood mRNA expression? BMC Med. 2013;11:28.
Hsieh MH. The microbiome and probiotics in childhood. Semin Reprod Med. 2014;32(1):23-7.
Ikekpeazu E, Neboh E, Ejezie F, Ibegbu M, Ike I. Oxidative stress and glycaemic control in type 2 diabetic patients in enugu, South-East Nigeria. Ann Med Health Sci Res. 2011;1(1):123-8.
Isolauri E, Salminen S. The impact of early gut microbiota modulation on the risk of child disease: alert to accuracy in probiotic studies. Benef Microbes. 2015;6(2):167-71.
Jeurink PV, van Esch BC, Rijnierse A, Garssen J, Knippels LM. Mechanisms underlying immune effects of dietary oligosaccharides. Am J Clin Nutr. 2013;98(2):572S-7S.
Julio-Pieper M, Bravo JA, Aliaga E, Gotteland M. Review article: intestinal barrier dysfunction and central nervous system disorders–a controversial association. Aliment Pharmacol Ther. 2014;40(10):1187-201.
Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.
Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology. 2002;46(2):76-84.
Kane AV, Dinh DM, Ward HD. Childhood malnutrition and the intestinal microbiome. Pediatr Res. 2015;77(1-2):256-62.
Kawatani M, Tsukahara H, Mayumi M. Evaluation of oxidative stress status in children with pervasive developmental disorder and attention deficit hyperactivity disorder using urinaryspecific biomarkers. Redox Rep. 2011;16(1):45-6.
Kuwabara H, Yamasue H, Koike S, Inoue H, Kawakubo Y, Kuroda M, et al. Altered metabolites in the plasma of autism spectrum disorder: a capillary electrophoresis time-of-flight mass spectroscopy study. PLoS One. 2013;8(9):e73814.
Lambert B, Kobliner V. A compromised generation : the epidemic of chronic illness in America’s children [Internet]. 1st Sentient Publications. Boulder, CO: Sentient Publications; 2010. xiv, 358 p.
Landrigan PJ. Neurologic effects of exposure to lead. J Pediatr. 1979;94(3):504-5.
Landrigan PJ, Whitworth RH, Baloh RW, Staehling NW, Barthel WF, Rosenblum BF. Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet. 1975;1(7909):708-12.
Ly NP, Litonjua A, Gold DR, Celedon JC. Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity? J Allergy Clin Immunol. 2011;127(5):1087-94; quiz 95-6.
Maher P. Methylglyoxal, advanced glycation end products and autism: is there a connection? Med Hypotheses. 2012;78(4):548-52.
Maksimova OV, Gervazieva VB, Zverev VV. [Intestine microbiota and allergic diseases]. Zh Mikrobiol Epidemiol Immunobiol. 2014(3):49-60.
Marazziti D, Baroni S, Picchetti M, Landi P, Silvestri S, Vatteroni E, et al. Psychiatric disorders and mitochondrial dysfunctions. Eur Rev Med Pharmacol Sci. 2012;16(2):270-5.
Mavragani CP, Patronas N, Dalakas M, Moutsopoulos HM. Ill-defined neurological syndromes with autoimmune background: a diagnostic challenge. J Rheumatol. 2007;34(2):341-5.
McCloud E, Papoutsakis C. A medical nutrition therapy primer for childhood asthma: current and emerging perspectives. J Am Diet Assoc. 2011 Jul;111(7):1052–64.
Montero D, Walther G, Perez-Martin A, Roche E, Vinet A. Endothelial dysfunction, inflammation, and oxidative stress in obese children and adolescents: markers and effect of lifestyle intervention. Obes Rev. 2012;13(5):441-55.
Nankova BB, Agarwal R, MacFabe DF, La Gamma EF. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells–possible relevance to autism spectrum disorders. PLoS One. 2014;9(8):e103740.
Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol. 2005;3(5):431-8.
Pfeffer PE, Mann EH, Hornsby E, Chambers ES, Chen YH, Rice L, et al. Vitamin D influences asthmatic pathology through its action on diverse immunological pathways. Ann Am Thorac Soc. 2014;11 Suppl 5:S314-21.
Renteria I, Arenas Berumen E, Arellano Garcia ME, Carrasco-Legleu CE, De Leon-Fierro LG, Arenas-Berumen EA. [Factors affecting oxidative damage in obese children: an exploratory study]. Nutr Hosp. 2015;31(4):1499-503.
Rollins B, Martin MV, Sequeira PA, Moon EA, Morgan LZ, Watson SJ, et al. Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One. 2009;4(3):e4913.
Rook GA, Raison CL, Lowry CA. Microbiota, immunoregulatory old friends and psychiatric disorders. Adv Exp Med Biol. 2014;817:319-56.
Rosa JS, Oliver SR, Flores RL, Ngo J, Milne GL, Zaldivar FP, et al. Altered inflammatory, oxidative, and metabolic responses to exercise in pediatric obesity and type 1 diabetes. Pediatr Diabetes. 2011;12(5):464-72.
Sabuncuoglu O. Understanding the relationships between breastfeeding, malocclusion, ADHD, sleep-disordered breathing and traumatic dental injuries. Med Hypotheses. 2013;80(3):315-20.
Sanchez M, Panahi S, Tremblay A. Childhood obesity: a role for gut microbiota? Int J Environ Res Public Health. 2015;12(1):162-75.
Song S, Zhang L, Zhang H, Wei W, Jia L. Perinatal BPA exposure induces hyperglycemia, oxidative stress and decreased adiponectin production in later life of male rat offspring. Int J Environ Res Public Health. 2014;11(4):3728-42.
Szaflarska-Poplawska A, Siomek A, Czerwionka-Szaflarska M, Gackowski D, Rozalski R, Guz J, et al. Oxidatively damaged DNA/oxidative stress in children with celiac disease. Cancer Epidemiol Biomarkers Prev. 2010;19(8):1960-5.
Theoharides TC. Is a subtype of autism an allergy of the brain? Clin Ther. 2013; 35(5):584-91.
Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, et al. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflammation. 2012;9:153.
Vaarala O. Is the origin of type 1 diabetes in the gut? Immunol Cell Biol. 2012;90(3):271-6.
Vaarala O. Gut microbiota and type 1 diabetes. Rev Diabet Stud. 2012;9(4):251-9.
van Hemert S, Breedveld AC, Rovers JM, Vermeiden JP, Witteman BJ, Smits MG, et al. Migraine associated with gastrointestinal disorders: review of the literature and clinical implications. Front Neurol. 2014;5:241.
Waggiallah H, Alzohairy M. The effect of oxidative stress on human red cells glutathione peroxidase, glutathione reductase level, and prevalence of anemia among diabetics. N Am J Med Sci. 2011;3(7):344-7.
Wang L, Conlon MA, Christophersen CT, Sorich MJ, Angley MT. Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomark Med. 2014;8(3):331-44.
West CE, Renz H, Jenmalm MC, Kozyrskyj AL, Allen KJ, Vuillermin P, et al. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J Allergy Clin Immunol. 2015;135(1):3-13; quiz 4.
METRICS AND BIOMARKERS
The Documenting Hope Project aims to evaluate the clinical needs of enrolled children by using a comprehensive set of non-and minimally-invasive assessments that have high predictive value and clinical significance. The use of predictive biomarkers allows for the assessment of upstream causes of symptoms/disease and the ability to monitor the impact of interventions. Objective measures like laboratory data will be used in conjunction with important empirical observations made by the participating families, health coaches and practitioners.
Predictive biomarkers used in the Documenting Hope Project may include, but are not limited to:
- Hgb A1c: Sugar, insulin, energy metabolism
- Homocysteine: Methylation, epigenetics, detox
- hsCRP: Inflammation, repair ability
- Oxidized LDL/HDL & 8 oxo-guanine: Antioxidant sufficiency,oxidative stress free radical activity
- Vitamin D: Cell communication & adhesion
- 1st AM urine pH: Mineral status & acidosis risk
Additional assessments focused on structural, sensory, and developmental status will be integrated with predictive biomarkers and other functional assessments. For a complete list of assessments, please refer to the Documenting Hope Project Manual.(link)
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Alabdali A, Al-Ayadhi L, El-Ansary A. Association of social and cognitive impairment and biomarkers in autism spectrum disorders. J Neuroinflammation. 2014;11:4.
Alabdali A, Al-Ayadhi L, El-Ansary A. A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders. Behav Brain Funct. 2014;10:14.
Al-Mosalem OA, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to energy metabolism in Saudi autistic children. Clin Biochem. 2009;42(10-11):949-57.
Ahmed T, Haque R, Shamsir Ahmed AM, Petri WA, Jr., Cravioto A. Use of metagenomics to understand the genetic basis of malnutrition. Nutr Rev. 2009;67 Suppl 2:S201-6.
Ahmed S, Mahabbat-e Khoda S, Rekha RS, Gardner RM, Ameer SS, Moore S, et al. Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood. Environ Health Perspect. 2011;119(2):258-64.
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Arnold D, Jones BL. Personalized medicine: a pediatric perspective. Curr Allergy Asthma Rep. 2009;9(6):426-32.
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Bitsika V, Sharpley CF, Andronicos NM, Agnew LL. Hypothalamus-pituitary-adrenal axis daily fluctuation, anxiety and age interact to predict cortisol concentrations in boys with an autism spectrum disorder. Physiol Behav. 2015;138:200-7.
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Bradstreet JJ, Smith S, Baral M, Rossignol DA. Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Altern Med Rev. 2010;15(1):15-32.
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Brown CM, Austin DW, Busija L. Observable essential fatty acid deficiency markers and autism spectrum disorder. Breastfeed Rev. 2014;22(2):21-6.
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Ceylan MF, Guney E, Alisik M, Ergin M, Dinc GS, Goker Z, et al. Lipid peroxidation markers in children with anxiety disorders and their diagnostic implications. Redox Rep. 2014;19(2):92-6.
Ceylan MF, Sener S, Bayraktar AC, Kavutcu M. Changes in oxidative stress and cellular immunity serum markers in attention-deficit/hyperactivity disorder. Psychiatry Clin Neurosci. 2012;66(3):220-6.
Dziaman T, Gackowski D, Rozalski R, Siomek A, Szulczynski J, Zabielski R, et al. Urinary excretion rates of 8-oxoGua and 8-oxodG and antioxidant vitamins level as a measure of oxidative status in healthy, full-term newborns. Free Radic Res. 2007;41(9):997-1004.
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Fukuda K, Fujita Y. Determination of the discriminant score of intestinal microbiota as a biomarker of disease activity in patients with ulcerative colitis. BMC Gastroenterol. 2014;14:49.
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Ghanizadeh A. Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. Dis Markers. 2013;35(5):281-6.
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Kaluzna-Czaplinska J, Zurawicz E, Struck W, Markuszewski M. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;966:70-6.
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