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Gluten, Leaky Gut and Autism: a Serendipitous Association Or a Planned Design?

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Gluten, Leaky Gut and Autism: a Serendipitous Association Or a Planned Design? Gluten, Leaky Gut and Autism: A Serendipitous Association or a Planned Design? Item Type Poster/Presentation Authors Fasano, Alessio Publication Date 2009 Keywords zonulin; Wheat Hypersensitivity; Autistic Disorder; Genetics-- trends; Diet, Gluten-Free Download date 07/10/2021 23:03:02 Item License https://creativecommons.org/licenses/by-nc-nd/4.0/ Link to Item http://hdl.handle.net/10713/2932 Gluten, Leaky Gut and Autism: A Serendipitous Association or a Planned Design? Fall 2009 ARI/Defeat Autism Now Autism Research Institute Conference – Dallas October 08-12, 2009 Alessio Fasano, M.D. Mucosal Biology Research Center University of Maryland School of Medicine Disclosures: •Alba Therapeutics: Financial Interest Lecture Objectives ASD, Leaky gut, and Gluten: Connecting the Dots Genes & Environ- ment? Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Pathogenesis Genetics Environment + = ASD are Genetic Disorders . Families • Risk of autism in siblings of autistic probands - 2-5% • Risk increase at least 8 to 10-fold . Twins • 66 Twin Pairs – 3 Studies • Concordance in MZ twins ~ 66% • Concordance in DZ twins ~ 2-3% Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Etiologic Heterogeneity . Study samples include mixing of cases with distinct causal origins . In the past - inconsistent case definition across studies – limits replicability . Today - more uniform case definition Purposeful stratification by phenotypic markers in the hopes of capturing genetic heterogeneity What markers are the right markers? Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health ASD are highly heritable but… Twin and other family studies completed over the last 25 years demonstrate the heritability of autism MZ twins share 100% of the genome Study MZ (N) DZ (N) Britain (’77) 36% (11) 0% (10) DZ twins share 50% of the genome, on average USA (’85) 96% (23) 24% (17) Nordic (’89) 91% (11) 0% (10) If autism is heritable, MZ concordance > DZ concordance Britain (‘95) 60% (25) 0% (20) Segregation analyses have not discerned a model of autism inheritance – “probably polygenic” Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Summary of Linkage Findings across Studies Source; Folstein and Rosen-Sheidley, Nat Rev Genet., (2001) Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Why Environmental Risk Factors ? Increasing concerns Descriptive data on recent about environmental exposures rise in autism prevalence and neurodevelopment in general Provocative Increased focus on data on mechanisms by which environ- environmental exposure mental exposures might cause and autism autism Epidemiologic data on environmental exposures and autism Lack of a definitive genetic model for autism •Many theories… Little to no evidence… Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Persons with Autism in California Department of Developmental Services Client Database by Year Source: DDS. Autism Spectrum Disorders – Changes in the California Caseload. An update: 1999 through 2002; April 2003 Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Prevalence* (per 10,000) of children with an autism special education classification in Maryland, by age and year 40 35 30 Age-Group 25 3-5 6-11 20 12-17 18-21 15 TOTAL 10 5 Prevalence (per 10,000 children) 10,000 (per Prevalence 0 1995 1996 1997 1998 1999 2000 2001 2002 * Prevalence based on MSDE Special Education Censuses - Autism Source: MD State Department of Education Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Autistic disorder prevalence from epidemiologic surveys by study year & global region 60 Japan 50 North America Scandinavia 40 Western Europe 30 20 Prevalence of Autistic Disorder (per 10,000) (per Disorder of Autistic Prevalence 10 0 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 Year of Publication Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health ASD Prevalence: US ADDM ASD Prevalence, 2000 12 10 8 6 (per 1,000) (per1,000) Prevalence of ASD Prevalence 4 in8-year-old Children 2 WV MD SC AZ GA NJ Site Location Source: MMWR, 56(1), 1-11 Gentle concession by Dr. Li-Ching Lee, Johns Hopkins Blumberg School of Public Health Environmental Triggers: Gut Microorganisms Gut Microorganisms: Are we sure they are just environment? The Complexity of the Human Body Over the years we came to appreciate the complexity of the human body Only 30,000 genes, 99.5% identical to chimpanzee, cannot explain such complexity and difference with other primates. However, it would be inappropriate to describe the human body without considering the 300,000,000,000 bacteria (collectively defined as microbiome) gladly living inside us and that express ~100 fold more genes that the human genome. The Real Story of Our Genetic Complexity: We Inherit two Parallel Genomes Microbiome: Human Genome: Inherited from the mother, Inherited from both parents, stable, extremely dynamic, changes never change in its composition from individual to individual and in the same individual over time Microbiome Human Genome Metabonome (140-fold Human Genome) (~30,000 genes) Dynamic Stable Jazz Pop Classic Clinical Outcome Environmental Triggers: Gluten and Casein Dietary Factors The Grass Family - (GRAMINEAE) Subfamily Festucoideae Tribe Hordeae Oryzeae Zizaneae Aveneae Festuceaea Chlorideae Wheat rice wild rice oat finger millet teff Years rye 2.5 M 2009 The Human race appears on the face of hearth barley 10,000 Change from nomadic to settled life style Diet Fruits, nuts, tubers Occasional meat Advent of agriculture Development of gluten containing grains Intestine: Interesting Facts ~20 ft long ~3,000 sf!!! The Paracellular Pathway Absorption of large molecules: Mission Impossible Environment (gluten, casein, bacterial products, etc) Barrier impermeable to macromolecules Genes load The Leaky Gut Theory: Facts and Fantasies The Paracellular Pathway PURIFICATION PROTOCOL FROM HUMAN INTESTINE 1 2 3 4 1 2 3 4 1: Tissue lysate 2: Sephacryl-S300 …Tight junctions are a ‘dark horse’ implicated in a host of disease states, ranging from acute injury to chronic 3: Q-sepharose inflammation and autoimmune diseases 4: Immuoaffinity Coomassie Western blot Zonulin Gene Located on the High ASD Risk Chromosome 16 and Its Evolution Zonulin ancestor Zonulin 2 M years ago 2.5 M years ago Zonulin ancestor (not active) Zonulin Characterization and Signaling Zonulin signaling Freeze-Fracture Following Pathway Activation Resting State Fasano et al, J Clin Invest 1995;96:710-20; el Asmar et al Gastroenterology 2002;123:1607-15 Novel Theories for Inflammatory/Autoimmune Diseases Pathogenesis, Including ASD Genetics Environment Mucosal Barrier ASD ASD • A third key element necessary to develop inflammation/autoimmunity is the loss of the mucosal barrier function, so allowing the interplay between genes and environment. A. Fasano and T. Shea Donohue, Nature Clin Pract Gastroenterol Hepatol 2005; Fasano Scientific American 2009 The Holy Trinity of the Autoimmune Mechanisms in Celiac Disease Fasano A; Scientific American Aug. 2009 Possible Steps Leading to Gut Inflammation in ASD Increased permeability Gut Inflammation Restructuring of Enhanced neutrophil intestinal mucosa recruitment Zonulin Pathway: Studies on Cell Lines El Asmar et al Gastroenterology 2002; Drago et al Scand J Gastroenterol 2006 Studies on Cell Lines: Zonulin Release CONTROL GLIADIN CASEIN Zonulin Actin Nucleus Drago et al Scand J Gastroenterol 2006; 41:408-19. Studies on Cell Lines: Zonulin Release 9 Control 8 Bacteria/gliadin 7 6 5 4 3 Zonulin (ng/mg protein) 2 1 0 IEC-6 T84 Caco2 Drago et al Scand J Gastroenterol 2006; 41:408-19. Chemokine Receptor CXCR-3 • CXCR-3 is a seven-transmembrane G couple protein receptor that is preferentially expressed on activated T lymphocytes and subset of B and NK cells. • Three known CXCR3 ligands CXCL-9, -10, -11 are produced at the site of inflammation and elicit migration of pathological Th1 cells. • CXCR3 has been implicated as a potential target for impeding T-cell- mediated destruction in autoimmune diseases such as multiple sclerosis (MS) and insulin-dependent diabetes (IDD) Lammers K et al, Gastroenterology, 2008;135:194-204 Gluten Causes Leaky Gut by Releasing Zonulin Intestinal lumen gliadin zonulin CXCR3 Lamina propria In Vivo Effect ZO-1 E-Cadherin of gliadin on Control Junctional Proteins’ Arrangement 1mg gliadin How Neutrophils are Attracted in the Gut? Gluten Causes Early Neutrophil Recruitment Control Gluten Total time recording: 60 min Impaired intestinal barrier Is Involved in the Pathogenesis of Inflammation Autism Gluten • Multiple Sclerosis, Stroke • Asthma, COPD, ARDS • Dilatative cardiomyopathy, Ischemia- reperfusion • Systemic sclerosis Transplant Rejection • Type 1 Diabetes, Autoimmune thyroiditis • Celiac Disease, PBC, IBD. • Glomerulosclerosis, Acute Renal Failiure • Rheumatoid Arthritis • Metastatic Disease Intestinal Permeability in Children Affected by ASD L. De Magistris, personal communication Effect of a Gluten- and Casein-Free Diet on Intestinal Permeability in Children Affected by ASD L. De Magistris, personal communication How Gut Leakiness and Inflammation relate to ASD? Activated Gliadorphins Casomorphins inflammatory cells Prove of Concept on Alternative Treatments of Leaky Gut-Related Diseases: The Celiac Disease Paradigm Genetics
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