UCSF Osher Center for Integrative Medicine What are these kids taking? An Integrative Approach to Autism Sanford C. Newmark M.D. Pediatric Integrative Neurodevelopmental Clinic
Disclosure No one involved in the planning or presentation of this activity has any relevant financial relationships with a commercial interest to disclose.
Autism A Neurodevelopmental Syndrome characterized by: Difficulty with communication and interaction with other people. Restricted interests and repetitive behaviors Symptoms that hurt the person’s ability to function properly in school, work, and other areas of life
The Autism “ Epidemic ” • Prevalence in the 1960’s 5-6/10,000 • CDC Prevalence now 1 in 59 or 147/10,000 ( recent study 1 in 40) • Much of increase in prevalence likely due to better surveillance and awareness, and looser definition of autism.
Autism 1 in 68 children
What Causes Autism? • Autism is a Phenotype Defined by a set of observable behaviors – Communication Deficits – Deficits in social interaction – Repetitive behaviors • This may represent very different genetics, epigenetics and physiologies
Genetic Predisposition + Environmental Influences Autism
Genetic Predisposition Environmental Influences Prenatal Perinatal Postnatal Toxin Exposure Prematurity Toxin Exposure Medication use C-section Antibiotics Maternal Illness Nutritional Deficiencies Nutritional Deficiencies Autism
Can toxic exposures cause Autism? • Compared: level of environmentally released mercury with special education and autism students • for each 1000 lb. of environmentally released mercury , there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. • Health Place. 2006 Jun;12(2):203-9
Risk of Autism – Fetal Pesticide Exposure - California • 465 autistic children, 7000 controls • Calculated pesticide exposure weeks 1 through 8 of gestation Risk of autism was 6x as great for mothers living within 500 meters of highest pesticide application Roberts EHP 2007
Autism – Pesticide Risk & Folic Acid CHARGE Study – 296 autism + controls Compared to those with Folic Acid intake > 800 Mcg • ORs for the combination of low FA and indoor pesticide exposure was 2.1 • ORs for the combination of low FA and regular pregnancy exposure to pet pesticides was 3.9 • ORs for the combination of low FA and regular pregnancy exposure to outdoor sprays and foggers was 4.1 Schmidt Environ Health Perspect; 2017
Genetic Predisposition Environmental Influences Epigenetics Prenatal Perinatal PostNatal Toxin Exposure Prematurity Toxin Exposure Medication use C-section Antibiotics Maternal Illness Nutritional Deficiencies Nutritional Deficiencies Autism
Conventional Paradigm-Brain Disorder • Genetically based, hard wired brain disorder. • The genes affect the brain, and the brain affects the behaviors. • A “static encephalopathy .” A brain condition with limited capacity for change
Old Paradigm Genetics + Environment Brain Disorder Treatment = Therapy
Problems with Brain Disorder Model • Does not explain why children with autism have the following problems: • Gastrointestinal abnormalities • Chronic inflammation • Metabolic abnormalities • Abnormal Immunity • Allergic problems • Nutritional Deficiencies • Mitochondrial Deficiencies
New Paradigm Genetics + Environment Physiological and Epigenetic Changes Affecting Multiple Systems Including the Brain Autism
Genetic Predisposition Environmental Influences – Prenatal Perinatal Postnatal GI disturbances Metabolic derangement Allergy Nutritional Deficiencies Oxidative stress Abnormal immunity Inflammation Autism
Why is this Important? • Because, if autism is an ongoing systemic disease in which immune and metabolic and allergic abnormalities affect the brain, • Then we may be able to treat the abnormalities, improve brain function, and improve the core symptoms of autism.
Neuroglial activation and neuroinflammation in the brain of patients with autism. • We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. • Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. • CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. • Ann Neurol. 2005 Jan;57(1):67-81.
A Systemic Disease Affecting Brain Function? “... Could it be that dysregulation from immune or biochemical or other metabolic or infectious problems can have an impact across the blood brain barrier and affect brain function?” • “We are asking if autism is a dynamic, or even a metabolic encephalopathy, … a metabolic disturbance of the ways the cells can function in the brain. (Martha Herbert)
Gastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis • Odds ratio for GI symptoms 4.2 • Odd ratio for diarrhea 3.6 • Odds ratio for constipation 3.9 • Odds ratio for abdominal pain 2.5 • Pediatrics 2014
GI Abnormalities in Children with Autism • Not only do these children have symptoms, but many have significant bowel pathology of various types.
36 children with autism and GI Sx • Grade I or II reflux esophagitis in 25 (69.4%). • Chronic gastritis in 15(42%) • Chronic duodenitis in 24(67%). • Often, these children are nonverbal , and cannot tell you they are in pain. Journal of Pediatrics . 1999 Nov.
“Leaky Gut” – Increased Intestinal Permeability • Intestinal permeability test in 21 autistic child ren who had no clinical and laboratory findings consistent with known intestinal disorder s. • Altered intestinal permeability 9 of 21 (43%) autistic patients, 0 of 40 ( 0%) controls . D'Eufemia P. et. Al. . Acta Paediatrica., 1996
Leaky Gut – Intestinal Permeability • Abnormal Intestinal Permeability Autism (36.7%) Relatives (21.2%) Normal subjects (4.8%) • “The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism” J Pediatr Gastroenterol Nutr. 2010 Jul 28
Abnormal Gut Flora • A number of studies have shown abnormal gut flora in autism • Increased clostridia species • Decreased levels of Bifidobacteria (a beneficial probiotic) • Distinct and less diverse gut microbial populations • “Taken together, autism and accompanying GI symptoms were characterized by distinct and less diverse gut microbial compositions with lower levels of Prevotella, Coprococcus, and unclassified Veillonellaceae.” • PLOS One 2013
Treating Autistic Mice?? • “Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors.” • Cell 155, 1–13, December 19, 2013
Creating Autistic Mice • Transplant of gut microbiota from human donors with autism into germ- free mice. • Colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors. • The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. • Cell 177, May 30, 2019
Fecal Microbial Transplant - Autism • 18 subjects: Autism and moderate to severe GI symptoms • FMT (Fetal Microbial Transplant) Standardized human gut microbiota > 99% bacteria • 8 weeks – delivered orally or rectally • Results – some improvement in GI and Autism Symptoms • Weakness – small, unblinded. Microbiome 2017
Immune Dysregulation in Autism • Review of 39 studies strongly suggest a proinflammatory state in ASD as compared to controls, • Pro-inflammatory Cytokines increased -– several up- regulated in brain itself • TNFa, IL-6, and IL-17a have all been increased in children with ASD. • Low levels Natural Killer cells • Deficiencies in Regulator T-cells • Several studies indicate role of maternal anti-fetal autoantibodies
Autoimmunity • IgG anti-brain autoantibodies 27% with ASD, 2% controls • IgM anti-brain autoantibodies 36% with ASD 0% of controls • In another study 69% had anti- caudate antibodies Journal of Pediatrics., 1999 •
Significance of Autoantibodies • … ” elevated levels (of autoantibodies),, may be representative of a continuous cycle of immune activation and antibody production , potentially resulting in the generation of pathogenic autoantibodies”. • Wills 2007
Mitochondrial Dysfunction Autism • 14 of 69 abnormal plasma lactate • Muscle Biopsy-5 of 11 patients definite mitochondrial disorder • Overall 7.2% of autistic patients mitochondrial disorder Presence in general population 0.01%. • Other studies similar results • Developmental Medicine & Child Neurology 2005
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