GI Biology Pathology and Treatment Strategies Autism One

GI Biology, Pathology, and Treatment Strategies Autism One Conference Canada October 2009 Sonja Hintz, R. N. Anju Usman, M. D. True Health Medical Center Naperville, Illinois

What Defeat Autism Now Doctors know about GI issues… • Autism is a neuro-immune inflammatory • • condition affecting the gut and brain Much of the inflammation originates in the gut Many of the symptoms we call autistic, are related to the gut Treating the gut, is one of the most successful biomedical interventions Healing the Gut is the Key to success

What does the gut do for us? • • Protection/Barrier Immune Protection Provides Fuel/Nutrition Transportation/Motility Digestion (stomach, duodenum, jejunum) – Fats – Carbohydrates – Protein Absorption (ileum) Waste Removal (colon)

The GI tract is our first line of defense against the outside world.

• Absorptive surface of the GI tract is 200 times larger than the surface area of the skin (400 square meters)

GI Histology

100 trillion bacteria in the gut Early disruption of gut flora, affects later immune function, potential allergies and autoimmunity Good flora protects us from pathogens Aids with digestion of carbohydrates and fiber to form SCFA which in turn fuels enterocytes Gut Microbiota

Human Microbiome Project • 5 yr/ $140 million effort to study and explore how the • • • trillions of microscopic organisms in our bodies affect our health. Total microbial cells found in association with humans may exceed the total number of cells making up the human body by a factor of 10: 1. The total number of genes associated with the human microbiome could exceed the total number of human genes by a factor of 100: 1 Organisms expected to be found, bacteria yeast, protazoa, parasites viruses, bacteriophages

The Immune System in the Gut GALT (gut-associated lymphoid tissue) with organized lymphoid structures — Peyer's patches and isolated lymphoid follicles The diffuse tissues of the lamina propria contain a large number of immunoglobulin A (Ig. A)+ plasma cells, T and B cells, macrophages, dendritic cells (DCs) and stromal cells (SCs)

The Gut/Brain/Immune Connection The Vagus nerve inherently communicates with the splenic nerve to suppress TNF alpha production by macrophages in the spleen and modulate immune function. (Dr. Rosas-Ballina) • Parasympathetic • Efferent or Motor • Afferent or Sensory (80%) • Back to the brain from the ear, tongue, larynx, GI • Dorsal Vagal Nucleus • Motor to Pharynx, Larynx, GI. . • Releases ACh (acetylcholine) • Nicotinic Receptors • Muscarinic Receptors

Physiology and immunology of the cholinergic anti-inflammatory pathway J Clin Invest. 2007 Feb; 117(2): 289 -96. Tracey KJ. • The nervous system, via an inflammatory reflex of • • • the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine

Gastrointestinal Dysfunction (literature) • Maldigestion – – Decreased activity of digestive enzymes (Horvath, 1999. Buie, 2004) High levels of opioid peptides found in urine of autistics. (Reichelt, 1997) • Malabsorption • Dysbiosis – Dysbiosis or altered bowel flora (Rossenau, 2004) – Clostridial overgrowth (Sandler, 2002) – Persistent measles virus (Wakefield, Krigsman) • Immune Dysregulation (allergy, autoimmunity, inflammation, deficiency) – Autistic Enterocolitis, Lymphoid Hyperplasia (Wakefield, Krigsman, Balzola – Increased intestinal permeability leading to food sensitivities and autoimmunity (Vodjani, 2002) – Increased pro-inflammatory cytokines – LP, TNF alpha, IFN gamma (Ashwood, 2004) – Proinflammatory response to dietary proteins (Jyonuchi, 2004) – Low Secretory Ig. A (Gupta, 1996) • Motility – Gastroesophageal Reflux associated with aggressive behavior(Buie)

Gastrointestinal Dysfunction (experience) • Maldigestion – – Ig. G Food Sensitivities (dairy, gluten, soy…) Poor weight gain Low Essential Amino Acids Low Stomach Acid/Bloating – – Fat Soluble Vitamin Deficiencies Essential Fatty Acid Deficiencies Low weight and height Dry-Bumpy Skin, Ear Wax Excess, Floating Stools – – Chronic Strep Issues Chronic Anaerobic Overgrowth (clostridia sp. ) Chronic Small Bowel Bacterial Overgrowth (SBBO) Chronic Yeast/Fungal Overgrowth • Malabsorption • Dysbiosis (fungal, bacterial, viral) • Immune Dysregulation/Inflammation – Behaviors, Stims, Sleep disorder, Posturing, Aggression, Self Injurious • Motility – Chronic Constipation, Reflux, Burping, Hypotonia

Measles Virus, Colitis, and ASD • Mol Pathol. 2002 Apr; 55(2): 84 -90. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Uhlmann V, Martin CM, Sheils O, Pilkington L, Silva I, Killalea A, Murch SB, Walker-Smith J, Thomson M, Wakefield AJ, O'Leary JJ. A disease (ileocolonic lymphonodular hyperplasia) Seventy new form of inflammatory bowelchildren with developmental disorder. This study five of 91 patients with a histologically confirmed has been described in a cohort of investigates thelymphonodular hyperplasia and enterocolitis presence of persistent measles virus in diagnosis of ileal(new variant inflammatory bowel disease)the intestinal tissue of by these patients and a series of controls were positive analysis. molecular for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal identified within the follicular dendritic cells and measles virus in their lymphonodular hyperplasia and enterocolitis were positive for some intestinal tissue compared with five 70 control patients. Measles lymphocytes in foci of reactive of cells and some lymphocytes virus was follicular hyperplasia. foci of identified within the follicular dendritic in reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300, 00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder. PMID: 11950955

Bacterial Co-infections and ASD • J Neurosci Res. 2007 Apr; 85(5): 1143 -8. Evidence for Mycoplasma ssp. , Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. Nicolson GL, Gan R, Nicolson NL, Haier J. – We examined the blood of 48 patients from central and southern California diagnosed with autistic spectrum disorders (ASD) by using forensic polymerase chain reaction and found that a large subset (28/48 or 58. 3%) of patients showed evidence of Mycoplasma spp. infections compared with two of 45 (4. 7%) age-matched control – We found that Mycoplasma-positive and -negative ASD patients had similar percentages of C. pneumoniae and HHV-6 infections, suggesting that such infections occur independently in ASD patients. Control subjects also had low rates of C. pneumoniae (1/48 or 2. 1%) and HHV-6 (4/48 or 8. 3%) infections, and there were no coinfections in control subjects. – The results indicate that a large subset of ASD patients shows evidence of bacterial and/or viral infections (odds ratio = 16. 5, P < 0. 001). The significance of these infections in ASD is discussed in terms of appropriate treatment. (c) 2007 Wiley-Liss, Inc. PMID: 17265454

Propionic Acid, Dysbiosis and ASD • Behav Brain Res. 2007 Jan 10; 176(1): 149 -69. Epub 2006 Sep 1. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Mac. Fabe DF – PPA is a by-product of a subpopulation of human gut enterobacteria and is a short chain fatty acid an important intermediate of cellular metabolism. Also a common food preservative. – PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. – Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e. g. , lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase. – PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD 68 immunoreactivity) suggestive of a neuroinflammatory process. PMID: 16950524

Clostridia and ASD • Clin Infect Dis. 2002 Sep 1; 35(Suppl 1): S 6 -S 16. Gastrointestinal microflora studies in lateonset autism. Finegold SM – Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. – The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. – The most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. – These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.

Clostridia and ASD • J Child Neurol. 2000 Jul; 15(7): 429 -35. Links Short-term benefit from oral vancomycin treatment of regressive-onset autism Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Väisänen ML, Nelson MN, Wexler HM. – We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. – Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. – Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. – These results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism. PMID: 10921511

PANDAS Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus • Presence of obsessive-compulsive disorder and/or a tic disorder • Pediatric onset of symptoms • Episodic course of symptom severity • Association with group A Beta-hemolytic streptococcal infection (a positive throat culture for Strep or history of Scarlet Fever) • Association with neurological abnormalities (motoric hyperactivity, or adventitious movements, such as choreiform movements) • Diagnoses based on symptoms and High ASO and Anti. DNAse AB

Chronic Infectious Agents and Chronic Disease Effects • These agents create inflammation, free radicals • • and oxidative stress. Some of these biologic agents produce neurotoxins and excitotoxins and other toxic byproducts. Some agents increase cell membrane permeability. Our body may produce antibodies to these agents. These antibodies may cross react with our own tissue creating an autoimmune reaction. This is called molecular mimicry. Chronic infections disrupt neurotransmitters

Impact of Oxidative Stress on Methionine Metabolism Methionine MAT THF SAM MTase MS B 12 BHMT 5 -CH 3 THF Betaine Choline THF: tetrahydrofolate SAHH Adenosine Homocysteine B 6 CBS AK AMP ADA Inosine Cystathionine Cysteine Enzymes Methylation of DNA, RNA, Proteins, Catecholamines, Phospholipids, Creatine Glutathione Transsulfuration Pathway GSSG

Basic Biomedical Strategy • • • History and Physical Examination Laboratory Testing Clean Up – Environmental Controls – Dietary Interventions – Address Gastrointestinal Health • Foundational Nutrients • Treat Underlying Immune Issues and • • • Inflammation Support Detoxification Pathways, esp. Methylation and Sulfation Address Mitochondrial Dysfunction Heavy Metal Detoxification

History - Gastrointestinal • • • History of Colic, Reflux Frequent Antibiotics Dairy Intolerance, Sugar Cravings Frequent Otitis Media or Sinusitis History of Thrush, Severe Diaper Rash Poorly Formed Stools, Odd Color, Consistency, Odor, Mucus, “Soft Serve” Undigested Food in Stools, Floating Stools Constipation, Chronic Diarrhea, Both Abdominal Distention, Gassiness Abnormal Posturing Self Injurious Behavior, Aggression Poor Sleeping Habits

Physical • Poor growth – height, weight, head circumference • Pale skin, spider veins, long eye lashes • Skin- rash, sand paper skin, eczema, warts, acne • • • molluscum contagiosum, red anal ring Dilated pupils, lack of eye contact, divergent gaze, poor visual tracking, squinting Allergic shiners, Nasal crease, Mouth breathing Nails – spots, ridges, fungus Coated tongue or thrush, mouth ulcers, cracked lips Enlarged tonsils Lymphadenopathy Spleen tenderness Abdominal bloating Hypotonia, W-sitting, Flabby muscles, Strabismus Ligamentous laxity (double jointed) Signs of precocious puberty- facial hair, pubic hair 24

Clean up the Child’s Diet • Casein-free/Gluten-free/Soy-free Diet Trial for 3 -6 months. • Avoid sugar and refined starch, high fiber diet, maximize • • • antioxidants, cruciferous veggies, turmeric, garlic… Limit processed and preserved foods; organic is best. Avoid excitotoxins (ex. Caffeine, MSG, Nutra. Sweet, red/yellow food dyes, nitrites, sulfites, glutamates, preservatives). Limit intake of phenolics (apples, grapes, strawberries). Limit sources of Copper (chocolate, shellfish, tap water, artificial food dyes). Drink plenty of clean filtered water. Eliminate seafood. Begin meals with raw fruits and veggies. Add good fats (cold pressed, hexane-free) – oils, nuts, seeds. Avoid hydrogenated, trans-fats, fried or heated fats. Buy hormone-free, antibiotic-free, organic, GMO-free especially animal products such as eggs, meat and dairy. Add fermented foods (coconut kefir, cabbage, kombucha).

Dietary Detours CF/GF Diet Persistent Gut Issues Hyperactivity/Stimming Specific Carbohydrate Diet Avoid Excitotoxins Body Ecology Diet Low Phenolic/Feingold Diet Low Oxalate Diet Low Copper Diet Elimination/Rotation Diet

Opioid Peptides • Casein/gluten peptides are broken down by the enzyme DPPIV(dipeptidyl dipeptidase 4). This enzyme can be disabled by toxic metals and yeast. • These peptides act as false neurotransmitters, creating problems with behavior, focus, attention, mood regulation, and processing info. Other symptoms include high pain tolerance, dilated pupils, addiction to dairy and gluten products. • High levels of opioid peptides (gliadorphin and caseomorphine) found in urine of autistics. (Reichelt, 1997) • Casein-free, Gluten-free diet may be an effective intervention (Whiteley, 1999)

Specific Carbohydrate Diet Elaine Gottschall BA, M. Sc. • The allowed carbohydrates are monosaccharides and have a single • • • molecule structure that allow them to be easily absorbed by the intestine wall. Complex carbohydrates which are disaccharides (double molecules) and polysaccharides (chain molecules) are not allowed. Complex carbohydrates that are not easily digested feed harmful bacteria in our intestines causing them to overgrow producing by products and inflaming the intestine wall. “The diet works by starving out these bacteria and restoring the balance of bacteria in our gut. ” www. breakingtheviciouscycle. info/beginners www. pecanbread. com

Celiac Disease Presenting as Autism Stephen J. Genuis, MD, and Thomas P. Bouchard, BSc Gluten-restricted diets have become increasingly popular among parents seeking treatment for children diagnosed with autism. Some of the reported response to celiac diets in children with autism may be related to amelioration of nutritional deficiency resulting from undiagnosed gluten sensitivity and consequent malabsorption. A case is presented of a 5 -year old boy diagnosed with severe autism at a specialty clinic for autistic spectrum disorders. After initial investigation suggested underlying celiac disease and varied nutrient deficiencies, a gluten-free diet was instituted along with dietary and supplemental measures to secure nutritional sufficiency. The patient’s gastrointestinal symptoms rapidly resolved, and signs and symptoms suggestive of autism progressively abated. This case is an example of a common malabsorption syndrome associated with central nervous system dysfunction and suggests that in some contexts, nutritional deficiency may be a determinant of developmental delay. It is recommended that all children with neurodevelopmental problems be assessed for nutritional deficiency and malabsorption syndromes. Child Neurol Online. First, published on June 29, 2009

Low Oxalate Diet (LOD) Susan Owen BS • Oxalates are abundant in many plant foods • When the gut is inflamed or becomes permeable • • • excess oxalate from foods can be absorbed When present in high amounts can lead to oxidative damage, depletion of glutathione, and inflammation Excess oxalates form crystals after binding with calcium Symptoms include: Pain, Burning, Frequent Urination, Eye Poking, Family history of Kidney Stones, Vulvodynia Avoid High Oxalate Foods – Spinach, Greens, Nuts, Soy, Beets Avoid Calcium and High Doses of Vitamin C

Food additives and hyperactive behavior in 3 -yearold and 8/9 -year-old children in the community: a randomized, double-blinded, placebo-controlled trial • The Lancet 2007 • examined the effect of artificial coloring and preservatives on hyperactive behavior in children. After consuming an additive-free diet for six weeks, the children were given either a placebo beverage or one containing a mix of additives in two-week intervals. In the additive group, hyperactive behaviors increased. • the study caused many pediatricians to rethink their skepticism about a link between diet and A. D. H. D. “The overall findings of the study are clear and require that even we skeptics, who have long doubted parental claims of the effects of various foods on the behavior of their children, admit we might have been wrong, ” reported a February issue of AAP Grand Rounds, a publication of the American Academy of Pediatrics.

Excitotoxins - Glutamate • Anti- Glutamates • Glutamates – Monosodium Glutamate (MSG) – Hydrolyzed Protein – Modified Food Starch – Natural Flavors – Peas, Mushrooms, Tomatoes – Parmesan Cheese – Protein – – – Pycnogenol Rosemary, Lemon Balm Skull Cap, Chamomile Magnesium Taurine GABA L- Theanine Vitamin K Lithium Namenda (drug) Minocycline (antibiotic) Excitotoxins = Substances that cause an excess of excitatory neurotransmission in the brain. If inhibitory neurotransmission is lacking, the excess excitation may lead to neuronal death. Neuronal death leads to chronic inflammation in the brain.

Lab Options for Gut Issues • • • Urine Organic Acids Test (OATS, MAP) Stool Microbiology Stool Mycology Stool Parasitology Ig. G/Ig. E Food/Mold Antibody Panel Celiac Panel, Carnitine level, Vit D 25 OH, retinol Fecal Fat Breath Test for Fructose Malabsorption Inflammatory Markers (ESR, CRP, histamine, • • • Ammonia - blood, urine IBD Serology (prometheus testing) Endoscopy, Colonoscopy if necessary calprotectin, …)

General Treatment Strategies • Address Maldigestion – Add Digestive Enzymes • Address Malabsorption – Add Probiotics, Essential Fats – Address Fat Soluble Vitamin Deficiencies – Add Lipase • Address Dysbiosis • Diagnose and Treat Immune Dysregulation – Address Food Hypersensitivities – Treat Immunodeficiencies – Treat Chronic Inflammation • Address Motility/Constipation

Clean up the Child’s Gut • • Daily bowel movements are a goal. Add digestive enzymes with meals. Start high potency probiotics. Start treatment for dysbiosis. Address constipation. Check for high ammonia, treat accordingly If persistent symptoms: – Eliminate disaccharides from diet for 3 -6 months • Specific Carbohydrate Diet – Consider referral to knowledgeable GI specialist – Consider trial of IV or nasal Secretin – Add anti-inflammatory agents. Keep close eye on gut during any detox regimen. Acute regression most likely due to gut issues.

Constipation has got to go! • May mask as • • diarrhea Check a KUB xray If it takes greater than 24 hrs to pass charcoal or beets, consider motility issues • • • Magnesium citrate Buffered Vitamin C Increased fiber/fluids Avoid opiate peptides Massage, Rebounding Senna Polyethylene glycol Suppositories or Enemas if needed Cholinergic Agents – Urecholine – Phosphatidyl Choline

Treating Dysbiosis/Co-infections • Clostridia • Yeast • Bacteria and Strep • Parasites • Viruses

Clostridia produce toxins and enzymes that create severe gut inflammation and produce watery diarrhea

Clostridia Issues Symptoms – – – – Aggressive OCD Temper Agitation Irritable Very foul stools Mucus in stools Severe diarrhea following antibiotic use Treatment – Probiotics, High Potency single strain – Sacchyromyces Boulardii – Antibiotics • Vancomycin • Metronidazole (Flagyl) – Herbals – Immune modulators – Homeopathics – HBOT – Carnitine

Yeast Issues Symptoms – – – – Spacey Foggy thinking Inappropriate laughter Sugar cravings Poor sleep Frequent diaper rash Frequent urination History of frequent antibiotics Treatment Options – – – Limit carbs, sugar, yeast Probiotics Sacchromyces Boulardii Zinc, Molybdenum Antifungals • Drugs – – Nystatin, Ampho B Fluconazole Itraconazole Ketoconazole – – Berberine Grapefruit Seed Extract Oil of Oregano, Pau d’Arco Garlic, Samento, … • Herbals – Enzymes – Homeopathics

Strep Issues Symptoms – – – – Ritualistic Repetitive Verbal tics Obsessive Compulsive Verbal stims Frequent strep infections – Frequent bacterial infections Treatment Options – – Probiotics Alkalinization Xylitol Antibacterial Herbs • Goldenseal • Neem • Berberine – Immune modulators • Oral Immunoglobulins • Transfer Factors • Colostrum • Mushroom Extracts • Beta Glycans • Plant Sterols – Drugs • Penicillin • Zithromax – Homeopathics

Parasites Symptoms – – – Bizarre Behavior Insatiable Appetite Aggressive Worse at full moon Picking, biting, licking, itching, grinding – Fecal smearing – Restlessness Treatment – Probiotics – Antiparasitic Drugs • Flagyl • Paromomycin • Mebendazole • Alinia – Natural Remedies • Wormwood(artemesia) • Black Walnut • Pumpkin Seeds • Clove • Coconut Oil – Homeopathics • Combo remedies

Viral Issues Symptoms – Easy Fatigue – Visual Issues • Squinting • Divergent Gaze • Poor Eye Contact – Cold sores – Warts – History of Regression after MMR or other live viruses Treatment Options – Antiviral Agents • Olive Leaf Extract, Elderberry • Caprylic Acid • High Dose Vitamin A – Antiviral Drugs • • Acyclovir Valacyclovir Famvir Imunovir – Immune Support • • Low Dose Naltrexone Red. Glutathione Zinc Immune Modulators

Anti-inflammatory Agents • Herbs – Boswellia, Green Tea, Nettles, Slippery Elm, Cat’s Claw, DGLicorice, Aloe, Ginger, Garlic, Echinacea, Ginseng, … • Bioflavinoids (carotenoids, catechins) – Curcumin, Hesperidin, Pycnogenol, Quercetin and Rutin. • Antioxidant rich fruits and veggies, and nutrients – Glutathione • Omega 3 and Omega 6(DGLA) EFAs • Sulfates help to seal a leaky gut- Epsom Salts Baths, … • Cholinergic agonists • – Phosphatidyl Choline, Phosphatidyl Serine, Galantamine, Nicotinic Acid Meds – Singulair, Actos, Celebrex… Aggarwal, B. B. and K. B. Harikumar, Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, Aggarwal, autoimmune and neoplastic diseases. Int J Biochem Cell Biol, 2009. 41(1): p. 40 -59. 41(1):

Additional Sources of Information • Autism: Effective Biomedical Treatments, Pangborn and • • • Baker Healing the New Childhood Epidemics, Ken Bock, MD Children with Starving Brains, Jaquelyn Mc. Candless MD Special Diets for Special Kids, Lisa Lewis Changing the Course of Autism, B. Jepson MD and Jane Johnson Nourishing Hope, Julie Matthews Nourishing Traditions, Sally Fallon

Thank You.