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NAA May, 2019

Nancy Hofreuter O’Hara, MD, MPH, FAAP

www.drohara.com

New Treatment Options

Moving Forward:

Therapies to Consider

and Why

Autism prevalence USA

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The Yin and Yang Between Tolerance and Immune Response Leading To Autoimmunity

EnvironmentalFactors

HumanGenome

ClinicalOutcome

IncreasedGutPermeability

Microbiome

ImmuneResponse

“Now another concept may be emerging, which might be called the ‘keystone

relationship’. “The interaction between fiber and microbes that consume it, is the

fundamental keystone interaction that everything else is built on in the gut. It may lie

at the heart of the symbiotic pact between microbes and humans.”

Nature 518, S3–S11 (26 February 2015)

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New Discoveries -> Paradigm Shifts

Vs Status Quo and Denials

  Problem: Doctors give names to things they don’t understand so they can start the process of understanding.

  Bigger problem: Naming something gives the impression we understand it.

  Quotes:   – “Your blood sugar is high because you have diabetes.”   – “You feel sad because you have depression.”   – “Your blood pressure is high because you have hypertension.”   – “You have pain and feel sick because you have post-treatment Lyme disease

syndrome.”   – “Your son can’t speak because he has autism.”

  How do you escape these misleading fallacies?

  – Find the root cause of the disease (not just the symptoms) and direct new treatments at the root of each illness.

  • Maybe there is a common cause for many chronic illnesses.

The Cell Danger Response   First wave of danger signals

  Release of metabolic intermediates such as   ATP, ADP   Krebs cycle intermediates   Reactive oxygen species

AND is sustained by purinergic signaling extracellularly

  After the danger has been eliminated -> choreographed sequence of anti-inflammatory and regenerative pathways activated – HEALING

  Abnormal persistence of CDR -> disturbance in whole body metabolism, gut microbiome, multiple organ performance, behavior changes -> chronic disease

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Persistent Cell Danger Response Abnormal Purinergic Signaling in ASD

  Cell Danger Respone (CDR) – evolutionarily conserved metabolic response that protects cells and hosts from harm.

  Triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis.

  In ASD and other chronic illnesses -> Persistent Cell Danger Response

Abnormal Purinergic

Signaling in ASD

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Anti-Purinergic Therapy • Phase I clinical trial - safety and tolerability of a single dose of suramin in children with autism. Randomized, double-blind, placebo controlled; 10 boys; 5-14 years with ASD

• Hypothesis: Hyperpurinergia is a core feature of ASD; single dose of antipurinergic therapy with suramin can temporarily reverse some of the speech, social, & ANS deficits in ASD

• Intervention: Single dose of suramin administered IV

• Outcomes: Statistically significant improvement in CGI, OCD, social interactions, expressive language; dozens of metabolic abnormalities improved

• Each treated child -> non-core symptom improvements (none in placebo group)

– Accelerated developmental and learning milestones

– Decreased anxiety and meltdowns in novel situations

– Improved sleep and interest in new foods

– Improved GI function (suramin restored microbiome diversity in mice)

Mindd International Forum 31

Dozens of Metabolic Abnormalities were Improved by One Treatment

MIA

OxalateB2-Riboflavin

Biopterin

GABA/GluBioamines*Trp/5HT/KynurenineAmino sugars

PurinesBile acids

MicrobiomePhospholipids

SAM/SAH/GSHPyrimidinesGlycolysis

SphingomyelinsCeramides*CholesterolKrebs cycle

Eicosanoids*Fatty acid oxidation

Cardiolipin*Glycosphingolipids*Branch Chain AA

NO/ROS

Pentose PhosphatePropionate (IVTM)

B6-Pyridoxine

Fragile X

Human ASD

21%

40%

g-Glutamyl DipeptidesTaurine*, Histamine

Vitamin C, D*, Phe/Tyr1-Carbon/Folate

Myoinositol*

25%

14%

75% Shared withMouse Models

Before

6-Week

sBef

ore6-W

eeks0

2

4

6

8

10

ADOS

Com

pariso

n Scor

e

Suramin Treatment Improved ADOSScores by 1.6 Points in 6 Weeks

Suramin

Placebo

ASDNot ASD

3 doses in3 months?

Suramin Placebo

1.6 ± 0.55(p < 0.0028)

0.4 ± 0.55(p = ns)

Suramin Treatment Decreased Autism Core Symptoms Significantly in 6 weeks

62

Off spectrum?

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Metabolic Features of the CDR and Its Evolutionary Origins in the Seasons

From Naviaux RK. Metabolic Features of the Cell Danger Response. Mitochondrion, 2013.

(Scarce Calories)

(Plentiful Calories)

The Persistent Cell Danger Response

  For More Information

  • PubMed:

  – The Metabolic Features and Regulation of the Healing Cycle. Naviaux RK. Mitochondrion, September 2018.

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The changing face of gut microbes

The Epidemics of Immune-Mediated Diseases In The Western Hemisphere: The Hygiene Hypothesis

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RESTORING THE BIOME: HELMINTHS For A HEALTHY

IMMUNE SYSTEM

You are 10% YOU

The adult human body has about 10 trillion cells (with

your own DNA)

The adult human body has about 100 trillion other

organisms…with their own DNA

YOU ARE AN ECOSYSTEM

So what happens if you change even one element in an ecosystem?

Reintroduction of wolves to Yellowstone National Park

Wolves reduced the elk population

The elk had been eating the willows

With more willows -> more beavers

Beavers built dams -> changed stream hydrology

Changes in the water and ecosystem!

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Now let’s look at the YOU In the last 100 or so years, we completely

changed our evolutionary-history lifestyles:   Started to use toilets   Started wearing shoes everywhere, all the time   Started eating highly processed foods   Started drinking processed water   Stopped regularly breastfeeding   Started to use antibiotics   Started doing c-sections more and more   Started wearing sunscreen and working indoors

more often   Etc. etc. etc.

Why HDC is Our Organism of Choice Ø  The low cost of cultivation facilitates its use for

normalization of the immune system by the population as a whole. ($)

Ø  No transmission from human-to-human is possible Ø  The distribution of the HDCs in the human body is strictly

limited to the lumen (inside) of the gut, unlike nematodes currently in use (hookworms and whipworms) which breach the barrier of the gut. Minimal risk of infestation.

Ø  HDCs are raised in grain beetles (Tenebrio molitor), which are normally found in the human food supply as a harmless contaminant in a wide variety of grains.

Ø  HDC is a mutualist! NOT A PARASITE! Ø  HDCs evoke an immune system response which we

NEED as it is a normal part of our immune conditioning.

Ø  www.biomerestoration.com      

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Biome depletion results in increased inflammation (Molecular & Biochemical Parasitology (2009) 167: 1–11)

Concerns   Post HDC inflammatory reaction

  Start with lower dose HDC   Increase q 3 wks   Ibuprofen   Antihistamine

  Infestation   Constipation/Slow transit time   Immunocompromised status or medications   Symptoms – severe cramping and pain   Treatment – billtiricide 20 mg/kg/day divided into 3 doses

treats infestation

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Additional thoughts   Chance of infestation 0.1% in children

  Increased chances of colonization with immunosuppression and being a child

  Tapeworm colonizations are notoriously asymptomatic, although abdominal pain can sometimes occur

  Sometimes the eggs get released sporadically or in “bursts” - important to do repeated stool checks to make sure that there are no adults present

  The HDC organisms are not like bacteria in the sense that they don’t multiply inside the body. Thus they cannot adapt like bacteria. All are sensitive to Billtricide

  Why HDCs?   Microbiome diversity   Changes in immune function   Reduction of total toxic load   Return to preindustrial tolerance

TheSandwich

Whilesomewouldsaythat“everythingisautoimmuneuntilprovenotherwise”readingthechaptersinthisbookwrittenbyworldleadersinautoimmunitybringsonetotheconclusionthateverythingafterallisinfectiousuntilprovenotherwise(includingautoimmunediseases).

RoseNE,Shoenfeld Y(Editors)InfectionandAutoimmunity,2005

“Everything is autoimmune until proven otherwise” and everything after all is infectious until proven otherwise (including autoimmune diseases). Rose NE, Shoenfeld Y Infection and Autoimmunity, 2005, p 1

What Dr. Shoenfeld says is that common sense demands a trial of safe measures to restore immune tolerance in all complex chronic illnesses.

Sid Baker’s guru

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The Microbiome as Possible Transducer of All Environmental Factors Affecting Onset of CID in

Genetically Susceptible Individuals

Martin VJ, et al J Pediat 2016 Sept 12, (Epub ahead of print)

Dysbiosis is one of the key factors causing zonulin release and subsequent loss of

barrier function

© MAPS 2013

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Chronic Inflammatory Response Syndrome   Studied and researched by Ritchie Shoemaker (Pokomoke, MD –

Pfiesteria outbreak -> watermen ill with biotoxin illness improved with CSM); Continued research by Neil Nathan

  Genetic susceptibility and exposure to biotoxins   Failure to mount an effective immune response to biotoxins   Neuroimmune, vascular, endocrine dynamics   Linked to Aspergillus, Penicillium, Chaeitomium, Wallemia,

Borrelia, Babesia, Bartonella, Anaplasma and Ehrlichia

  Biotoxin driven multisystem and multisymptom pathway Berndtson, CIRS:Overview,Diagnosis and Treatment, 2013

CIRS   History, signs, symptoms consistent with biotoxin exposure

  CIRS-causing biotoxins are ionophores, disrupt nerve function

  Exposure to toxin-producing molds documented by EPA-approved ERMI test

  Genetic predisposition – HLA susceptibility (HLA DRB and DQ)   25% population genetically prone   2% highly susceptible to disabling symptoms   Warming campfire becomes devastating wildfire (N Nathan)

  Biomarkers consistent with abnormalities in following systems   Neurologic (neurotoxins first and foremost)   Immunologic   Vascular (cardiovascular and GI – ANS connections)   Endocrine Shoemaker et al, Env Health Pers, 2001

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© MAPS 2013

CIRS - It is not just Mold   Mold spore fragments

  Volatile Organic Compounds (VOCs)

  Microorganisms (Actinomycetes, Mycobacteria, Lyme)

  Beta glucans, hemolysins, mannans, proteinases

  THINK CIRS when you hear (pathognomonic)   Electric shock sensations   Ice pick or lightening bolt pains   Pulsing or vibrating sensations (especially down spine)

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Visual Contrast Sensitivity   Biotoxin exposure can impair

  Optic nerves   Ability to see patterns impaired

  98% who fail VCS & have 8 sxs   Have a biotoxin illness

  Fail if NOT reach lower line   Nothing visible in Row E   Barely able in Row D   Test failed = biotoxicity Interpretation – note hand drawn checks & ovals

Check = black and white component seen clearly Oval means component not seen from TOXIC by Neil Nathan, MD Forward by Robert Naviaux, MD, PhD

Mycotoxin Testing   Real Time or Great Plains urine testing

  Best done after   Two week course of oral glutathione   IV glutathione   Sauna

  Watch for worsening of symptoms during challenge

  More specific and less invasive testing

  May worsen as start treatment   N of 1 (testing as guide)

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CIRS Diagnosis   Detailed history of exposure and symptoms   Visual contrast testing deficit – monitor changes over treatment

course

  Check HLA susceptibility and appropriate biomarkers (MSH, VEGF, TGF-beta, Leptin) and/or urine mycotoxin testing

  Check MARCoNS NASAL SWAB (may need to check family dog!)   Treat with nasal spray if positive (1 squirt/nostril 2x/day)   BEG – Bactroban 0.2%, EDTA 1%, Gentamicin 0.025%, additions

  Run ERMI tests (home, office, school, other) – vacuumed dust examined for 36 mold toxins

  Shoemaker and House, 2006

CIRS Treatment Steps   Remove from exposure and retest (ERMI vs HERTSMI-2)

  Preload with EFAs 3-4 grams/day for at least 5 days   CSM/Welchol/Binders (Charcoal, Zeolite) - COMPOUNDED

  Eradicate MARCoNs

  Correct Antigliadin antibodies; remove gluten

  Rebooting and Reassessing (metabolic, immunologic, gut…)   Sleep, exercise, meditation and DIET!   Probiotics, prebiotics, antioxidants (vitamin D, GSH, oils…)   Minerals – zinc, magnesium   Mitochondrial support

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CIRS Treatment   Antifungals – oral and intranasal

  Binders (depending on mycotoxin results)   Cholestyramine (compounded) – best for Ochratoxins   Charcoal – best for Aflatoxins   Chlorella and bentonite clay (limited information) – consider with

charcoal for Trichothecenes

  Additional agents   Glutathione and N-acetyl cysteine – consider for Gliotoxins   S Boulardii – consider for Gliotoxins   DHEA   Glutamate modulators - consider lamictal, Topamax, Gabapentin,NAC,

Amantadine, Strattera, Dextromethorphan, Huperzine A, Butyrate (gammahydroxy butyrate), Cannabinoid

CIRS •  Think CIRS

•  Symptoms in 6 clusters •  Commonly up to 10

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Excellence is the result of caring more than others think is wise, risking more than others think is safe, dreaming more than others think is practical and expecting more than others think is possible

CBD and Hemp Oils

  CBD (Hemp Oil) – Cannabidiol   Reverses mCPP-induced marble burying in mice

 Nardo et al, 2013; Delana et al, Psychopharm, 2012

  Nonpsychoactive, anxiolytic, antipsychotic

  Decreases inflammation and pain

  Anticonvulsant

  Multiple brands (test at Proverde in Milford, MA; www.proverdelabs.com)

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CORTISOL  Elevation - associated with Insomnia, decreases the amount and quality of REM sleep

 Increases pro-inflammatory cytokines à INFLAMMATION

 Prolonged elevated cortisol increases risk for chronic illnesses

 Elevated cortisol decreases TSH and ability for proper conversion of T4 à T3

 Elevated cortisol - Decreases mitochondrial energy production capacity à MITOCHONDRIAL DYSFUNCTION

 Elevated cortisol ->   Insulin receptor insensitivity   Insulin resistance

•  Carlsson et al. Psychological stress in children may alter the immune response. J Immunol. 2014. •  Moreyet al. Current Directions in Stress and Human Immune Function. Current opinion in

psychology 2015. Van Cauter et al. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels. JAMA. 2000.

•  Walter et al. Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women. Thyroid Research 2012.

•  Picard et al. Psychological Stress and Mitochondria: A Systematic Review Psychosomatic medicine. 2018 •  Geer, Eliza B et al. “Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue

function and lipid metabolism” Endocrinology and metabolism clinics of North America . 2014.

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SUPPORTING THE ADRENALS   Ashwaganda – calming, thyroid support

  Rhodiola – fatigue, enhances endurance, situational anxiety, mental clarity, inflammation

  Gotu Kola – ADHD, mental chatter

  Holy Basil – blood sugar regulation, metabolic syndrome

  Siberian Ginseng – improves fatigue, concentration, enhances oxygen metabolism, etc.

  Licorice – hypoadrenalism, fatigue, antiviral

  Healthy, well balanced, organic, non-processed diet

  Exercise – to the point of sweating! Plus spend time outdoors!

  Meditation, relaxation techniques, mantras, tapping, sleep hygiene

  IONCLEANSE BY AMD

MEASURING EFFECTS OF IONCLEANSE BY AMD ON CORTISOL LEVELS IN CHILDREN

WITH ASD   Clinically, we were seeing that the IonCleanse by AMD decreases stress and sensory overload (specifically sound sensitivity) in

children with ASD, particularly children of adolescent age

  Lead us to conduce a small study in our office   The sample included 10 children with a diagnosis of ASD between

the ages of 6 – 19 years old (mean = 12 years old).

  Participants were chosen based on ASD diagnosis and clinical symptoms consistent with stress and suspected adrenal dysfunction.

  Inclusion criteria included at least one symptom of the following: sleep disturbances, anxiety, sensory overload, hyperactivity, OCD, perseverations, aggression, and self-injurious behavior.

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MEASURING EFFECTS OF IONCLEANSE BY AMD ON CORTISOL LEVELS IN

CHILDREN WITH ASD   Cortisol was collected by blood and saliva.

  AM fasting blood cortisol   4 point saliva cortisol - AM, afternoon, late afternoon, evening   Tests were done 7 days before the introduction of the IonCleanse footbath and 7 days

after the 60-trial period.

  Parents of the participants listed the top 3-5 symptoms for which they would like improvement at the beginning of the study. Each week parents were required to submit a parent observation sheet ranking the prevalence of the initial symptoms reported.   The scale was from 0-12 (0-3 minor, 4-8 moderate, 9-12 severe).

  The footbaths were done on the schedule of 2 days on, 1 day off for a 60-day period.

  The length of time for the footbaths were dependent on the participants age.

  60-day, 100% money back guarantee; no forms, no restocking fees, etc

SALIVARY CORTISOL AM RESULTS

SALIVARY CORTISOL AFTERNOON RESULTS

SALIVARY CORTISOL LATE AFTERNOON RESULTS

SALIVARY CORTISOL EVENING RESULTS

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RESULTS   Blood cortisol and salivary cortisol results were not statistically

significant. Likely due to extremely small sample size.

  There were benefits reported on the parent observation sheets (i.e attention, sleep disturbances, fatigue, eye tics, rigidity, and bruxism).

  Some children experience severe herxheimer reactions

  1/3 of the participants purchased the the IonCleanse unit after the end of study to continue treatment based on the benefits seen.

  Future Plans: Phase II to include a larger sample size with stricter regulations in sample collection and inclusion criteria and including biochemical, inflammatory and metabolic markers.

AUTISM Autism– TMR Study

 Autism Treatment Evaluation Checklist(ATEC)changes analyzed by The Thinking Moms Revolution

 27 participants

 4 months of use – 3 days of cleansing, 1dayoff,repeat

 Results:55% Average ATEC Reduction

  (64% for Teenagers)

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GLYPHOSATE Glyphosate Evaluation

 2018

 Great Plains Labs

 Measure of glyphosate excretion in urine

 30 day period

 9 in control

 10 in therapy group   12 sessions (M,W, F)

Control IonCleanse Therapy

-14%

-48%

Glyphosate level vs. baseline test

“Follow those who seek the truth but flee from those who have found it.”

Yaclav Havel/Andre Gide

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Stem Cell Therapy

  Mechanisms of underlying therapeutic effects   Immunomodulatory properties – change in

proinflammatory and anti-inflammatory cells   Paracrine effect (cytokines, chemokines, growth factors

and restoration of injured tissues)

  Stem Cell Types   Fetal   Bone marrow derived   Adipo   Umbilical cord and amniotic

Stem Cell Therapy & Animal Models   Beneficial effects in mouse models

  Improved repetitive behaviors   Decreased cognitive rigidity   Improved social interactions   Improved hippocampal neurogenesis

  Segal-Gavish et al. Mesenchymal stem cell transplantation promotes neurogenesis and ameliorates autism related behaviors in BTBR mice. Autism Res. 2016

  Perets et al. Long term beneficial effect of neurotrophic factors-secreting mesenchymal stem cells transplantation in the BTBR mouse model of autism. Behav Brain Res. 2017

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Stem Cell Therapy and Clinical Trials

  Improvements in social relationships and reciprocity

  Improvements in cognitive aspects (attention, concentration, and time of response)

  Improvements in speech and language patterns

  Trophic and induction changes not cell replacement   Sharma A, Gokulchandran N, Sane H, et al. Autologous bone marrow mononuclear cell

therapy for autism: an open label proof of concept study. Stem Cells Int. 2013   Dawson G, Sun JM, Davlantis KS, et al. Autologous cord blood infusions are safe and

feasible in young children with autism spectrum disorder: results of a single-center Phase I open-label trial. Stem Cells Transl Med. 2017

  Hess DC, Borlongan CV. Stem cells and neurological diseases. Cell Prolif. 2008

What lies behind us and what lies before us are small matters compared to

what lies within us.

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MICROBIALCOMMUNITIESINASDAREDIFFERENTFROMTHOSEIN

CONTROLS RoseD.R.etalBrain,Behav,immun2018

52

Behavioral Measures In ASD Children +/- GI Symptoms

RoseD.R.etalBrain,Behav,immun2018

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FMT - Background   Short-term benefit from oral vancomycin treatment of regressive-

onset autism (Sander et al J Child Neurol 2000)   Killing off bacteria (good, bad and ugly)   Initial hyperactivity, then temporary gains   Lost all gains after stopping treatment

  Children with ASD who had GI symptoms   Higher ATEC scores (speech, social, cognitive, sensory issues)

  Lower microbial diversity in children with ASD (Kang et al 2013)   Low levels of Prevotella (higher if high fiber diet)   Lower butyrate (starving for fiber)

FMT - Autism   FMT for Clostridia Difficile (one fecal transplant)

  Dr. Thomas Borody (GI from Australia) used FMT in ~ 5000 patients, including 9 children with autism for 3 months   Improved bowel function and sleep   Increased vocabulary, attention and task performance

  Initial study protocol at Arizona State University   2 weeks oral vancomycin   1 day fasting and bowel cleanse   High dose, highly purified microbiota (oral or rectal)   7-8 weeks low dose microbiotia (different donor)

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Fecal Transplants – FMT Adams et al. Arizona State University. Scientific Reports. 2017

  What they did   18 children with ASD & moderate/severe GI sxs (aged 7 to 16) received MTT   20 equivalent control subjects who had neither gut problems nor ASD diagnosis   Both groups were treated for 10 weeks & follow-up testing for a further 8 weeks

  What they found   Mothers with ASD and GI sxs (low maternal fiber, lower rate BF, higher rate C section birth

and increased antibiotic use)   Fewer gut problems (80% reduction in symptoms) – better with oral than rectal   Ongoing improvements in ASD symptoms two years after procedure (58% reduction in

symptoms)

  Originally ASD symptoms eased or vanished for at least a couple of months after treatment ended (at least 47% overall reduction)

  After 2 years, diversity even higher & the presence of beneficial microbes remained (4 fold increase Bifidobacterium and 84 fold increase in Prevotella)

FMT – What’s Available   FMT

  Need more trials as “poop is a drug”   Only allowed for recurrent C Diff

  Ongoing studies (Phase 2)   New Child Study - pending funding   Adult study – Treating Adults with ASD (Adams and Frye)

  Randomized, double blinded, placebo controlled

  Open Biome   Capsules and by endoscopy or colonoscopy   Only available to gastroenterologists and infectious disease

specialists & must have documented C Difficile

  Home use – BE CAREFUL!   Need clean, healthy donor & oral route better

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CNS & Neurological Disorders - Drug Targets, 2015, 14, 110-131

Evidence obtained from human and animal studies provides a unifying paradigm of a vicious cycle in that:

changes in gut flora dysbiosis gut inflammation gut dysfunction (intestinal permeability) systemic inflammation neuroinflammation, disparate pathophysiological alterations including behavioral changes (Fig. 1).

Altered Mucosal Integrity

Poor dietary choices

Altered Intestinal

Permeability

Stress

Infection

Dysbiosis

Inflammation

Systemic Disease

Low Stomach Acid

Toxic Exposure

Ischemia, low O2

Food Allergy, Sensitivity, &

Intolerance

Malnutrition

Toxic Overload

Elevated Total Toxic &

Antigenic Burden

Systemic Disease

WHAT DO WE DO???

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Suzuki et al, Cell Mol Life Sci, 2013

Antoine Louveau, Structural and functional features of central nervous system lymphatic vessels, Nature 523, 337-341

Value of Sleep: Detoxification   Sleep deprivation stressed the immune

system like physical stress or illness

  The brain has a unique waste management system - glymphatic system - which is active during sleep

  The glymphatic system pumps cerebral spinal fluid through your brain’s tissues, flushing the garbage from your brain into your bloodstream and into your liver, for elimination

  Your brain cells also shrink about 60 percent during sleep for more efficient waste removal

  Atlas Orthogonal Chiropractic Manipulation

  Vagal Nerve Stimulation

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The “Anti-Inflammatory” Diet

The Human race appears on the face of hearth

Years

2.5 M

DietFruits, nuts, tubers

Occasional meat

Change from nomadic tosettled life style

10,000

Advent of agricultureDevelopment of gluten

containing grains

2009The Human race appears

on the face of hearth

Years

2.5 M

DietFruits, nuts, tubers

Occasional meat

Change from nomadic tosettled life style

10,00010,000

Advent of agricultureDevelopment of gluten

containing grains

2009

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