Autsim File Conference Presentation 2010

1. The Wet Surfaces, The
Immune System & The
Brain.
Why And How they
May Affect Behaviour
And Function In
People With Autism
Michael Ash
BSc (Hons) DO ND
F.DipION

2. • The aetiology of ASD is largely unknown, but
genetic, environmental, immunological, and
neurological factors are thought to play a role in
the development of ASD.
• Recently, focused on the connections between
the immune system and the nervous system.
• These neuroimmune interactions begin early
during embryogenesis and persist throughout an
individual’s lifetime, with successful
neurodevelopment contingent upon a normal
balanced immune response
Ashwood P, Wills S, Van de Water JThe immune response in autism: a new frontier for autism research.
. J Leukoc Biol. 2006 Jul;80(1):1-15. Epub 2006 May 12. Review. View Paper

4. Genetic Determinism
• Your genome, or any part of it, is not you
• The concept that our DNA sequence our
genome- does not equal or predict our
destiny has been extremely difficult for some
geneticists to accept.
• We don’t even have a good idea how many
genes there are, let alone how these genes
work with each other and the environment to
orchestrate human development.
• LL McCabe & ERB McCabe. DNA Promise and Peril. University of California Press; 1 edition (1 Mar 2008)

5. Oct 2010

8. • Autism may in fact be a systemic disorder with
connections to abnormal immune responses.
• M Careaga, J Van de Water, and P AshwoodImmune dysfunction in autism: a pathway to treatment. Neurotherapeutics,
July 1, 2010; 7(3): 283-92. View Abstract
• Immunological factors have provided more
support for a probable immunological process
or for processes that may play a role in the
acquisition of an autistic condition.
• MG Chez and N Guido-Estrada. Immune therapy in autism: historical experience and future directions with
immunomodulatory therapy. Neurotherapeutics, July 1, 2010; 7(3): 293-301. View Abstract
• ....significantly shifted cytokine profiles in ASD.
These findings suggest that ongoing
inflammatory responses may be linked to
disturbances in behaviour.
• P Ashwood, P Krakowiak, I Hertz-Picciotto, R Hansen, I Pessah, and J Van de WaterElevated plasma cytokines in autism
spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome.
Brain Behav Immun, August 9, 2010; View Abstract

9. About to be Published data ---
• ....an altered activation profile for T cells in
ASD. Overall these data indicate
significantly altered adaptive cellular
immune function in children with ASD that
may reflect dysfunctional immune
activation, along with evidence that these
perturbations may be linked to disturbances
in behaviour and developmental functioning

10. Traditional View of Immune System
• Seen as a system of organs, molecules and
tissues that defend us from disease by
eliminating bad guys.
• This promotes the dichotomy model
good vs bad
• There have been changes to the model of
self/nonself and they are relevant to autism.

11. Changing Models
• Immunology is no
longer good Vs bad –
• it is the homeostasis
of the superorganism!
• Complexity is
required to apply
therapy well

12. Immune
Concepts
Evil-
Microbiota
Non-Self
Evil-
Altered Self
Pathogens
Good –
Self
Tolerance/
ignorance
Good-
Normal Self
Mutualists
Continuum
Model
Ancestral
Dualistic Model
Modern
Dualistic Model

13. • The continuum model states that the perceived
duality of mutualistic and pathogenic microbes,
normal and altered self, and regulatory or
inflammatory immunity, represents extremes of
a continuous reality.
• Microbes can express different levels of
mutualistic or pathogenic properties and these
levels can vary during interaction with the host.
• Similarly, the state of self and of immune
responses can navigate between well-described
extremes, and the most likely states are
combination of these extremes.

14. Danger
Good – Regulation/Tolerance
Mutualists/Normal self
Evil- Inflammation
Pathogens/A
ltered Self
Strangers
Pathological Inflammation
Friends
Physiological Inflammation
Health of Host
Health of
Local tissue
Timing
Genes
Nutri-
genomics
Nutrition
Modern Dualism
Continuum Model

15. Mutualist Pathogen
Regulation/Tolerance Inflammation
Development of Adaptive Immunity
(AgS) Control by Innate Immunity (MAMPs)
Lymphoid Tissues
Lymphocyte Sub Sets
Lymphocyte Memory
Microbes
Immune Responses
IL-2
IL-10
TGFB
RA
IL-23
IL-12
IL-1
TNFα

16. • Cytokines
• Inflammation
• Old Friends
• Mucosal
Tolerance
Hygiene
Hypothesis
• Kyneurenines
• Enzymes
• Cytokines
• Stressors
• IDO
Gastro-
Neuro-
degeneration
hypothesis
ASD

17. Wet Surfaces -Massive Area of Contact
– GI. Mucosal surface area 300m2
• Respiratory mucosa 100m2
• Skin 1.5 m2
• Thickness 0.03mm (1/2 width of 60gsm)
‘Tightly regulated mucosal
Immunity is essential to
maintain health’

18. “the mucosa is directly exposed to the
external environment and taxed with
antigenic loads consisting of
commensal bacteria, dietary antigens,
and viruses at far greater quantities on
a daily basis than the systemic immune
system sees in a lifetime”.
Mayer L. Mucosal immunity. Pediatrics. 2003 Jun;111(6 Pt 3):1595-600.

19. Confusion
• “People tend to get the immune system the
wrong way around;
• We’re so focussed on the immune system
responding to things, that we forget that
99.99% of the time, its job is NOT to respond
to things.
• There’s you, your breakfast and your gut, for a
start. That’s a lot of stuff not to respond to”.
Handley C. Should auld acquaintance be forgot… EMBO Reports Vol 5, No 12, 2004

20. Mucosal Immune System For Host
Protection
The mucosal immune system consists of an integrated
network of:
Macrophages and dendritic cells, T lymphocytes and their cytokines play
a key role in orchestrating a specific mucosal immune response.
An uncontrolled mucosal immune system may lead to immunologic
diseases such as allergy and hypersensitivity.

21. Humans Are Superorganisms
Cells
1 Trillion human cells
10 Trillion bacterial in and on
10 x ratio
DNA
Humans have approx 25,000
genes and bacteria have an
estimated 100 times more.
Who has more genes – grape,
chicken or human?

22. Our relationship extends
Beyond the shared
Environmental benefits –
and extends to:
•Nutrient harvesting
•Gene expression
•Mood regulation
•Illness prevention
•Illness resolution
•Weight management
•Immune control
This raises the possibility that the mammalian immune system,
which seems to be designed to control microorganisms,
is in fact controlled by microorganisms.
Nature Reviews Immunology 9, 313-323 (May 2009) | doi:10.1038/nri2515
The gut microbiota shapes intestinal immune
responses during health and disease
“We respond to our microbiota from birth to death”
Swidinki,A

23. Evidence Is Accumulating
• to suggest that gut microbes (microbiota) may
be involved in neural development and
function, both peripherally in the enteric
nervous system and centrally in the brain.

24. HOW DOES THIS
RELATE TO AUTISM?
www.alexnail.com

25. NKc

26. IMMUNE SYSTEM
CLASSIFICATION
INNATE
IMMUNITY
ADAPTIVE
IMMUNITY
TLR’S – NO
MEMORY
DEVELOPS
MEMORY
GUT

27. Immune- Cytokines - Autism
• Immunological findings in autism.
HH Cohly and A Panja Int Rev
Neurobiol, January 1, 2005; 71: 317-
Link
• Activation of the inflammatory
response system in autism. J
Croonenberghs, M Maes et.al
Neuropsychobiology, January 1,
2002; 45(1): 1-6. Link
• Elevated cytokine levels in children
with autism spectrum disorder.
CA Molloy, et al. J Neuroimmunol,
March 1, 2006; 172(1-2): 198-205.
Link
• It is hypothesised that
increased production of
proinflammatory
cytokines could play a
role in the
pathophysiology of
autism.

28. Cytokines - Autism 2010
• In conclusion, using larger number of
participants than previous studies, we report
significantly shifted cytokine profiles in ASD.
These findings suggest that ongoing
inflammatory responses may be linked to
disturbances in behaviour
• Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum
disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav
Immun. 2010 Aug 10 View Abstract

29. The Innate Immune Response In Autism
www.alexnail.com

30. • Dysregulated innate immune responses in
young children with autism spectrum
disorders: their relationship to
gastrointestinal symptoms and dietary
intervention.H Jyonouchi, et al.
Neuropsychobiology, January 1, 2005;
51(2): 77-85.
• Impact of innate immunity in a subset of
children with autism spectrum disorders: a
case control study. H Jyonouchi, et al. J
Neuroinflammation, January 1, 2008; 5:
52.
• Proinflammatory and regulatory cytokine
production associated with innate and
adaptive immune responses in children
with autism spectrum disorders and
developmental regression. H Jyonouchi, et
al J Neuroimmunol, November 1, 2001;
120(1-2): 170-9.
• Intrinsic defects of innate
immune responses in GI(+)
ASD children but not in
NFH* or GI(-) ASD children,
suggesting a possible link
between GI and
behavioural symptoms
mediated by innate
immune abnormalities.
• TNFα, IL-1, IL-6,
• IL-10, TGF-β
• *Non Allergic Food Hypersensitivity

31. Regulatory Cytokine Transforming
Growth Factor Beta-1
• Decreased serum levels of
transforming growth factor-beta1 in
patients with autism. K Okada, et al.
Prog Neuropsychopharmacol Biol
Psychiatry, Jan 2007; 31(1): 187-90.
•
Decreased transforming growth
factor beta1 in autism: a potential
link between immune dysregulation
and impairment in clinical
behavioural outcomes.
P Ashwood, et al. J Neuroimmunol,
Nov 2008; 204(1-2): 149-53.
• These findings suggest
that decreased levels of
TGF-beta1 may be
implicated in the
pathophysiology of
autism.
• Such that lower TGF beta
1 levels were associated
with lower adaptive
behaviours and worse
behavioural symptoms.

32. Autism & The Gut
www.alexnail.com

33. Comparisons of the prevalence
of gastrointestinal symptoms
between autistic children and
their healthy siblings

34. • Reasons to consider that microorganisms may be involved in
late‐onset autism include
• onset of the disease often follows antimicrobial therapy,
• gastrointestinal symptoms are common at onset and often
persist,
• antimicrobials (e.g., oral vancomycin) may lead to a clear‐cut
response and relapse may occur when the vancomycin is
discontinued, and
• some patients have responded to several courses of
vancomycin and relapsed each time it was discontinued.
Clinical Infectious Diseases 2002; 35(Suppl 1):S6–16 Link

35. Regulation Inflammation
Symbionts Commensals Pathobionts
Immunological Equilibrium
Regulation
Inflammation
Immunological Disequilibrium Dysbiosis/Pathogens
The gut microbiota shapes intestinal immune responses during health and disease
June L. Round & Sarkis K. Mazmanian. Nature Reviews Immunology 9, 313-323 (May 2009)

36. N
C
Occludin
Cgn
PILT
bCtnn
ZONAB
Epithelial Tight Junctions
F-Actin
F-Actin
Cell
Adhesion
Cell
Adhesion
Cell
Migration
Cytoskeletal
Organization
Vesicular
Trafficking
Cell Cycle Progression
Intracellular Membrane Transport and
Exocytosis
Vesicular
Trafficking
Cytoskeletal
Organization Exocyst
Complex
Assembly of
v-SNARE and
t-SNARE Complexes
Cell
Proliferation
Cell
Adhesion
G1/S Phase
Transition
mRNA Cleavage and Processing
Cell Adhesion
and Apoptosis
Epithelial
Cell Proliferation and
Differentiation
Non-CiliatedEpithelial
Cell
CiliatedEpithelial
Cell
RhoA
PathwayActin
Based
Motility
Actin Nucleation and Branching
ZONAB
CDK4 AP-1 CEBP
Paracellular Signaling
RhoA
SAFB
ZO2
Ras
Stx4
mLGL
Myosin
Crb1,3
Afadin
SMURF1
PTEN
HSF1
CSTF
aCtnn
Rab
GTPases
PIP3
PIP2
Cell
Adhesion
Ga12
Ga12
ARP
2/3
PAR-3 Rac1
TGFbR
C
C JAMs JAMs
TIAM1
PAR-3
CDC42
MAGI
2,3
GSK3ILK
JNK
Sympk
TNFaR
TNFa
p130
CAS
Integrins
MAGI1
N
C
Claudins
N
C
Occludin
N
C
Claudins
PKA
VAP33
Akt
Plasmamembrane
2009
ProteinLounge.com
C

37. Leaky Gut and Autism
• CONCLUSIONS: The results obtained support the
leaky gut hypothesis and indicate that measuring
IP could help to identify a subgroup of patients
with autism who could benefit from a gluten-free
diet. 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.
• de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni
R, Bravaccio C.Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree
Relatives. J Pediatr Gastroenterol Nutr. 2010 Jul 28 View Abstract

38. SIgA Vs Autism
www.alexnail.com

39. • The production of immunoglobulin A (IgA) in
mammals exceeds all other isotypes, and it is
mostly exported across mucous membranes.
60mg/kg daily
• It is now clear that SIgA can function in high-
affinity modes for neutralisation of toxins and
pathogenic microbes, and as a low-affinity
system to contain the dense commensal
microbiota within the intestinal lumen.
• A J Macpherson, K D McCoy, F-E Johansen and P Brandtzaeg. The immune
geography of IgA induction and function. Mucosal Immunology (2008) 1, 11–
22. doi:10.1038/mi.2007.6 Link

40. SIgA
• When depleted the mucosal barrier
management of antigen is compromised and
microbial translocation (LPS) can occur, a
consequence of which:
• Increased pro inflammatory cytokines
• Increased IL-17

41. Conditions That Can Change The Level
Of Secretory IgA In Oral Fluid
• Increased SIgA Level
• Acute stress
• Some medications
• Orophanrygeal carcinoma
• Chronic oral infection
• Chronic GI infection
• Heavy smoking
• Alcoholism
• Periodontitis
• Dental plaque accumulation
• Intestinal barrier
dysfunction
• Multiple Myeloma
• Decreased SIgA Level
• Chronic stress (frustration)
• Some medications
• Adrenal insufficiencies
• Bacterial colonisation on molar
surfaces
• Recurrent tonsillitis
• Adenoid hyperplasia
• Cutaneous candidiasis
• Asthmatic with recurrent
respiratory tract infection
• Intestinal barrier dysfunction
• Nutritional deficiencies
• Recurrent herpes infection
• Coeliac, Crohn’s, Ulcerative
colitis

42. SIgA Levels In Clinic Tests
M.Ash 2000
SIgA 10
100
200
300
400
500
600
700
1 2 4 6 8 10 12 14 16 18 20 22 24 26 28
SIgA 1
28 Children with Autism 26♂2♀ ave age 7
Ug/ml

43. Serotonin &
Autism
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44. Serotonin Vs Autism
• Studies demonstrating impaired serotonin synthesis
in the brains of autistic individuals
• Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental
changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol.
1999;45:287-295. FULL TEXT
• Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani
HT. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann
Neurol. 1997;42:666-669. FULL TEXT
• -a worsening of repetitive behaviours after
tryptophan depletion…
• McDougle CJ, Naylor ST, Goodman WK, Volkmar FR, Cohen DJ, Price LH. Acute tryptophan
depletion in autistic disorder: a controlled case study. Biol Psychiatry. 1993;33:547-550. FULL
TEXT

45. Serotonergic Neurons
• are generated early in brain development and
establish extensive cortical and subcortical
connections.
• Serotonin regulates growth cone motility,
synaptogenesis, synaptic plasticity, and the
development and activity of multiple neuronal
subtypes.
• Sodhi MS, Sanders-Bush E. Serotonin and brain development. Int Rev
Neurobiol. 2004;59:111-174. Link

46. SSRI Study Response
• 129 children – 2-8 yrs of age
• 17% excellent, 52% good, 31% fair to poor
• DeLong GR, Ritch CR, Burch SA: Fluoxetine response in children with
autistic spectrum disorders: correlation with familial major affective
disorder and intellectual achievement. Devel Med Child Neurol 2002;
44(10):652–659 Link
1/2

47. Serotonin Vs Indolamine 2,3
• It is concluded that the (TRYCATS) kynurenine,
kynurenic acid, and xanthurenic acid have
anti-inflammatory effects trough a reduction
of IFNgamma,
• Whereas quinolinic acid has pro-inflammatory
effects in particular via significant decreases in
IL-10.
• M Maes, I Mihaylova, MD Ruyter, M Kubera, and E Bosmans The immune effects of TRYCATs
(tryptophan catabolites along the IDO pathway): relevance for depression - and other
conditions characterized by tryptophan depletion induced by inflammation. Neuro
Endocrinol Lett, December 1, 2007; 28(6): 826-31 LINK

48. Indolamine (IDO)
TRYCATS &
Autism
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49. TDO
IDO
Tryptophan
IFN γ
TNFα
Kyneurenine
3-Hydroxykynurenine
Quinolinic acid
Nicotinamide
NMDA Receptor
Kyneurenic acid
5 - Hydroxytryptophan
Serotonin
P38MAPk
+
+
Stressor
Immune Induction Of Neurotoxins
BBB
Liver 95%
Brain 5%>
IDO – Indolamine 2,3 dioxygenase
TDO – Tryptophan 2,3 dioxygenase
N-methyl-D-aspartate

50. Quinolinate/Kyneurenate
• An imbalance in the production or removal of
either of these substances would be expected
to have profound implications for brain
function, especially if that imbalance were
present chronically.
• Identified in Organic Acid test
• Stone TW. Neuropharmacology of quinolinic and kynurenic
acids. Pharmacol Rev. 1993 Sep;45(3):309-79. Link

51. Quin leads acutely to neuronal death or chronically to
neuronal function by at least 6 mechanisms.
1. Activation of the NMDA receptor in
pathophysiological concentrations
2. Increase glutamate release by neurons,
inhibition of glutamate uptake by astrocytes,
decrease in glutamine synthetase activity.
3. Lipid peroxidation of the membrane
4. Quin can potentiate its own toxicity and that
of other excitotoxins (NMDA and glutamate)
in the context of energy depletion
(mitochondrial dysfunction)

52. 5. Quin induces iNOS (astrocyte) and nNOS
(neuron) leading to over production of NO (=
Oxidative stress)
6. Destabilisation of the cellular cytoskeleton
Nady Braidy, Ross Grant, Seray Adams, Bruce J. Brew and Gilles J. Guillemin
Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons
Neurotoxicity Research Volume 16, Number 1, 77-86, DOI: 10.1007/s12640-009-
9051-z View Abstract

53. • Proinflammatory cytokines induce IDO under stress,
promote the KYN pathway, deprive the 5-HT pathway
of TRP, and reduce 5-HT synthesis. The resultant
decrease in 5-HT production may relate to the
monoamine hypothesis of major depression.
• The hippocampal atrophy that appears in chronic
depression may be associated with imbalances in KP
neurotoxic/neuroprotective metabolites.

54. Quinolinate acts as a most
potent endogenous excitotoxin
to neurons.

55. Cytokine regulation of tryptophan metabolism in the hypothalamic-
pituitary-adrenal (HPA) axis: implications for protective and toxic
consequences in neuroendocrine regulation.
• Our results indicate that cytokines such as IFN-
gamma and IL-10 are able to regulate IDO
expression in cells of hypothalamic and pituitary
origin. The ability of IL-10 to suppress IFN-gamma
induced IDO expression implies that -
• IL-10 has a putative neuroprotective role in the
HPA axis. It can act at two levels, systemically by
inhibiting sickness behaviour-related Th1
cytokine synthesis and more centrally by
inhibiting the kynurenine pathway.
• Tu H, Rady PL, Juelich T, Smith EM, Tyring SK, Hughes TK.. Cytokine regulation of
tryptophan metabolism in the hypothalamic-pituitary-adrenal (HPA) axis:
implications for protective and toxic consequences in neuroendocrine regulation.
Cell Mol Neurobiol. 2005 Jun;25(3-4):673-80 Link
Cytokine regulation of tryptophan
metabolism in the hypothalamic-
pituitary-adrenal (HPA) axis:
implications for protective and toxic
consequences in neuroendocrine
regulation.

56. Bacteria – Friend and Foe &
Autism
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57. Bacterial Species In The Genomic Era
• RECENT FINDINGS:
• Upwards of 40,000 bacterial species are
estimated to comprise the collective
gastrointestinal microbiome, most of which have
not been characterised by culture.
• Frank DN, Pace NR. Gastrointestinal microbiology enters the
metagenomics era. Curr Opin Gastroenterol. 2008 Jan;24(1):4-
10.

58. Yet …
• About 200 different bacterial species are
known to cause human disease.
• Mascie-Taylor, C. G. & Karim, E. The burden of chronic disease.
Science 302, 1921−1922 (2003). Article

59. Treg - Immunommodulation
Low ratio of Treg to
effector Tcells
Normal ratio of Treg
to effector T cells
Effective levels of sIgA,
IL-10 & TGF-β to
control adverse
inflammation
ASD Anxiety and
Allergies
IL-10, TGF-β, sIgA
Th1 Th2
(IFN-γ, IL-1, TNF-α) (IL-4, IL-5, IL-13)
Th17
Retinoic Acid
59

60. Probiotics
Old friends
(innocuous
environmental
microorganisms,
helminths)
Treg T
Bystander
suppression
Old friends
IL-10
TGF-β
Retinoic Acid
TregT
IL-10
TGF-β
Retinoic Acid
Specific
suppression
Self/gut
contents
allergens
T cells
Immature DC
Regulatory DC
(DCreg)
sIgA sIgA
Reduction of
peripheral/CNS
inflammation 60

61. Probiotics May Ease Anxiety: Pilot study
• “Two months of supplementation with the bacterial
strain from a sachet was associated with a decrease in
anxiety symptoms.”

62. 62
For instance a specific part of the microbiota has been shown to cooperate
With the development of regulatory instead of the inflammatory IL-17 producing
T helper cells in the small intestine.
Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR
Specific microbiota direct the differentiation of IL-17-producing T-helper cells
in the mucosa of the small intestine.Cell Host Microbe. 2008 Oct 16;4(4):337-49. View Full Paper

63. 63
Tolerance
Vit A
TH-17
Treg
TGF-β
& Autism
www.alexnail.com

64. Retinoic Acid
• Is autism a G-alpha protein defect
reversible with natural vitamin A?
MN Megson Med Hypotheses, June
1, 2000; 54(6): 979-83.
• Symptomatic Vitamin A and D
Deficiencies in an Eight-Year-Old
With Autism Joseph H. Clark, Donna
K. Rhoden, and Denece S. Turner
JPEN J Parenter Enteral Nutr, May
1993; 17: 284 – 286
• Serum values of cytokines in children
with vitamin A deficiency disorders
JY Leal, HV Castejon, T Romero, P
Ortega, G Gomez, D Amaya, and J
Estevez Invest Clin, September 1,
2004; 45(3): 243-56
• Lack of Vitamin A -
Reduced IL-10 and
reduced Treg and
increased TH-17 IL-17
production

65. TGFβ
• TH17
• IL-17
• IL-6
• IL-21
• Retinoic Acid
• IL-10
The Role of Th17 in Neuroimmune Disorders: A Target for CAM Therapy.
Part III Aristo Vojdani, Jama Lambertand,Gottfried Kellermann eCAM Advance Access published
online on July 21, 2009 eCAM, doi:10.1093/ecam/nep064
•In each case, retinoicacid greatly reduced RORt expression
•which resulted in a measurable reduction of Th17 mucosal T cells.
•IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune
inflammation in the brain

66. HISTORICAL
DIETARY CHANGE
↓ INTAKE
• PREBIOTICS
• MICRONUTRIENTS
↓HARMLESS
• HELMINTHS
• ‘OLD FRIENDS’
↓ DEVELOPMENT
DCreg AND Treg
↑ SUSCEPTABILTY TO
LOCAL & SYSTEMIC
PARA-INFLAMMATION
↑ GUT
PERMEABILITY
ALTERED SIgA
PRODUCTION
↑ LOCAL AND SYSTEMIC
PRO-INFLAMMATORY
CYTOKINES
↑ MEDICALISATION
• ANTIBIOTICS
GUT ORIGINATING CYTOKINE DRIVEN ILNNESS AND DYSFUNCTION
↓ LOCAL AND SYSTEMIC
ANTI-INFLAMMATORY
CYTOKINES
IL-1, IL-6, TNFα,
IFNγ, NFκB. IL-17
IL-10, IL-2, TGFβ

67. HISTORICAL DIETARY
CHANGE
↓ INTAKE
• PREBIOTICS
• MICRONUTRIENTS
↓HARMLESS
• HELMINTHS
• OLD FRIENDS
↓ DEVELOPMENT
DCreg AND Treg
↑ SUSCEPTABILTY TO
PARA-INFLAMMATION
↑ GUT
PERMEABILITY
ALTERED SIgA
PRODUCTION
↑ LOCAL AND SYSTEMIC PRO-
INFLAMMATORY CYTOKINES
↑ MEDICALISATION
• ANTIBIOTICS
GUT ORIGINATING CYTOKINE DRIVEN ILLNESS AND DYSFUNCTION
↓ LOCAL AND SYSTEMIC
ANTI-INFLAMMATORY
CYTOKINES
IL-1, IL-6, TNFα,
IFNγ, NFκB
IL-10, IL-2, TGFβ
↓ ANTI-INFLAMMATORY
CHOLINERGIC REFLEX
• DIETARY FATS
• LIFESTYLE
• ENZYMES (CCK/BILE)
RISK FACTORS
↑ IN UTERO STRESS
↓ MUCOSAL MATURITY
↑ INTERNAL STRESSES
↑ EXTERNAL STRESSES
OXIDATIVE &
NITROSITATIVE DAMAGE
↑ H2O2, O2
↑ NO2, NO, ONOO
↑ DNA DAMAGE
↑ ROS/NS
↑ Ω-3, 6, 9 DEMAND ↓ NEUROGENESIS
↓ NCAM (neural cell adhesion mols)
↓ BDNF
↓ FGF(Fibroblast growth factor)
AUTO-IMMUNE DISEASE
THYROIDITIS
RA
MS
IBD’s
CANCER
+
+
+
↓Zn,Se
+
NEUROACTIVE
MOLECULES
↑ IDO
↑ TRYCATS
↑ QUINOLINATE
↑ KYNEURENATE
↓ GABA
↓ MELATONIN
SEROTONIN
P38 MAPK
-+
-
-
-
-
ASD?

68. NEURODEGENERATION
ALZHEIMERS
SENILITY
AUTISM
ROS/NS
IL-1β, TNFα
CORTISOL INDUCED ATROPHY
DEPRESSION
Imbalanced Cytokine
Induction and Binding
Is ‘Regressive Autism’
an Immune Mediated Disorder

69. What Can You Do?
www.alexnail.com

70. Antioxidants Inhibit IDO
• Thomas SR J Immunol. 2001 May
15;166(10):6332-40.
• Antioxidants inhibit indoleamine 2,3-
dioxygenase in IFN-gamma-activated human
macrophages: post translational regulation by
pyrrolidine dithiocarbamate.
• Glutathione (NAC)

71. Clinical Strategies
• Assess patient as potential GIT candidate
• Improve daily nutrition
• Include probiotics (Human Strain)
• Build Beneficial Bio Film
• Remove non beneficial Bio Films
• Include PUFA’s for brain function and improving
Bacterial/Immunological cross talk &Treg
• Pro-biotics do not appear to have any
contraindications with medications involved in mood
disorders.

72. Supermarket dairy shelves are filled with yogurt products containing live cultures of
'probiotic' bacteria — species that live in the human gut and are proposed to deliver
health benefits when eaten at high levels. Three probiotic species seem to alter gene
expression in the gut lining of volunteers consuming the cultures. The effect was
similar to that of drugs for conditions including inflammation and high blood
pressure. Michiel Kleerebezem at NIZO Food Research in Ede, the Netherlands, and his
co-workers analysed the gene-expression profiles of tissue taken from the small
intestinal inner lining of seven healthy volunteers who had eaten a placebo and three
probiotic cultures — Lactobacillus acidophilus, L. casei and L. rhamnosus — in a
random order. The altered gene-expression profiles resembled those associated with
the regulation of immune responses, cell growth, metabolism and even wound repair

73. Protocol
• Saccharomyces Boulardii 150-600mg
• Lactobacillus GG 30-609 CFU
• Lactobacillus Caseii 20-609 CFU
• Lactobacillus Paracaseii 20-609 CFU
• Lactobacillus, plantarum, rhamnosus,
salivarius 20-609 CFU
• Bifido-Bifidus 20-609 CFU
• DHA > EPA (CLO) concentrate 2-4gms
(GPR120)
• Vit A 5000 -12000 iu & Vit D 6-12000iu

74. Current Understood Uses of PB’s
21
3 4

75. • The gut maintains an extensive and highly active
immune system, environmental factors can
induce dysregulation of the mucosal immune
system and potentially damage tissue locally and
systemically.
• In the healthy gut, Th1,Th2,Th17 responses are
carefully managed by regulatory T cells
(CD4+CD25+) expressing IL- 10 and TGF-β.
• Depletion of IL-10- and TGF-β-producing
regulatory T cells, or homing of CD4+CD25RBHIGH
T cells in the GI tissue of children with autism,
may be responsible for GI pathology reported by
different investigators in autism.
Conclusions

76. Conclusions
• Regulatory T cells and TGF-β production measured
in the blood of children with autism are
inconsistent. T cell subtypes are different TH1>
Adversity. TH2 < ASD symptoms
• Immune function abnormalities, in particular, low
natural killer cell activity, low glutathione and
abnormal cytokine production, is part of the illness
in autism.
• Abnormal levels of neurotransmitters such as
serotonin, Indolamine (Quin/Kyn), dopamine,
epinephrine, and norepinephrine are detected in
children with autism.

77. • A gluten- and casein-free diet or a low
antigen diet, with clean omega-3 and
omega 6 oils, strain specific probiotics,
and moderate to high doses of vitamin-
A - can be extremely helpful towards
mucosal immune recovery for a
‘subgroup’ of children with autism.
• A low risk to reward strategy, and can be
observed to have effect in weeks
vol

78. The End
Thank You
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