Fascinating new research for autism and many other disorders on the rise

October 14, 2010

Fascinating research not just for autism, but helps explain the rise in other

disorders including metabolic and immune. . Also interesting to note the diet

once again is mentioned as playing a role for helping rid the body of " Protozoan

Parasites " . Diet; a possibly more important than previously thought,

under-appreciated possible simple solution?

Here's a clip

Volume 5, Issue 1, January-March 2011, Pages 14-59

Review

Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in

individuals with autism spectrum disorders, Down syndrome and Alzheimer disease

may be caused by congenital and/or acquired chronic cerebral toxoplasmosis

Department of Social Pediatrics, Faculty of Health Sciences, University Medical

School, 5 Bartla Street, 51-618 Wroclaw, Poland

Received 19 January 2010;

revised 17 March 2010;

accepted 18 March 2010.

Available online 28 April 2010.

Abstract

Toxoplasma gondii is a protozoan parasite that infects about a third of human

population. It is generally believed that in immunocompetent hosts, the parasite

infection takes usually asymptomatic course and induces self-limiting disease,

but in immunocompromised individuals may cause significant morbidity and

mortality. T. gondii uses sulfated proteoglycans for host cell invasion and

sulfated sugars on the surface of host cells may functions as key parasite

receptors. Patients with autism spectrum disorders (ASD) have many inborn or

acquired abnormalities of metabolism, including impaired sulfation and

sulfoxidation. The impaired sulfation of dehydroepiandrosterone (DHEA) to DHEA-S

affected normal development of various brain functions because DHEA-S inhibited

vascular neuroinflammation in ASD individuals probably caused by cerebral

toxoplasmosis (CT). Treatment of endothelial cells with DHEA-S dramatically

inhibited the TNF- & #945;-induced activation of NF- & #954;B, an inflammatory

transcription factor, and increased protein levels of the NF- & #954;B inhibitor,

I & #954;B- & #945;. A significant decrease in sulfation capacity found during

pregnancy compared with post partum probably reflect a defense reaction of the

host due to increased production of proinflammatory cytokines associated with

frequent and widespread infection with this parasite. This suggestion may be

supported by the finding that TNF and IL-1 mediated inhibitory effect of

lipopolysaccharide on DHEA sulfotransferase mRNA level in Hep3B human hepatoma

cells. It seems however that the impaired sulfation and sulfonation may be also

beneficial for the host because lack or a markedly diminished anionic charge of

the host cells associated with this event did not promote binding to the

negatively charged outer leaflet of T. gondii plasma membranes. Phosphorylation

of the parasite and/or host proteins is also of great importance in the process

of T. gondii–host cell interaction. Furthermore, the increased male to female

ratio characteristic for autistic participants most likely resulted from

significantly increased testosterone levels associated with congenital T. gondii

infection. It was demonstrated that the parasite, aging and dietary restriction

have been able to induce DNA breakage, therefore one may suggest that such an

epigenetic mechanism play an important role in development of Down syndrome

(DS). Several data may support this notion: (a) autism occurs 10 times more

often in children with trisomy 21 than in the general population, ( the

parasite can be transmitted by semen and ovum, © autistic children exhibit

impaired DNA methylation capacity, and (d) T. gondii affect chromatin structure

and may cause dysregulation of the host cell cycle. Alzheimer disease (AD) also

may be caused by CT because this abnormality is more prevalent in women,

characterizes with a skewed capacity for xenobiotic metabolism especially of

compounds containing sulfur that manifest as a decreased plasma levels of

DHEA-S, and has marked immune irregularies in part due to aging. Moreover,

chronic neuroinflammation characteristic for AD and DS individuals is associated

with vascular lesions, patients with AD have increased levels of DNA breaks in

the cerebral cortex, markedly enhanced production of proinflammatory cytokines,

reactive oxygen species, and lipid peroxidation, disturbances in glucose

metabolism, and irregularities in hypothalamic–pituitary axis. It must be noted

that similar metabolic and endocrine disturbances have been reported also in

humans and mice with chronic toxoplasmosis. Overproduction of IFN- & #947; and

other proinflammatory cytokines associated with persistent neuroinflammation

resulted in neurodegeneration and induced amyloid- & #946; production also in DS,

as well as accounted for cognitive impairment. Because bradyzoites and

sporozoites throughout their life cycle accumulate large amounts of crystalline

storage polysaccharide granules analogous to amylopectin within the cytoplasm

and are able to build more complex macromolecules, they may be at least in part

responsible for the production of amyloid- & #946; senile plaques. Moreover, it

seems that the accumulation of iron in senile plaques reflect a defense of the

host against T. gondii because this transition metallic ion is necessary for

proliferation of tachyzoites. Finally, the beneficial effects of ibuprofen in

the patients with AD that restored cellular immunity, decreased production of

proinflammatory cytokines, NO, amyloid- & #946;, reduced lipid peroxidation and

free radical generation, were consistent with the suggestion that congenital

and/or acquired chronic latent CT play an important role in development of these

types of neurodegeneration.

Keywords: Autism spectrum disorders; Alzheimer disease; Down syndrome;

Metabolism disturbances; Immune changes; Epigenetic irregularities; Carbohydrate

metabolism; Phenotypic abnormalities; Testosterone levels; Amyloid- & #946;

plaques

Article Outline

1.

Introduction

2.

Abnormalities in transsulfuration and transmethylation metabolism and DNA

hypomethylation in children with ASD and their parents

2.1. Impaired sulfation and sulfoxidation metabolism

2.1.1. Patients with ASD

2.1.2. T. gondii infection

2.2. Impaired methylation capacity

2.2.1. Patients with ASD

2.2.2. Effect of growth factors, copper, and dopamine on methylation

ability

2.2.2.1. Growth factors

2.2.2.2. Divalent copper

2.2.2.3. Dopamine and other catecholamines

3.

T. gondii affects host cell chromatin structure which may, at least in part,

participate in development of DS

3.1. Chromosomal disturbances in ASD

3.2. Chromosomal abnormalities in DS

3.3. Effects of T. gondii infection on mitosis and cell proliferation

3.4. Epigenetic chromosomal changes

4.

Disturbances in phosphorylation

4.1. Hypophosphorylation of salivary peptidome in ASD individuals

5.

Host cell manipulation by T. gondii

6.

Neuroinflammation and other molecular abnormalities in AD participants

7.

Dysregulated brain carbohydrate metabolism in patients with ASD, DS, and AD

7.1. Abnormal glucose metabolism in DS participants

8.

T. gondii infection causes marked disturbances in carbohydrate metabolism

9.

Pathophysiological role of amyloid- & #946; plaques

9.1. Patients with AD

9.2. T. gondii infection and possible generation of amyloid plaques

9.2.1. Crystalline storage polysaccharide analogous to amylopectin

produced by T. gondii bradyzoites may be, at least in part, responsible for

development of amyloid- & #946; containing plaques in ASD, DS, AD, and other

neurodegenerative diseases

10.

Increased activation of tryptophan metabolic pathway in AD individuals

11.

A patient with AD and concomitant T. gondii infection

12.

Disturbances of fatty acid profiles in ASD participants may, at least in part,

be due to T. gondii infection

13.

Increased phospholipase A2 (PLA2) levels in ASD/Asperger's syndrome individuals

may enhance host cells invasion by T. gondii through increasing their

penetration

14.

T. gondii requires polyamines for proper growth, and heparan sulfate facilitates

salvage of extracellular polyamines. Inhibitory effects of polyamines on lipid

peroxidation

15.

Disturbances of aminoacids levels in ASD participants

16.

Important role of vasoactive intestinal peptide (VIP) in development of DS and

ASD

17.

Disturbances of sulfation of sugars on the surface of the host cells and

irregularities of T. gondii and/or host proteins phosphorylation are important

for invasion of the parasite to the host cells

18.

Impaired sulfation of dehydroepiandrosterone (DHEA) to DHEA-S may reflect a

defense reaction of ASD patients against T. gondii infection. Deficiency of

DHEA-S affects however normal development of various brain functions and

decreases efficiency of inhibition of vascular inflammation

18.1. T. gondii infection

19.

Possible causes of the increased male to female ratio in ASD individuals

19.1. Increased testosterone and other androgens serum levels in patients

with ASD

19.2. Women infected with T. gondii have more sons. Increased saliva

testosterone concentrations in men with T. gondii infection

19.3. Effect of T. gondii infection on personality profiles of men and women

19.4. Correlation between T. gondii infection, salivary testosterone levels

and lower left hand 2D:4D ratios

19.5. Handwriting impairments in children with ASD and shorter life span of

left handed than right handed men

20.

Abnormalities of steroid and hypothalamo–pituitary hormone levels and

endocrinologic disturbances reported in patients with ASD, DS, and revealed

during congenital or chronic T. gondii infection

20.1. ASD individuals

20.2. Patients with DS

20.3. Congenital toxoplasmosis

20.4. Acute toxoplasmosis

20.5. Mice

21.

Important effects of the increased testosterone levels on the host

References

Thumbnail image

Fig. 1. Various pathways of the essential amino acid tryptophan metabolism.

About 99% of the dietary tryptophan is metabolized along the kynurenine pathway.

Alternative pathways are the conversion of tryptophan to 5-hydroxytryptamine

(5-HT) and then to melatonin, or to tryptamine and then to the kynuramines (or

kynurenamines). 3-HAO, 3-Hydroxyanthranilate oxidase; IDO, indoleamine

2,3-dioxygenase; KAT, kynurenine aminotransferase; MAO, monoamine oxidase; QPRT,

quinolinic-acid phosphoribosyl transferase; TDO, tryptophan 2,3-dioxygenase.

Reproduced and modified with permission from Nature Reviews Drug Discovery

(Stone & Darlington, 2002) copyright (2002) Macmillan Magazines Ltd.

View Within Article

Thumbnail image

Fig. 2. Interrelationships between indoleamine 2,3-dioxygenase (IDO) and nitric

oxide synthase (NOS) in macrophages or glial cells, and the potential

interactions with neurons by means of N-methyl-d-aspartate

(NMDA)-receptor-induced nitric-oxide (NO) formation. Arg, Arginine; 3-HAA,

3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; IFN- & #947;,

interferon- & #947;; IL, interleukin; Kyn, kynurenine; KynA, kynurenic acid; LPS,

lipopolysaccharide; mRNA, messenger RNA; iNOS, inducible nitric-oxide synthase;

TGF- & #946;, transforming growth factor- & #946;; TNF- & #945;, tumor necrosis

factor- & #945;; Trp, tryptophan; xA, xanthurenic acid. The broken lines represent

possible reactions.

Reproduced with permission from Nature Reviews Drug Discovery (Stone &

Darlington, 2002) copyright (2002) Macmillan Magazines Ltd.

View Within Article

Thumbnail image

Fig. 3. Possible model for NO-mediated regulation of IDO in IFN- & #947;-primed

mononuclear phagocytes. NOS, Nitric-oxide synthase; IDO, indoleamine

2,3-dehydrogenase, l-Arg, l-arginine; l-Trp, l-tryptophan; IFN- & #947;,

interferon- & #947;; NO, nitric oxide; Kyn, kynurenine; 3-HAA,

3-hydroxyanthranilic acid; QA, quinolinic acid; SNP, sodium nitroprusside; GTN,

glyceryl trinitrate; SNAP, S-nitroso-N-acetylpenicillamine; DEANO,

diethylaminodinitric oxide. SNP, DEANO, and SNAP release NO extracellularly,

while GTN is thought to release NO intracellularly. Nitric Oxide Inhibits

Indoleamine 2,3-Dioxygenase Activity in Interferon- & #947; Primed Mononuclear

Phagocytes, vol. 269, pp. 14457–14464/The Journal of Biological Chemistry by

SR, Mohr D, Stockert R. Copyright [1994] by The American Society for

Biochemistry and Molecular Biology. Reprinted by permission of The American

Society for Biochemistry and Molecular Biology via the Copyright Clearance

Center.

View Within Article

Table 1.

Glycolytic enzymes identified in T. gondii (Fleige et al., 2007; with own

modification).

View table in article

View Within Article

Table 1A.

Selected modifications in the proteomes of human foreskin fibroblasts infected

with T. gondii: proteins implicated in metabolism (acc. to et al., 2008;

with own modification).

View table in article

Host cell proteins were designated as being downregulated in expression

( & #8595;), upregulated ( & #8593;), or modulated (M). Modulated proteins had

expression altered across several isoforms on the same gel using the Amersham

difference gel electrophoresis, and this probably indicated a posttranslational

modification event ( et al., 2008).

a The host cell proteins, which also changed expression in the brains of

patients with mild cognitive impairement, early AD, or AD (Butterfield and

Lange, 2009).

View Within Article

Table 1B.

Selected modifications in the proteomes of human foreskin fibroblasts infected

with T. gondii: proteins implicated in glycolysis (acc. to et al., 2008;

with own modification).

View table in article

Host cell proteins were designated as being downregulated in expression

( & #8595;), upregulated ( & #8593;), or modulated (M).

a These host cell proteins also changed expression in the brains of patients

with mild cognitive impairement, early AD, or AD (Butterfield and Lange, 2009).

It must be noted that T. gondii tachyzoites are thought to rely upon both

glycolysis and the tricarboxylic acid cycle, while bradyzoites are largely

dependent upon glycolysis (Tomavo et al., 2001; Xia et al., 2008). Although

tachyzoites utilize both glycolysis and oxidative phosphorylation to obtain

energy, glycolysis seems to be the predominant pathway for ATP synthesis in the

bradyzoite ([Coppin et al., 2003] and [Denton et al., 1996]). Moreover, ENO2 and

lactate dehydrogenase1 are only found in tachyzoites while ENO1 and lactate

dehydrogenase 2 are exclusively expressed in bradyzoites ([Dzierszinski et al.,

2001] and [Ferguson et al., 2002]). Silencing of tachyzoite ENO2 altered nuclear

targeting of bradyzoite ENO1 in T. gondii (Holmes et al., 2009).

View Within Article

Table 1C.

Selected changes in the proteomes of human foreskin fibroblasts infected with T.

gondii: proteins implicated in cell cycle, transcription, and translation (acc.

to et al., 2008; with own modification).

View table in article

Host cell proteins were designated as being downregulated in expression

( & #8595;), upregulated ( & #8593;), or modulated (M).

View Within Article

Table 1D.

Selected proteins modulated in the parasite-modified parasitophorous

vacuole-associated organelles from T. gondii infected and noninfected cells

(acc. to et al., 2008; with own modification).

View table in article

Host cell proteins were designated as being downregulated in expression

( & #8595;), upregulated ( & #8593;), or modulated (M).

a These host cell proteins also changed expression in the brains of patients

with mild cognitive impairement, early AD, or AD (Butterfield and Lange, 2009).

Interestingly, host cell invasion and egress induce marked relocations of

glycolytic enzymes in T. gondii tachyzoites and this ability allows the parasite

to optimize ATP delivery to those cellular processes that are important for

survival outside host cells and those required for growth and multiplication

(Pomel, Luk, & Beckers, 2008). On the other hand, treatment of macrophages with

ATP activates ROS-dependent oxidative stress response and secretion of

proinflammatory cytokines (Cruz et al., 2007), characteristic for

neuroinflammation and neurodegeneration processes in ASD, DS, and AD.

View Within Article

Table 1E.

Selected changes in the proteomes of human foreskin fibroblasts by T. gondii

infection: various proteins (acc. to et al., 2008; with own

modification).

View table in article

Host cell proteins were designated as being downregulated in expression

( & #8595;), upregulated ( & #8593;), or modulated (M).

a The host cell proteins changed expression also in the brains of patients with

mild cognitive impairement, early AD, or AD (Butterfield and Lange, 2009).

View Within Article

Table 2.

Immune system abnormalities in autistic individuals (acc. to Ashwood, Wills, &

de Water, 2006, with own modification).

View table in article

PDD, pervasive developmental disorder; TLR2, toll-like receptor 2 (lipoteichoic

acid); TLR4, lipopolysaccharide; TLR9, synthetic oligonucleotides containing

CpG-B motifs, GM-CSF, granulocyte/macrophage colony stimulating factor. It must

be noted that IL-6 promoted innate NK cell production of IL-17 during

toxoplasmosis (Passos et al., 2010). aLeptin has the structure similar to that

of IL-2 and may activate the innate immune system and shift the cognate immune

system toward a predominance of a proinflammatory TH1 T cell population while

reducing the regulatory TH2 phenotype. bIt is interesting that antibodies raised

against T. gondii predominantly belonged to the IgG2a subclass, an isotype of

which production is usually mostly controlled by TH1 cytokines, and especially

IFN- & #947; ([Nguyen et al., 2003] and [Markine-Goriaynoff et al., 2000]). c,dThe

complement system proteins are involved in the lysis and removal of infectious

organisms in blood, and may be involved in cellular apoptosis in brain ([Chauhan

et al., 2005] and [Chauhan and Chauhan, 2006]).These increases may therefore

reflect immune defense of the host because complement has membrane lytic

activity directed against the extracellular stage of T. gondii (Seeber, 2000).

It must be noted that reduced serum levels of transferrin in autism (Chauhan,

Chauhan, Cohen et al., 2004) affect normal early T-cell differentiation (Macedo

et al., 2004).

View Within Article

Table 3.

Partial downregulation of cell-mediated immune responses after infection with T.

gondii (Lang et al., 2007, with own modification).

View table in article

CIITA, master regulator of major histocompatibility complex class II

transcription; CCR5, CC chemokine receptor; DCs, dendritic cells; iNOS,

inducible nitric oxide synthase; IRF-1, interferon regulatory factor-1; LXA4,

lipoxin A4; MHC, major histocompatibility complex molecules; PGE2, prostaglandin

E2; TGF- & #946;, transforming growth factor- & #946;. Proliferation of T. gondii in

inflammatory macrophages was associated with diminished ROS production in host

cells (Shrestha, Tomita, Weiss, & Orlofsky, 2006). In young children with

congenital toxoplasmosis specific T cell response to the parasite antigens was

impaired and such hyporesponsiveness has been restored during childhood. The

acquisition of functional T cell response was disease-unrelated and

indistinguishable in terms of strength, epitope specificity, and cytokine

profile from the corresponding responses in immunocompetent adults with

asymptomatic acquired T. gondii infection (Guglietta et al., 2007). In pregnant

mice, T. gondii infection caused a decrease of CD4+CD25+-regulatory T cells (Ge

et al., 2008). It must be noted that peripheral blood leukocytes (PBL) from

healthy children older than 36 months responded to several stimuli at levels

comparable to those of PBL from adults, but surprisingly, cord blood leukocytes

appeared to be more efficient in antigen-presenting function than PBL from

children younger than 13 months (Clerici, Depalma, Roilides, Baker, & Shearer,

1993).

View Within Article

Table 3A.

Suppression of immune responses to T. gondii by parasite-triggered modulation of

host cell apoptosis (acc. to Lang et al., 2007; with own modification).

View table in article

CTL, Cytotoxic T lymphocyte; Fas, receptor; FasL, Fas ligand (a cell surface

molecule belonging to TNF family and death factor, which binds to its receptor

Fas, thus inducing apoptosis of Fas-bearing cells); NK, natural killer cells;

PARP, poly(ADP-ribose) polymerase.

a T. gondii delayed neutrophil apoptosis by inducing granulocyte

colony-stimulating factor and granulocyte-macrophage colony-stimulating factor

secretion by the parasite-infected human fibroblasts. Although neutrophils are

unable to kill T. gondii, this can retard their division time from the usual 6-8

hrs cycle to a 24 hrs cycle and this enhanced neutrophil survival may contribute

to the robust proinflammatory response elicited in the pathogen-infected host

cells (Channon, Miselis, Minns, Dutta, & Kasper, 2002).

View Within Article

Table 4.

Biomolecules of T. gondii regulating the host innate immune responses (Pollard

et al., 2009; with own modification).

View table in article

CCR5, CC-chemokine family receptor; GPI, glycosyl-phosphatidylinositol; HSP70,

heat shock protein 70; ROP, T. gondii rhoptry; TLR, toll-like receptor ligands,

TLR2, lipoteichoic acid; TLR4, LPS; TLR11, is one of three mouse TLRs activated

specifically by uropathogenic bacteria.

View Within Article

Table 5.

Proteins undergoing a change in phosphorylation state following T. gondii

infection (acc. to et al., 2008; with own modification).

View table in article

T. gondii kinase activity is involved in phosphorylation of host I & #954;B & #945;

and this unusual mechanism can be utilized in manipulating the NF- & #954;B

pathway (Molestina & Sinai, 2005). It must be noted that in DS, T cell

activation deficiency was associated with an aberrant pattern of protein

tyrosine phosphorylation after CD3 perturbation (Scotese et al., 1998). Abnormal

hyperphosphorylation of tau and abberrant tau aggregation has been also found in

AD ([Avila, 2000] and [Avila, 2006]). It must be noted that

psudohyperphosphorylated tau was toxic to cells and was associated with

induction of apoptotic cell death (Shimura et al., 2004).

View Within Article

Table 6.

Bradyzoite and tachyzoite stage-specifically expressed genes coding the enzymes

involved in T. gondii amylopectin metabolism (acc. to Coppin et al., 2005; with

own modification).

View table in article

& #8593; & #8593; & #8593;, Markedly increased gene expression; & #8593; & #8593;,

increased expression; & #8593;, weak expression; 0, no gene present. T. gondii

enzymes were identified at the genome Web site: htttp://www.toxodb.org. The

parasite genome encodes two fructose 1,6-biphosphatase isoenzymes, a single

pyruvate-carboxylase, and two PEP-carboxykinases. The conversion from

glucose-6-phosphate into glucose-1-phosphate, which forms the link between

amylopectin metabolism and gluconeogenesis, is catalysed by two isoforms of

glucosephosphate-mutase (Fleige, Pfaff, Gross, & Bohne, 2008). The following

soluble tachyzoite antigenic proteins have been identified: a putative protein

disulfide isomerase, Hsp60, Hsp70, a pyruvate kinase, a putative glutamate

dehydrogenase, a coronin, a protein kinase C receptor 1, a malate dehydrogenase,

a major surface antigen 1, an uridine phosphorylase, and a peroxiredoxin (Ma et

al., 2009).

View Within Article

Table 7.

Drugs tested for in vitro activity against T. gondii (acc. to -Brando et

al., 2003; with own modification).

View table in article

DMSO: dimethylsulfoxide; Toxo CGM: Toxoplasma cell growth medium. Valproic acid

at a concentration of 1 & #956;g/ml inhibited 7% of the tachyzoites and

trimethoprim at 3.2 & #956;g/ml produced 2% inhibition, but the combination of

these two compounds at those concentrations resulted in a potentiating effect

inhibiting 55% of the tachyzoites.

a Median inhibitory dose, a measure of tachyzoite inhibition.

b Median toxicity dose, a measure of cytotoxicity.

c Therapeutic index, a measure of efficacy determined by TD50/ID50 ratio.

View Within Article

Table 8.

Hypoxia inducible gene expressiona (acc. to Prandota, 2004).

View table in article

a T. gondii activates hypoxia-inducible factor 1 (HIF1) already at

physiologically relevant oxygen levels and requires HIF1 for growth and survival

(Spear et al., 2006).

View Within Article

Corresponding Author Contact InformationTel.: +48 071 348 42 10; fax: +48 71 345

93 24.

Research in Autism Spectrum Disorders

Volume 5, Issue 1, January-March 2011, Pages 14-59

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For more on why whole food may help

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=====

October 14, 2010

Yes--fascianting research for sure --Thank you for posting it.Â it is well

known in the reseearch literature that environemntal toxins weaken the immune

system and predispose it to opportunistic

infections---viruses--bacteria--parasites, fungi etc. The honey bees are

experiencing a similar thing-----fungi infection it seems in their case---but

toxic exposure caused the fungi to take hold over entire bee colonies and we all

know what the demise of bees means for the rest of the ecosystem.

http://www.naturalnews.com/030027_colony_collapse_disorder_Bayer.html

All the best,

ElenaÂ

From: kiddietalk <kiddietalk@...>

Subject: [ ] Fascinating new research for autism and many

other disorders on the rise

Date: Thursday, October 14, 2010, 12:02 PM

Fascinating research not just for autism, but helps explain the rise in other

disorders including metabolic and immune.Â . Also interesting to note the diet