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Review ArticleZinc in Gut-Brain Interaction in Autism andNeurological Disorders

Guillermo Vela,1,2 Peter Stark,1 Michael Socha,1 Ann Katrin Sauer,3

Simone Hagmeyer,3 and Andreas M. Grabrucker3,4

Zinpro Corporation, Eden Prairie, MN , USA Autismo ABP, Monterrey, NL, Mexico

WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, Ulm, Germany Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

Correspondence should be addressed to Andreas M. Grabrucker; [email protected]

Received February ; Accepted March

Academic Editor: Richard Dyck

Copyright © Guillermo Vela et al. Tis is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A growing amount o research indicates that abnormalities in the gastrointestinal (GI) system during development might be acommon actor in multiple neurological disorders and might be responsibleor some o the sharedcomorbidities seen among thesediseases. Forexample, many patientswith Autism Spectrum Disorder (ASD) havesymptoms associated with GI disorders. Maternal

zinc status may be an important actor given the multiaceted effect o zinc on gut development and morphology in the offspring.Zincstatus inuences and is inuencedby multiple actors and an interdependence o prenatal and early lie stress, immune systemabnormalities, impaired GI unctions, and zinc deciency can be hypothesized. In line with this, systemic inammatory eventsand prenatal stress have been reported to increase the risk or ASD. Tus, here, we will review the current literature on the roleo zinc in gut ormation, a possible link between gut and brain development in ASD and other neurological disorders with sharedcomorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain unctions later inlie.

1. Introduction

Research rom the last decades clearly shows that zinc hasa vital role in neonatal development. Zinc is an essential

trace element in humans and animals and is involvedin countless metabolic and signaling pathways within thebody. However, a particular role o zinc in the immunesystem and brain has been reported []. Zinc is one o the most prevalent metal ions in the brain and participatesin the regulation o neurogenesis, neuronal migration, anddifferentiation, thereby shaping cognitive development andmaintaining healthy brain unction. Zinc deciency duringpregnancy results in specic impairments in the offspring,which have been observed in animal models but might alsobe present in humans []. Intriguingly, among individualswith Autism Spectrum Disorders (ASD), the incidence rateo zinc deciency has been reported to be signicantly

increased compared to age matched healthy control subjects[]. Te occurrence o zinc deciencies in ASD is particularly pronounced in very young age [, ], where a rate o almost% was reported in the age group o – years []. Tese

low levels o zinc ofen occur along with copper overloadand the Cu/Zn ratio was reported to correlate with theseverity o symptoms associated with autism [–]. Tis early occurrence o zinc deciency with decline later in lie and themaniestation o some o the core eatures o ASD, such asimpaired social behavior and language and communicationproblemsin prenatal zinc decient mice [], have recently putmaternal zinc status in the ocus as a possible environmentalactor in the etiology o ASD. Tus, maintaining adequatezinc status during pregnancy might be a promising approachto prevent cognitive and neurobehavioral decits later in lie.However, meeting the zinc requirement o the mother can bechallenging.

Hindawi Publishing CorporationNeural Plasticity Volume 2015, Article ID 972791, 15 pageshttp://dx.doi.org/10.1155/2015/972791

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wo major pools o zinc can be ound within the body:a slowly zinc exchanging pool that contains about % o the body’s zinc and a pool that rapidly exchanges zinc withthe plasma. Te latter, which contains the other % o zinc, is the one that is especially reactive to the amount o absorbed zinc and is the rst to be depleted under conditions

o zinc deciency. Plasma zinc is also the source o theembryo’s zinc supply. In order to maintain proper zinc levelsduring pregnancy, both endogenous losses and the increaseddemand resulting, or example, rom synthesis o novel tissuemust be covered by absorption o zinc rom dietary sources.Tus, while the metabolic zinc requirement o . mg/d oran adult woman is generally met when consuming daily to mg zinc, due to the additional need or zinc duringpregnancy, an additional – mg zinc per day must beconsumed to meet the increasing demand o ., .,., and . mg o metabolic zinc per day or the ourquarters o pregnancy []. Similarly, during lactation, themetabolic daily requirement increases by another . mg perday. Meeting these requirements is challenged by severalactors. First, it is not uncommon or women o childbearingage to consume low zinc diets. Second, zinc status o womenmay be compromised due to increased intake o dietary constituents that reduce the availability o zinc.

Impact o low zinc status o the mother can be magnieddepending on time and severity o the deciency, rangingrom teratogenic effects with severe deciency to unctionalimpairments acting, or example, on brain development withmild deciency. In particular, teratogenic effects have beenreported in rodent models [, ] as well as in humans,where women with Acrodermatitis enteropathica, a geneticdisorder resulting in impaired zinc absorption, show a highincidence o birth deects []. In general, although the brainseems most vulnerable, all organ systems are affected by systemic zinc deciency in times o active prolieration anddifferentiation. Tus, although mild zinc deciency does notlead to gross morphological malormations in the offspring,the reported behavioral impairments might result rom acombination o alterations in brain development and otherorgan systems. Tis novel vista on the role o zinc deciency in ASD broadens the ocus rom the action o zinc within thebrain to other organs such as the GI system.

Proper zinc status is necessary or healthy gut devel-opment and both pre- and perinatal zinc deciency mightaffect the neonate and potentially trigger downstream eventsthat contribute to pathological processes []. Tese pro-

cesses may, among others, include inammation due toincreased intestinal epithelium permeability and immunesystem abnormalities including the generation o autoan-tibodies. Another consequence o impaired or delayed gutdevelopment will be lowered trace metal absorbance, whichmight contribute to the slow normalization o biometals inchildren with ASD afer birth []. GI discomort, changes ingut microbiome, ood aversion, and an increased intestinalpermeability have been shown to correlate with the severity o behavioral symptoms in individuals with ASD [–].

Given that inammatory cytokines and other immunesignaling molecules originating rom the GI tract interactwith the hypothalamic-pituitary-adrenal gland (HPA) stress

axis, prenatal stressitsel canbe integratedin thispathomech-anism, targeting the same structures []. Tus, some o themajor environmental risk actors orthe development o ASDare linked in this model.

aken together, maternal zinc deciency might impairthe gut development o the offspring and thereby increase

the risk or GI problems, inammatory events, abnormalimmune signaling, trace metal imbalances, and ultimately altered brain unction. Data supporting this hypothesis willbe discussed urther in more detail.

2. Zinc and Gut Formation

A well-orchestrated sequence o highly specialized processesis required or the development o the intestine rom theembryonic gut tube to a complex organ responsible or ooddigestion and absorption o essential nutrients. Particularly the sophisticated intestinal epithelium is strongly dependenton a proper development in order to ulll its widespread

unctions ranging rom deense o antigens to absorptiono important nutrients. Tese processes are dependent onthe correct sequence o cell prolieration, differentiation,and apoptosis. Given that these processes require a plethorao zinc dependent enzymes, it is quite obvious that zincdeciency especially during the embryonic development o the gutmight lead to alterations in intestinal morphology andcell composition resulting in possible unctional alterations(Figure ). Unortunately, only very limited data is availableon the precise effects o prenatal zinc deciency during etaldevelopment and differentiation o the small intestine.

Intriguingly, researchers ound that eeding sows anadditional ppm zinc rom zinc amino acid complexduring the last trimester o pregnancy resulted in improvedintestinal development o pigs. Te offspring o sows ed theadditional zinc had increased villous height and villus/cryptratioin the jejunum and higher goblet cell counts in the ileum[]. Furthermore, intestinal deenses o these pigs againstpathogens appeared to have been improved as indicated by an increased number o intraepithelial lymphocytes in theduodenum and ileum.

However, most o the available data on the role o zincin gut development originate rom induced zinc deciency in immature and mature animals. Several studies have shownatal consequences o acute and chronic zinc deciency onthe structure and unction o the small intestinal epithe-

lium. For example, zinc is crucial or the maintenance o the small mucosal integrity [–] and zinc deciency accompanied with mucosal necrosis and ulceration as wellas increased mucosal apoptosis, inammation, oedema, andstructural alterations o villi. Tus, it is not surprising thatzinc supplementation has been shown to have benecialeffects on mucosal integrity in many pathophysiological andinammatory conditions o the small intestine [, ].Further, individuals with Acrodermatitis enteropathica whosuffer rom severe zinc deciency showed villus atrophy andgut necrosis [].

Zinc deciency also results in morphological and unc-tional changes o the intestinal epithelium. When zinc

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Mucus

Paneth cell

Villus

Crypt

Enterocyte

Enteroendocrine cell

Goblet cell

Intestinal lumen

Villus height and villus/crypt ratio sensitive to Zn levels

Increase afer Znsupplementation,

number affected by MMP9 activity

Mucosal necrosis, ulceration,increased mucosal apoptosis, inammation,and oedema upon Zn deciency

Reduction in mucosal cell prolierationand slower cell migration upon Zn deciency

Altered composition o intestinal mucinupon Zn deciency

Brush border

Alterations in the activities o brush borderenzymes upon zinc deciency

Zinc nger transcription actors Gata4 and Gata6promote enteroendocrine cell differentiation

Epithelial stem cell

Development o paneth cells sensitiveto activity o Zn nger transcriptionactor BLIMP1

F : Inuence o zinc levels on gut ormation. Zinc levels mediate villus height and villus/crypt ratio in the jejunum. Zinc deciency

results in a shortening and narrowing o the villi and thus a reduction in absorptive surace. Tis may be mediated by a reduction inmucosal cell prolieration and slower cell migration, as well as an increase in the number o apoptotic cells in villi and crypts. Te zinc ngertranscription actors Gata and Gata are involved in intestinal epithelial cell differentiation and promoteenteroendocrine cell differentiation.Moreover, the number o goblet cells increases afer zinc supplementation and is dependent on the activity o the zinc binding matrixmetalloproteinase- (MMP-). Goblet cells secrete mucins and an altered composition o intestinal mucin was reported in zinc decientanimals. Additionally, several alterations in the activities o brush border enzymes result rom zinc deciency. Te development o panethcellsis accelerated by the zinc dependent transcription repressor BLIMP. Furthermore, zinc deciency is accompanied with mucosal necrosisand ulceration, inammation, and oedema.

decient diet is ed to immature male rats or days, asignicant reduction o small intestinal length and urther

morphological changes in the jejunum, including shorteningand narrowing o the villi, reduction in absorptive surace,and an increased number o villi per unit area o serosa,were reported that could be restored by zinc supplementation[, ]. Further, a reduction in mucosal cell prolierationand slower cell migration were shown []. Moreover, ultra-structural changes on a cellular level, such as appearance o membrane-bound autophagic vacuoles, pyknotic nuclei, anddilated nuclear periphery can be observed in zinc decientrats []. Additionally, a study in zinc decient rats and sheeprevealed an altered composition o intestinal mucin hintingtowards unctional alterations in mucin-secreting goblet cells[]. Goblet cells reside throughout the GI tract producing

a protective mucus blanket. Tis mucin-containing mucuslayer has an important role in innate host deense.

Zinc deciency leads to a reduction in crypt cell pro-lieration []. A actor contributing to this impairmentmight be an increase in the number o apoptotic cells in

villi and crypts, especially in the midzone o the crypts thatserves as the zone o renewal o the intestinal epithelium[, ]. Tis hints towards a reduced renewal capacity o the intestinal epithelium that is required or its properunction. A positive effect o zinc supplementation on therepair capacity o the small intestine, especially the thirdsegment, has been reported in mice []. Tese mice showeda higher intestinal epithelium cell production rate andshorterduration o mitosis compared to their control littermates[].Tus, besides the effects o zinc deciency on morphology o

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the small intestine, the maintenanceand repair capacity o theepithelium are affected.

During development, small intestine maturation is mea-sured by indicators like increased cell prolieration anddifferentiation as well as an altered activity o brush borderdisaccharidases like lactase and sucrase [] due to changing

nutritional demands. Lactase and sucrase serve as markerso enterocyte maturity and unctional capacity as well as villus height and crypt depth []. Several alterations inthe activities o brush border enzymes have been reportedto result rom zinc deciency. Chronic zinc deciency,or example, reduces the activity o disaccharidases likesucrase, trehalase, lactase, leucine aminopeptidase, alkalinephosphatase, and maltase by –% at the brush bordero the small intestine [, , ]. Correct unction o intestinal disaccharidases is inevitable or proper digestiono carbohydrates and absorption o saccharides. Further, thezinc dependent metalloenzyme alkaline phosphatase showedsimilar reduction in activity. Given that zinc is crucial ormaintenance o membrane structure and unction, the losso brush border integrity due to zinc deciency might leadto the dysunction o these enzymes [] and thus altered gutmaturation.

Additionally, many genes regulating the differentiationinto intestinal epithelium in adults as part o a sel-renewalprocess o the epithelium by intestinal stem cells localized inthe base o crypts also play a crucial role in the regionalizationo the gut during the development []. Zinc dependenttranscription actors are highly involved in the regulation o these genes and their dysunction has severe consequenceson intestinal development. For example, the transcriptionactors Gata and Gata are involved in the proximal-distalspecication o the intestine as well as epithelial cell differen-tiation []. Gata seems to regulate sucrase-isomaltase andlactase transcription hinting towards a role in maturation o the enzymatic brush border composition [, ] and the losso Gata leads to decreased absorption o cholesterol and ats[]. Furthermore, the conditional knockout o Gata andGata results in reduced promotion o enteroendocrine celldifferentiation [].

A urther zinc dependent transcription repressor, Blymphocyte-induced maturation protein (BLIMP), isrequired to delay the nal maturation o suckling to weaningintestinal epithelium allowing the dietary transition rommother’s milk to solid diet and is thereore specically expressed in developing and postnatal intestine []. BLIMP

knockout mice are born with eatures resembling an adultintestine such as more serrated appearance o villi andaccelerated development o paneth cells [, ]. Duringsuckling period, the expression o disaccharidases, typically expressed in postweaning periods, is upregulated in BLIMPknockout mice whereas the expression o disaccharidasesimportant or lactose digestion is lost [, ].

Additional zinc dependent transcription actors like thegrowth actor independent (G-) and Mtgr are involvedin secretory cell differentiation [, ]. Although zinc isbound within zinc nger transcription actors with highaffinity and only potent zinc chelators are able to resolvezinc binding, it might be possible that, along normal protein

turnover, severe zinc deciency leads to less stable and/orunctional transcription actors. Further, zinc binds with lessaffinity to enzymes like class I histone deacetylases that havebeen reported to be involved in the regulation o intestinalepithelium differentiation []. Additionally, activity o thezinc binding matrix metalloproteinase (MMP-) seems to

inuence the number o goblet cells and by that increasessecretion o the mucin Muc- []. However, it has to bementioned that despite the benecial effects o zinc supple-mentation on small intestinal epithelial structure, excessiveamounts o zinc can lead to damage in vitro []. Tus, theappropriate zinc status during development is crucial or ahealthy unctional intestine.

aken together, zinc deciency in animals and humanshas strong effects on the intestinal epithelium structure andunction (Figure ). Due to these severe consequences it islikely that zinc deciency during embryologic developmentmight lead to morphological alterations resulting in unc-tional impairment o the small intestine. Tese impairments

might include malabsorption o essential nutrients leading tomalnutrition, diarrhea, and inammation in the immaturegut.

3. Gut-Brain Interaction in ASD and OtherNeurological Diseases

A growing amount o research indicates that at least a portiono the dysunctions associated with ASD is related to GIproblems []. However to date it remains unclear whetherGI problems are comorbidities or a causative pathomech-anism o ASD [, ]. It has been repeatedly reportedthat children with ASD requently suffer rom GI problemssuch as diarrhea, constipation, bloating, abdominal pain,and gastroesophageal reux [, ]. GI problems (based onparents’ reports) were identiedin %o children and% o controls, with constipation (%) and chronic diarrhea (%)being themost common symptoms []. Furthermore, alteredintestinal barrier unction has been ound in subjects withASD[] along with an increasedintestinal permeability [].Another contributing actor to GI problems in individualswith ASD might be an abnormal composition o gut micro-biota. In the GI ora o autistic children, using stool samples,lower levels o benecial Bidobacter species and higherlevelso Lactobacillus species were ound compared to controls.Other studies stated altered Clostridium species numbers

and types in children with ASD [–] and differencesconcerning the phylum level with an increase in Bacteroidesand a decrease in Firmicutes in the ASD group [–]. It hasbeen stated that GI disturbances correlate with the severity o ASD. Te stronger the GI symptoms are, the more likely children presented severe autistic symptoms [].

Te GI tract plays an important neurological unctionand thereore sometimes is reerred to as the “the secondbrain.” Via enteric nerves and networks, the GI tract is ableto affect the brain and vice versa [, ]. Intriguingly, inhealthy human subjects, modulation o the gut microbiomewas shown to have the potential to alter brain responsivenessto an emotion recognition task [].

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Besides the GI disorders ofen ound in ASD patients,the gut-brain interaction seems to play a role in otherneurological disorders as well []. Investigating the preva-lence o depression and anxiety disorders as comorbidity ininammatory bowel disease (IBD), individuals with Crohn’sdisease and ulcerative colitis, two types o IBD, are more

likely to suffer rom psychiatric disorders like depression andanxiety disorders in comparison to the general population[–]. When comparing the comorbidity o the GI disor-ders IBD and irritable bowel syndrome (IBS), signicantly more subjects were diagnosed with depression (IBS: %;IBD: %), generalized anxiety disorder (IBS: %; IBD:%), panic disorder (IBS: %; IBD: %), and agoraphobia(IBS: %; IBD: %) [], with a higher prevalence or alietime diagnosis o the aorementioned comorbidities incomparison to the general population [, ].

Intriguingly, along with the core eatures o ASD, comor-bidities occur requently in ASD patients such as seizures,depression, and anxiety disorders that have been associated

with zinc deciency beore.

4. Zinc, the GI Tract, Stress, andthe Immune System

Zinc deciency severely affects almost all components o theimmune system. Even marginal zinc deciency leads to aseriously depressed immune system. Tus, the susceptibility to inections is increasing with a decreasing zinc statusas reported rom animal models and human studies. Te

vulnerability to inections is associated with an impaired and B lymphocyte development and differentiation and theirreduced activity [–] whereby lymphocytes seemed to

be more seriously affected [] by zinc deciency. Studieson prenatal zinc decient animals have shown that zincdeciency, even a marginal one, results in smaller lymphoidorgans and less immunoglobulins []. Benecial effectso zinc supplementation in diseases include reduced inci-dence and duration o acute and persistent diarrhea [–],reduced incidence o acute lower respiratory inections [],and reduced duration o the common cold [].

A role o abnormal immune system unction in ASD haslong been hypothesized. In postmortem brains o individ-uals with ASD, similar to some animal models, activationo astroglia and microglia was reported, indicating somedegree o neuroinammation [–]. Furthermore, a rela-

tionship between amilial autoimmune disorders and anti-inammatory/immune-modulating drug in ASD has beenreported []. Inammatory events however, can also bemediated by abnormalities in the GI system. Usually theorganism ght against pathogens is initiated by the activationo the complement system as well as natural killer cells andpolymorphonuclear leukocytes. All these deending mecha-nisms are depressed by zinc deciency [–] resulting in aprolonged inammation. Te disruption o these processes isalso associated with diarrhea or inammatory bowel disease,both also consequences o zinc deciency.

Inammation in the GI tract can lead to intestinalpermeability, commonly called “leaky gut.” Here, increased

spaces present between cells in the small intestine may resultin incompletely broken down oods and other toxins enteringthe blood stream, which may lead to an immune systemresponse [] triggeringthe release o antibodies. Tis processmay result in chronic inammation that might inuencemicrobe prolieration in the GI tract and cause vitamin and

mineral deciencies, as well as ood allergies and autoim-mune diseases such as celiac disease []. Furthermore, adirect effect on the brain causing behavioral, cognitive, andpsychiatric impairments may occur [, ].

Additionally, gut inammation and zinc deciency arealso linked to physiological and psychological stress. Animalstudies haveshown that psychological stress decreased serumzinc levels []. Reduced zinc levels and psychological stressboth increase the release o glucocorticoids [, ]. Increaselevels o glucocorticoids in turn have been associated withthymic atrophy and reduced B lymphocyte numbers [, ,]. Furthermore, persistent high levels o glucocorticoidsmight lead to resistance o glucocorticoid receptors and in

turn lead to ailure o immune system downregulation. Tisdownregulation is necessary to avoid chronic inammatory processes.

aken together, GI abnormalities, immune system dys-unction, stress, and zinc deciency are highly linked pro-cesses (Figure ). Te nal result may be an altered signalingto and within the developing brain, possibly contributing tothe development o ASD.

5. Conclusions

.. A Model for Zinc in Gut-Brain Interaction in ASD. Dueto the multiaceted effect o zinc on gut development andmorphology, pre- and perinatal zinc deciency might affectgut development o the neonate and potentially mitigatemany o the dysunctions shared between ASD and otherneurological disorders. Based on this hypothesis, a modelemerges (Figure ) that might serve as starting point oruture studies.

Zinc is taken up rom our dietary sources and/or sup-plements in the proximal small intestine, either the distalduodenum or proximal jejunum [, ]. Within enterocytes,intracellular transporters and zinc buffering proteins such asmetallothioneins (Ms) inuence the transport and releaseo zinc in the blood stream. However, various agents candecrease zinc absorption []. For example, it is not uncom-

mon or women o childbearing age to consume calciumsupplements or the prevention o osteoporosis or drink waternaturally high in calcium. Similar to copper which has anantagonistic relationship with zinc [–], calcium mightinterere with the absorption o zinc, though this effect is notas well established [, ]. Research has shown decreasedzinc absorption when different orms o calcium have beeningested ollowing consumption o a zinc dose, suggesting anantagonist relationship between the minerals []. Ingestiono high concentrations o iron might also affect zinc uptake[–]. Additionally, olic acid is a nutrient commonly prescribed during pregnancy and supplied at higher levels inprenatal supplements. Folic acid has been shown to increase

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GI abnormalitiesZn deciency

Immune systemabnormalities

Stress

Diarrhea

Affected small intestinal epithelium

Impaired digestion o disaccharides

Malabsorption o vitamins and minerals

Altered microbiome

Altered mucus production

GI ulcers

Chronic inammation

Presence o autoantibodies directedagainst brain and gut

Altered cytokine levels

Abnormalities in number and unction o different immune cell types

High prevalence in ASD,especially young ageAltered cell prolierationAltered activity o Zn bindingenzymes and transcription actors

Altered stress response

Dysregulated stress pathways

Increased cortisol levels (mouse model)

Altered 5-HT levels and receptor activity (human)

F : GI abnormalities, immune system dysunction, stress, and zinc deciency may be highly linked processes contributing to thedevelopment o ASD. Zinc deciency mediates GI system abnormalities, severely affects many components o the immune system, and islinked to physiological and psychological stress. Although there is good reason to believe that maternal zinc deciency might be the initialtrigger, once this vicious cycle is activated in the offspring, GI abnormalities, impaired immune system, stress, and zinc deciency can beboth cause and consequence o each other and inuence the development o ASD. Tis is in line with the ofen reported symptoms andcomorbidities in ASD associated with problems linked to these our key eatures.

ecal zinc losses, indicating decreased zinc absorption [–]. Other dietary constituents that inuence zinc availability include phytate and high ructose corn syrup (HFCS). Inosi-tol hexaphosphates and pentaphosphates, the phytate ormsthat bind to zinc and reduce its availability, are present in

staple oods such as wheat, corn, and rice [, ]. HFCSis commonly used in the US to sweeten ood and drinkswith estimated yearly per capita consumption in the US being. kg in [, ]. Consumption o alcohol leads toa reduced placental zinc transport and it was hypothesizedthat the consequenceso “etalalcohol syndrome” may unoldnot only through the effects o ethanol but also throughzinc deciency []. Some drugs are also known to interactwith zinc. For example, ACE inhibitors used to treat highblood pressure may decrease blood zinc levels similar tothiazide diuretics, the anticonvulsant valproic acid (VPA)that was already reported to increase the risk or autismupon prenatal exposure [], tetracycline antibiotics, corti-

costeroids, acid blockers such as histamine- receptor antag-onists (H-blockers), and many neuropsychiatric drugs suchas Fluoxetine(Prozac),Paroxetine (Paxil), Sertraline (Zolof),Citalopram (Celexa), and Venlaaxine (Effexor) [].

Once absorbed, zinc passes into portal blood and istransported bound to proteins []. Placental transport o zinc is a ast process and inuenced by the number andsize o etuses present. However, due to low zinc diets orcompromised absorption due to increased intake o dietary constituents that reduce the availability o zinc, a zincdeciency o the embryo may occur. Zinc deciency mightinuence embryonic and etal development through severalmechanisms including abnormal nucleic acid metabolism,

reduced protein metabolism, reduced rates o tubulin poly-merization, high rates o cellular oxidative damage, higherrates o apoptosis, impaired cell migration, and reducedbinding o transcription actors and hormones that, amongothers, affect lymphocytes []. Tese actors will very likely

affect GI development.At least intestinal epithelial differentiation genes have

been implicated in development and differentiation o theintestinal epithelium [], and many o them have a directrelationship with zinc. Among them, adenomatous polyposiscoli (APC) is a crucial determinant o cell ate in themurine intestinal epithelium. Loss o APC perturbs differ-entiation along the enterocyte, goblet, and enteroendocrinelineages andpromotescommitment to the Paneth cell lineagethrough -catenin/c-mediated transcriptional control o specic markers o Paneth cells, the cryptdin/deensin genes.Conditional deletion promotes Paneth cell differentiation atthe expense o enterocyte, goblet, and enteroendocrine cell

differentiation []. Zinc stabilizes APC levels and inducescell cycle arrest in colon cancer cells [].

Furthermore, PR domainzinc nger protein also knownas BLIMP- has an effect on postnatal epithelial maturation,mediating the transition o neonatal intestinal epithelium toadult intestinal epithelium []. Caudal-related homeobox(Cdx) regulates intestinal development, differentiation, andmaintenance. Cdx is required or the transcriptional induc-tion o PPAR in intestinal cell differentiation []. Both

variants, Cdx and Cdx, contain a zinc nger moti at theirN-terminus.

Gata is another amily o zinc nger transcription actorsthought to regulate genes involved in embryogenesis. Gata,

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Zinc in ood and/or supplements

Zinc in ood is low or uptake is partially blocked inthe digestive tract by antagonists and interactions

GI problems are associated with issues seen in ASD and other neurological disorders

APC/BLIMP-1/Cdx/Gata4, -5, -6/IHH/KLF4/MMP/MAZ/Notch/VIK-1

Metallothionein dysunction

Plasma Cu/Zn inversion

Heavy metal overload

Candida and Clostridium overgrowth

Constipation and/or diarrhea

Leaky gut

Food sensitivities and allergies

Inefficient processing o gluten and casein

Enzyme deciencies

Vitamin and mineral malabsorption

Inefficient at digestion and metabolism

Esophagitis and GI ulcers

Low zinc in pregnant women affects the

Zn2+

Fe2+/Cu2+/Ca2+/olic acid/phytates/HFCS/some drugs

embryo’s gut epithelial development

F : A model or Zinc in gut-brain interaction in ASD and other neurological disorders. Zinc is taken up rom our dietary sourcesand/or supplements in the proximal small intestine. However, absorption o zinc can be decreased in response to various agents such as ironand/or calcium supplements, high copper levels, olic acid, phytate, high ructose corn syrup (HFCS), and/or several drugs. Alternatively,zinc levels may be low due to genetic variants in zinc homeostasis genes or general low availability o zinc in the diet. As a result o this,zinc deciency o the embryo may occur. Zinc deciency might inuence embryonic and etal development affecting the GI system throughimpaired unction o several key proteins contributing to many o the reported GI problems associated with ASD such as metallothioneindysunction, plasma Cu/Zn inversion, heavy metal overload, Candida and Clostridium overgrowth, constipation and/or diarrhea, leaky gut,ood sensitivities and allergies, inefficient processing o gluten and casein, enzyme deciency, vitamin and mineral malabsorption, inefficientat digestion and metabolism, and esophagitis and GI ulcers. Tese GI symptoms can give rise to behavioral difficulties.

-, and - are expressed in various mesoderm and endodermderived tissues such as heart, liver, lung, gonad, and gutwhere they play critical roles in regulating tissue-specic geneexpression. Gata, -, and - have been implicated in theregulation o epithelial cell differentiation [, ].

Indian hedgehog (IHH) is expressed by mature colono-cytes and regulates their differentiation in vitro and invivo. IHH binds zinc ions stabilizing the protein andmediating protein-protein interactions [, ]. Similarly,Kruppel-like actor (KLF, ormerly GKLF) is a zinc nger

transcription actor expressed in the epithelia o the GItract and several other organs. In vitro and in vivo studieshave suggested that KLF plays an important role in cellprolieration and/or colonic epithelial cell differentiation[].

Matrix metalloproteinases (MMPs) are a amily o zincbinding extracellular matrix degrading enzymes. MMP- isa zinc dependent endopeptidase, synthesized and secreted inmonomeric orm as zymogen and contributes to gut microbehomeostasis [, ]. Furthermore, MYC-associated zinc

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nger (MAZ) protein has been implicated as a criticaltarget o the canonical Wnt pathway, which is essential orormation and maintenance o the intestinal mucosa [,].

Te Notch signaling pathway promotes prolierative sig-naling during neurogenesis and is activated in the progenitor

domain o the gastrointestinal epithelium inuencing binary ate decisions o cells that must choose between the secretory and absorptive lineages in the gut []. Notch signalingtargets our different receptors reerred to as Notch-. Animportantrelationship between zinc and the Notch signalingpathway can be ound. Zinc inhibits Notch signaling by modulating the binding between Notch and RBP-Jk [].

It is thus likely that insufficient zinc supply will affectdevelopment o the etal GI tract contributing to many o the reported GI problems associated with ASD such asmetallothionein dysunction, plasma Cu/Zn inversion, heavy metal overload [, , –], Candida and Clostridiumovergrowth, constipation and/or diarrhea [, ], leaky gut, ood sensitivities and allergies, inefficient processing o gluten and casein [, , , –], enzyme deciency [, –], vitamin and mineral malabsorption [, –], inefficient at digestion and metabolism [], andesophagitis and GI ulcers [].

Tese GI symptoms cangive riseto behavioral difficulties,ranging rom inattentive or irritable behaviors to sel-injury []. Several human disorders with GI problems like includ-ing inammatory bowel disease (including Crohn’s Disease),irritable bowel syndrome, and obesity have a modulatory inuence on social, emotional, and anxiety-like behaviors.Changes in behavior thereby might be based on both acutealterations in brain unction as well as alterations duringbrain development [–]. For example, vagal afferentsignaling has been implicated modulating mood and affect,including distinct orms o anxiety and ear []. Moreover,although the GI symptoms might be transient, long lastingbehavioral changes have been reported. In rats, neonatalgastric irritation leads to increase in depression- and anxiety-like behaviors, increased expression o CRF in the hypotha-lamus, and an increased sensitivity o HPA axis to stress inadults []. Tus, it is possible that shared comorbiditiessuch as increased anxiety in ADHD, mood disorders, andASD correlate with abnormal GI development caused by zincdeciency or other actors.

Te presented model does not exclude the possibility thatthe GI symptoms are the consequence o altered brain togut signaling or the consequence o altered gut regulation by the enteric nervous system, which might occur in parallel.Synaptic genes affecting excitatory and inhibitory neuro-transmission might lead to alterations in neural or endocrineelements o the enteric nervous system. However, given thata central pathway at synapses related to ASD, Neurexin-Neuroligin-Shank signaling has also been shown to dependin part on the availability o zinc [], a link between zincdeciency and brain to gut signaling cannot be excluded.

.. Prevention and reatment Strategies. Supplementingwomen o childbearing age with an effective source o

zinc might help mitigate the negative effects o dietary constituents and nutrients in prenatal supplements on zincavailability, helping womenattain and maintain adequate zincstatus. Zinc amino acid complexes might be advantageousto zinc oxide and zinc sulate based on better absorption. Acombination o the inorganic and amino acid complexed zinc

might also be advantageous due to different absorption path-ways. Additionally, research has shown that zinc antagonistssuch as phytate and ber reduced the bioavailability o zincrom zinc sulate more than that rom a zinc amino acid com-plex []. Provided the amino acid remains complexed tothe zinc, interaction o the mineral with dietary componentssuch as phytate and ber preabsorption can be minimizedand zinc can be absorbed into the enterocyte via amino acidtransporters versus metal transporters, reducing competitionor absorption between zinc in the zinc amino acid complexand other dietary metals [] (Figure ).

Although measures to prevent maternal zinc deciency would be most desired, urther treatment strategies emergerom this concept or young children with ASD. For example,the use o probiotics in ASD has been suggested [, , ].However, probiotics have been used with variable efficacy and data on the effectiveness o probiotics is currently justemerging with more studies and meta-analyses needed inuture. Intriguingly, treatment o the offspring o maternalimmune activation (MIA) mice that are known to display ea-tures o ASD with the human commensal Bacteroides fragiliscorrected gut permeability, altered microbial composition,and ameliorated deects in communication, stereotypic- aswell as anxiety-like and sensorimotor behaviors [, ](Figure ). Additionally, a gluten and milk protein-ree diet(exclusion o the protein compound gluten ound in wheatproducts and casein contained in dairy) was reported topotentially be benecial to improve some behaviors inindividuals withASD and reduce intestinal permeability [,]. Elimination o cow’s milk protein rom the diet o ASD children via restrictive diet improved autistic behavior,while the oral challenge with milk protein seemed to havean opposite effect. When evaluating IgA, IgG, and IgMspecic antibodies, autistic children had signicantly higherserum levels o IgA antibodies, high levels o IgM antibodiesspecic or lactalbumin, and IgG and IgM levels or casein[, ]. However in a small sample size study with autistic children investigating the effects o a gluten-caseinree diet, no signicant differences between individuals on

the restrictive diet and nontreated controls could be oundalthough some o the parents claimed to have noticed animprovement regarding the child’s language, the occurrenceo tantrums, and the level o hyperactivity []. Tus,although some studies show inammation o the gut or aleaky gut in ASD and some studies report that gluten andcasein showed benecial effects, given that other scienticpublications did not indicate signicant improvements, moreresearch is needed to make a recommendation.

In general, the gut microbiome might have great impacton brain development early in lie. In an altered micro-biome, bacterial metabolites such as -ethylphenylsulphate(EPS) or the neurotransmitter-aminobutyric acid (GABA)

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Zn amino acid complex

Zn amino acid complexes pass theantagonistic interactions in the GI t ract

Increase or maintenance o zinc status duringpregnancy necessary or intact gut and brain development

Decrease o ASD-GI tract associated symptoms

Prenatal Early postnatal

Probiotics

Probiotics normalize/alter gut microbiome

Correction o gut permeability and microbialcomposition, decrease o toxic bacterial metabolites

Decrease o stress

5-HT agonists or antagonists

CRF receptor antagonists

Zn amino acid complex

Decrease o immune system activation

Gluten and milk protein-ree diet

and anti-inammatory,immune-modulating therapies

F : Prevention and treatment strategies. Zinc amino acid complexes might be an effective source to overcome the negative effects o dietary constituents and nutrients in prenatal supplements and help women to maintain adequate zinc status (prenatal prevention, lef panel).Zinc supplementation might also be useul in young children with ASD helping to overcome some impairments associated with acute zincdeciency (diarrhea, impaired immune unction, and neurosensory decits) (postnatal treatment, right panel). Furthermore, young childrenwith ASD might benet rom probiotic therapy that may correct gut permeability, alter microbial composition, reduce burden o bacterialwaste products and metabolites, and thereby ameliorate ASD symptoms. Additionally, a gluten and milk protein-ree diet was proposed topotentially be benecial or individuals with ASD. -H signaling may mediate both innate and adaptive responses in the immune systemand -H signaling important in the brain and in the GI tract; -H receptors are expressed. Tus, -H antagonists or -H agonistsmay have a modulatory effect. Moreover, therapeutics used to treat inammatory eventscaused by abnormal GI unction (anti-inammatory and immune-modulating therapies) might be benecial. Stress is linked to abnormalities in the GI tract and mediated by, among others, thecorticotropin-releasing actor (CRF) system on molecular level. Te use o CRF receptor antagonists might thereore provide new treatmentapproaches.

produced rom intestinal bacteria might affect brain develop-ment and, ultimately, behavior later in lie.

Serotonin (-H) signaling is not only important inthe brain, but also in the GI tract. Te -H(A) receptorplays an important role in the developing brain but isadditionally expressed in the gut []. -H is released romgut enterochromaffin cells and might contribute to -Hsignaling in the brain []. However, the gut and the brainare not the only sites o action or -H. Its receptors arealso present in the immune system where -H signalingmay mediate both innate and adaptive responses []. Itremains to be established whether -H antagonists (e.g.,

Ramosetron) or -H agonists can have a modulatory effectin ASD.

Moreover, the intestinal tract has a very importantimmune unction []. Besides markers or inammation,enhanced levels o cytokines and chemokines have beendetected in the brain and in the cerebrospinal uid o children with autism [, ]. Tereore, therapeutics usedto treat inammatory events caused by abnormal GI unction,such as in inammatory bowel disease (anti-inammatory,immune-modulating, and microbiome-modulating thera-pies) [], might be a potential source or novel treatmentstrategies.

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Furthermore, stress was implicated in many neuropsy-chiatric disorders. In particular, prenatal stresses, such asdepressive illness, anxiety disorders, and posttraumatic stressdisorders, are a risk actor or ASD [, ]. Chronic stressmay result in GI disorders and immune dysunction, amongothers. Maternal stress is able to alter microbial populations

and their transmission to the offspring. Tus, stress is alsoconnected to abnormalities in the GI tract, zinc signaling,and the immune system [, ]. Many studies support theinuence o the corticotropin-releasing actor (CRF) systemin stress response. Te use o CRF receptor antagonists sug-gested a signicant effect against stress-related behavior, butalso hyperalgesia, colonic secretion, and motility [, ].Tus, medications acting on CRF and CRF receptors thatare involved in neuroendocrine, autonomic, behavioral, and

visceral responses to stress, such as NBI and Astressin-B, respectively, might provide new treatment approaches.

Finally, zinc supplementation might also be useul inyoung children with ASD. Given that younger individuals

with ASD have an especially high risk o zinc deciency,zinc supplementation will help to overcome some impair-ments associated with acute zinc deciency. For example,diarrhea has been linked to zinc deciency [, ] andzinc supplementation was reported to signicantly reduce thesymptom [] as well as increase immune unction [, ]and ameliorate neurosensory decits associated with zincdeciency [] (Figure ).

Given that ASD is a heterogeneous group o disordersand zinc deciency or increased intestinal permeability only present in a subset o patients, unless clinical trials use patientpopulations that are enriched based on this particular clinicalhistory, clinical benets o any possible treatment will be hardto demonstrate. Additionally, ASD is a neurodevelopmentaldisorder. Tus, the pathomechanisms already act in utero,leading to alternative modeling o the brain. I therapies areto prevent or correct such changes, they may have to beimplemented in the perinatal period and may be ineffectivein an individual with ASD later in lie.

aken together, we conclude that due to multiacetedeffect o zinc on gutdevelopment and morphology improvingzinc status o the pregnant mother as well as the offspring hasthe potential to improve gut development o the neonate andpotentially mitigate dysunctions associated with ASD.

Conflict of Interests

Ann Katrin Sauer, Simone Hagmeyer, and Andreas M. Grab-rucker declare that there is no conict o interests regardingthe publication o this paper. Guillermo Vela, Peter Stark, andMichael Socha are employed by Zinpro Corporation.

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