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Artigo 1 1
Artigo 1 1
Affiliation: E. Karhu, R. Zukerman, J. Mittal, R. Mittal, and A.A. Eshraghi are with the Department of Otolaryngology, Miller School of
Medicine, University of Miami, Miami, Florida, USA. R.S. Eshraghi is with the Division of Gastroenterology, Department of Medicine, Miller
School of Medicine, University of Miami, Miami, Florida, USA. R.C. Deth, A.M. Castejon, and M. Trivedi are with the Department of
Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, USA. A.A. Eshraghi is with the
Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Correspondence: Adrien A. Eshraghi, Department of Otolaryngology and Neurological Surgery, University of Miami-Miller School of
Medicine, 1600 NW 10th Ave, Miami, Florida 33136, USA. E-mail: Aeshraghi@med.miami.edu
*EK and RZ contributed equally to this work.
Key words: Autism spectrum disorder (ASD), gluten-free diet, casein-free diet, ketogenic diet, specific carbohydrate diet, probiotics, polyunsatu-
rated fatty acids, dietary supplements
C The Author(s) 2019. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
doi: 10.1093/nutrit/nuz092
Nutrition ReviewsV Vol. 78(7):515–531
R
515
amino acids cysteine [CYS] and methionine [MET], fo- exists in nutritional interventions. Of note, greater than
late, vitamins B12 and B6), they are critical for ASD 80% of parents of children with ASD reported using
diets. some form of dietary intervention,18 although contro-
The gut-brain axis theory proposes that nutritional versy exists in the literature regarding the effectiveness,
programing in early life, reaching as far back as the ges- implementation criteria, and possible adverse effects of
tational period, may influence cognitive function and elimination or restrictive diets. In this review, we sum-
predispose to ASD in genetically susceptible individu- marize the current clinical and experimental literature
als.6,7 In several animal studies, researchers have on nutritional interventions in ASD, including gluten-
facilitates release of b-casomorphin-7 (BCM7), whereas from A1 or mixed A1/A2 cows.23 Additional studies are
BCM7 release from A2 b-casein is limited.20 Indeed, in needed to evaluate whether this difference contributes
a double-blind, crossover study in which consumption to the benefits of breastfeeding. Studies have reported
of milk containing a mixture of A1 and A2 b-casein was an association between decreased breastfeeding and au-
compared with only A2 b-casein, researchers reported tism,24,25 although no association was found in a study
that although both types of milk increased plasma GSH based on the US National Survey of Children’s
levels, consistent with their CYS-rich whey protein con- Health.26
tent, the GSH level was almost twice high with con- Besides opioids and b-casomorphin activity, it has
sumption of A2-only milk.21 Thus, opioid peptide been demonstrated that persons with ASD have ele-
release from casein appears to exert a significant inhibi- vated levels of antibodies to a series of dietary proteins
tory effect on CYS absorption, limiting systemic GSH including gluten/gliadin and milk proteins such as a-
levels. Assuming that opioid peptides released from glu- gliadin (eg, immunoglobulin [Ig] A and IgG), deami-
ten have a similar effect, a GFCF diet may be beneficial dated gliadin peptide (deamidated gliadin peptide–IgA
in ASD, because of augmented antioxidant status. The and IgG), total specific gliadin IgG (all fractions: a, b, c,
action of BCM7 to restrict CYS absorption applies not and x), and casein IgE.27 In addition, intestinal perme-
only to absorption of casein-derived CYS but also to ability was increased in 25.6% of children with ASD
CYS derived from other protein sources ingested along compared with 2.3% of healthy children. Interestingly, a
with milk.20 GFCF diet helped decrease the levels of some of these
The activity of casein- and gluten-derived opioid antibodies to dietary proteins. It was suggested that glu-
peptides is terminated upon their hydrolysis by dipep- ten and casein stimulate the immune system, leading to
tidyl peptidase IV, which is present on the surface of in- increased production of antibodies to dietary proteins
testinal epithelial cells and in various strains of gut in a subset of persons with ASD. A better knowledge
bacteria.22 Bacterial species commonly found in the in- about the antibody titers to food antigens will help
testine of infants (eg, strains of Bifidobacterium) exhibit identify persons with ASD who can benefit more from a
particularly high dipeptidyl peptidase IV activity,22 sug- GFCF diet, compared with nonresponders.
gesting the bacteria may limit BCM7 activity during Oxidative stress associated with low levels of GSH
early development. Notably, human b-casein is of the promotes the release of pro-inflammatory cytokines
A2 type, implying that BCM7 release from breastfeed- and can thereby contribute to GI inflammation.28 The
ing may be relatively low in comparison with formula actions of casein- and gluten-derived opioid peptides,
therefore, potentially can promote inflammation of the 12 months, whereas those studies in which significance
GI tract, which is a common feature of autism, and a could not be established had a duration of 12 weeks.24–28
GFCF diet may ameliorate GI inflammation. This suggests the benefits of a GFCF dietary intervention
Importantly, GI inflammation is associated with hyper- may not be apparent until a more prolonged treatment
permeability (ie, leaky gut),29 increasing the opportu- is implemented. It is highly plausible that the gut dys-
nity for opioid peptides to exert systemic effects. biosis, inflammation, and perturbations in intestinal
Systemic opioid effects can occur if the opioids can motility and permeability encountered in many patients
pass into the general circulation19 (Figure 2). Emerging with ASD take a substantial time to normalize on a
evidence indicates that, indeed, opioid receptors may be treatment diet after years of dysfunction. In a small,
involved in regulating aspects of social behavior and open-label, 12-week RCT, researchers found no signifi-
may contribute to the pathogenesis of ASD.20 However, cant differences between treatment and control
the theory has been criticized because of the inability of groups29 However, this study had a small sample size
studies to find abnormal levels of opioids in the plasma and short duration, which may have contributed to the
or central nervous system of children with ASD.19 lack of significant effect. In contrast, in a recent RCT
Exogenously, these opioid-like peptides are thought to with a larger sample size of 80 patients, researchers
be derived from the incomplete breakdown of certain found that a gluten-free diet alone was effective at im-
foods like gluten-containing cereals and dairy products, proving GI and behavioral symptoms after 6 weeks.30
possibly due to a deficiency in peptidases.6 According No adverse events were reported and no nutritional de-
to the leaky-gut hypothesis, these gluten- and casein-de- ficiencies were identified in any of the RCTs in which
rived peptides are then thought to enter the circulation, these metrics were investigated—addressing a common
due to increased intestinal permeability, which is often concern regarding special diets.25,27,29 In another recent
seen in patients with ASD along with comorbid GI RCT, a gluten-free, casein-free, and soy-free diet for
symptoms.11,16,17,21,22 Interestingly, gluten sensitivity 12 months, with additional supplements, was effective
has been implicated with other neuropsychiatric condi- at improving nutritional status, nonverbal intelligence
tions, including schizophrenia, ataxia, and attention- quotient, autism symptoms, and other symptoms in
deficit/hyperactivity disorder.23 most individuals with ASD.31 With the broad nature of
The literature on GFCF diets is conflicting. A re- the intervention, however, it is difficult to establish the
cent systematic review of 4 randomized controlled trials main factor contributing to the observed
(RCTs) on GFCF diets found a 50% efficacy rate of improvements.
treatment.23,24 Interestingly, the studies in which the A different approach was taken in an RCT in which
researchers found a significant effect had a duration of the effect of gluten and casein supplementation on
dietary interventions have been studied, there has robust. Lack of control groups in many studies and
been a lack of conclusive scientific data about the ef- high levels of parental or physician expectancy about
fect of therapeutic diets on autism, and as such, no the benefit of these interventions may bias the results of
definitive recommendation can be made for a specific dietary studies. It is also relevant to highlight the lack of
nutritional therapy as a standard treatment for ASD blinded studies to decrease bias in parents’ or care-
(Table 1).24–26,28–30,36–38,50,51,54,55,68–70,76–84,96,97,100–104, givers’ perception as well as behavioral raters in these
113,114,138,139,142,144,146,150–155
studies. An additional limitation in these studies is the
Although there is no conclusive evidence of the variety of outcome measurements used to evaluate be-
benefit of nutritional therapies for persons with ASD, havioral improvements that can range from parents or
many parents or healthcare providers choose to con- caregivers’ questionnaires to the use of diagnostic
tinue dietary interventions and have observed promis- instruments, such as the Autism Diagnostic
ing results with regard to behavior and GI Observation Schedule and CARS, not really designed to
abnormalities. A major problem in interpreting the detect changes in behaviors but rather to differentiate
available evidence for dietary interventions is the vari- individuals with ASD from those without ASD. This
ability in measurement of the therapeutic effect. Studies limitation poses a challenge when comparing different
often explore the effect of nutritional therapies on dif- studies using similar interventions. Furthermore, die-
fering aspects of ASD and rarely compare effectiveness tary intervention studies frequently have a small sample
with that of other interventions, making generalizability size that, again, affects the generalizability of the results.
and comparison between treatment modalities less It would be useful to better define and standardize what