nutrients

Review
Cow’s Milk Protein Allergy in Infancy: A Risk
Factor for Functional Gastrointestinal
Disorders in Children?
Licia Pensabene 1, *,† , Silvia Salvatore 2,† , Enza D’Auria 3,† , Francesca Parisi 1 ,
Daniela Concolino 1 , Osvaldo Borrelli 4 , Nikhil Thapar 4 , Annamaria Staiano 5 ,
Yvan Vandenplas 6 and Miguel Saps 7
1 Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro,
88100 Catanzaro, Italy; [email protected] (F.P.); [email protected] (D.C.)
2 Department of Medicine and Surgery, Section of Pediatrics, University of Insubria,
21100 Varese, Italy; [email protected]
3 Department of Pediatrics, Vittore Buzzi Children’s Hospital-University of Milan,
20154 Milan, Italy; [email protected]
4 Neurogastroenterology and Motility Unit, Department of Gastroenterology,
Great Ormond Street Hospital for Children, London WC1N 3JH, UK;
[email protected] (O.B.); [email protected] (N.T.)
5 Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”,
80131 Naples, Italy; [email protected]
6 KidZ Health Castle, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel,
1090 Brussels, Belgium; [email protected]
7 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Holtz Children’s Hospital,
University of Miami, Miller School of Medicine, Miami, FL 33136, USA; [email protected]
* Correspondence: [email protected]; Fax:+39-961-883489
† These authors contributed equally to this work.




Received: 16 October 2018; Accepted: 6 November 2018; Published: 9 November 2018


Abstract: The role and prevalence of cow’s milk protein allergy (CMA) in functional gastrointestinal
disorders remains unclear. The aim of this review is to update knowledge on the relationship
between CMA and functional abdominal pain disorders (FAPDs) in children. Cochrane Database
and Pubmed were searched from inception using general and specific terms for CMA and functional
gastrointestinal disorders. CMA is reported as a predisposing or coexisting factor in a wide range
of functional gastrointestinal disorders in infants and children. Pathogenesis of both conditions is
complex and multiple mechanisms including dysmotility and hypersensitivity might contribute to
the clinical manifestations. Data supporting the possible role of food allergies in the pathogenesis of
FAPDs are limited. CMA may predispose to early life inflammation and visceral hypersensitivity,
which in turn might manifest as FAPDs. The diagnosis of either CMA or FAPDs and distinction
between them is challenging because of nonspecific and overlapping symptoms. Lack of accurate
allergy tests in non-IgE (immunoglobulin E) mediated cases is also problematic. Oral food challenge,
following an elimination diet, should be performed to diagnose a suspected non-IgE CMA allergy in
children with FAPDs. In the management of FAPDs, an elimination diet should be considered for a
limited period to verify if the symptoms improve or resolve.

Keywords: CMA; allergy; hypersensitivity; FGIDs; gastrointestinal; abdominal pain

Nutrients 2018, 10, 1716; doi:10.3390/nu10111716 www.mdpi.com/journal/nutrients

Nutrients 2018, 10, 1716 2 of 15

1. Introduction
Cow’s milk (CM) allergy (CMA) is one of the most common food allergies in infants and young
children with a prevalence of 2–5% [1–6]. Food allergy is defined as an adverse health effect related to
the exposure to a given food, arising from specific immunoglobulin (Ig)E mediated, non-IgE mediated
(cellular mediated), or mixed [7,8] immune responses.
The major milk allergens are whey proteins (ß-lactoglobulin being the most abundant) and caseins [9].
Caseins consists of several isoforms: α s1-casein, α s-2 casein, β casein, and k-casein. Previous studies
over the past few decades have suggested that casein may be the major cow’s milk protein toward
which reactions might occur. Moreover, patients with persistent CMA showed IgE reactivity towards
casein epitopes, such as α s1 and β casein, compared to those whose developed clinical tolerance [10].
More recently, it has been shown that circulating casein-specific T cells (particularly α s1 and β casein) were
the most prevalent in children suffering from CMA, compared to non-CMA subjects [11,12], suggesting
the possible utility of T-cell responses as a promising tool to improve CMA diagnosis, which actually still
relies on oral food challenge.
There is also emerging evidence for a different pathogenetic role of the genetic types of β caseins,
for example, A1 and A2 in the development of gastrointestinal symptoms in humans [13].
The majority of patients with IgE CMA are sensitized to more than one CM allergen, with a great
variability in the specificity and intensity of the IgE responses. Molecular-based allergy diagnosis
allows to associate each patient with a specific immunoreactive profile and to identify different CMA
phenotypes [14].
CMA may be considered a predisposing or comorbid disease in patients with persisting functional
gastrointestinal disorders (FGIDs), including functional abdominal pain disorders (FAPDs). FGIDs
are common disorders with an estimated worldwide-pooled prevalence of 13%, which increases
to up to 40% of the population in certain areas [15–19]. FGIDs are defined as chronic or recurrent
gastrointestinal (GI) symptoms that are not explained by structural or biochemical abnormalities or
that after appropriate medical evaluation cannot be attributed to another medical condition [20].
CMA induces a diverse range of symptoms of variable intensity in infants with “immediate”
(early) and/or “delayed” (late) reactions. Immediate reactions usually occur from minutes up to 2 h
after the ingestion of the allergen in the cases that are IgE mediated, and anaphylaxis represents the
most severe clinical manifestation of IgE-mediated CMA. Conversely, in cases of non-IgE (cellular)
mediated immune mechanisms, the reactions to the CM proteins are delayed and may manifest up to
48 h or even one week following the ingestion, making its diagnosis difficult to demonstrate. Moreover,
there are no specific symptoms or biomarkers for non-IgE (cellular) mediated reactions. Combinations
of immediate and delayed manifestations to the same allergen may occur in the same patient [8].
Although CMA may sometimes be transient and benign, as is the case for non-IgE-mediated CMA,
it may overlap with or predispose to FGIDs. IgE-mediated CMA often persists into school age and is a
risk factor for other atopic diseases [2].
In the present review, we focus on both CMA-related GI symptoms and CMA as a predisposing
condition to subsequent FAPDs, defined as FGIDs with abdominal pain as a driving symptom.

2. Methods
We searched the Cochrane Database and PubMed from inception to 31 August 2018, using the
following Keywords: “food-hypersensitivity”, “dietary protein proctocolitis”, “dietary protein
enteropathy”, “neurogastroenterology”, “colic”, “constipation”, “abdominal pain”, “functional abdominal
pain”, “irritable bowel syndrome”, “IBS”, “functional gastrointestinal disorders”, “gastroesophageal
reflux”, “vomit”, “functional dyspepsia” and “cow’s milk allergy”, “cow’s milk protein allergy”,
“food allergies”. Limits related to age (children, aged 0–18 years) and languages (English) were
introduced. Intervention-controlled trials, reviews, guidelines, and meta-analyses on CMA were
considered. Additional strategies for retrieving studies comprised the reference lists of review articles and
included studies.
Nutrients 2018, 10, 1716 3 of 15

3. Association between Cow’s Milk Allergy and Gastrointestinal Disorders in Infants

and Children
CMA may involve different organs and systems, most frequently the skin and the GI
tract, followed by the respiratory tract [8,21]. GI symptoms include oral and perioral swelling,
dysphagia, and food impaction (impaired esophageal motility) [22], vomiting, regurgitation, dyspepsia,
early satiety and food refusal, failure to thrive [23], diarrhea (with or without malabsorption or
protein loss due to enteropathy), rectal bleeding [24], abdominal pain, severe colic [25], and persistent
constipation [26]. However, the clinical diagnosis is sometimes difficult, as signs/symptoms such as
regurgitation and colicky crying may also occur in more than 50% of healthy infants [15]. Thus, it is
important to make a correct CMA diagnosis to avoid unnecessary exclusion diets.
There are currently no laboratory tests available that can accurately and specifically diagnose
GI-CMA mainly because of the lack of a reliable test for non-IgE reactions. Skin prick testing and
allergen-specific IgE measurements only concur with IgE-mediated allergy. However, children with GI
manifestations of CMA are more likely to have a non-IgE mechanism, compared to patients with skin
manifestations; thus, a negative allergy test result does not exclude CMA [27,28]. In most cases, an oral
challenge test is necessary in order to confirm an adverse reaction to CM protein (CMP) [29]. At present,
the avoidance of CMP is the only management option for relieving or reducing the symptoms of
CMA [7,8]. In infants with CMA, extensive hydrolyzed or elementary formula in non-breast-fed infants
should be considered according to the severity of reactions [30–32]. In breast-fed infants, CM avoidance
in maternal diet may reduce infant symptoms related to CMA, as in severe colicky behavior. Tolerance
to CMP is often acquired in the first years of life [8]; hence, re-evaluation and reintroduction of CMP
should be considered after 2, 6, or 12 months of diet, according to initial manifestations and allergy
tests, in order to avoid a prolonged unnecessary diet [33].
In 2012, Iacovou et al. assessed the effect of a CMP elimination diet on colicky symptoms in a
systematic review [34]. Based on the results of eleven randomized controlled trials (RCTs), considered
of good quality, evaluating the effect of extensively hydrolyzed formulas or amino-acid-based formulas,
and of two previous separate reviews [35,36], breast-fed colic infants seemed to benefit from a maternal
low-allergen diet and formula-fed infants from the use of hydrolyzed formulas.
However, as data on reintroduction of CMP is missing in most of these studies, Lucassen et al.
have drawn different conclusions [35]. In another systematic review [37], the authors found no
conclusive evidence on the effectiveness of CMP exclusion on infant colic. Thus, the association of
infant colic with CMA is far from unambiguous and needs to be further investigated.
The role of crying and pain due to CMA in infants with regurgitation and gastroesophageal
reflux (GER) is also a controversial issue. Persisting regurgitation could be a nonspecific symptom of
CMA in infants; irritability, crying, pain, sleep and feeding disturbance, and respiratory symptoms
may occur both in CMA and primary and secondary (to CMA) GER [38]. CMA has been reported
in up to half of infants presenting with persisting GER [39,40]. In a proportion of cases, GER is
not only CMA-associated but also CMA-induced. Suspicion of CMA increases, especially in atopic
families, as well as if the children present symptoms involving more than one organ system [23,39,41].
Other manifestations of CMA, like atopic dermatitis, rectal bleeding, or signs of malabsorption
(such as diarrhea and failure to thrive), may reinforce the diagnosis, but are not necessarily present.
Allergy testing (specific IgE or a positive skin prick test) are positive in only 30–40% of infants with
CMA proven by a double-blind placebo-controlled challenge [28,42]. A typical pH-monitoring pattern,
characterized by a progressive, slow decrease in esophageal pH between feedings, has been suggested
by some authors, but not confirmed by others. As a consequence, if CMA is suspected, an elimination
diet for 2–4 weeks is the recommended intervention and an oral challenge should be scheduled in
“responder” infants to prove the diagnosis and, later, to identify the ones who acquire tolerance to
CMP. Forty years ago, Buisseret reported the presence of vomiting, colic, difficult feeding in infants,
growth retardation, psychological disturbance, and diarrhea in 79 children with CMA [33,43].
Nutrients 2018, 10, 1716 4 of 15

Later, the association between CMA and GER was reported in 15–42% of infants with symptoms
suggestive of both conditions [26,38,40,44–48]. Enteropathy was found in 20% of recurrent vomiting
infants [49].
The intestinal permeability test resulted >95% accurate in identifying CMA in 25 chronic vomiting
infants [44]. However, intestinal permeability studies are not easily performed in most hospitals,
are unspecific for CMA, and are of limited sensitivity in cases without enteropathy [50].
Several studies demonstrated that 2–100% of infants with GER symptoms who were not
responsive to reflux treatment had clinical improvement on a CM-free diet and relapsed on oral
challenge [38,51–54]. In 19 infants with irritability and vomiting attributed to GER (with esophagitis
in 9) that persisted despite extensive hydrolyzed formula and antireflux medications, symptoms
remitted in all patients within two weeks of starting aminoacid formula. After 2–12 months,
a double-blind placebo-controlled challenge (DBPCC) showed that 12 infants were still intolerant to
other formulas [55].
Common allergic tests and the family or patient’s medical history of allergy were not always
positive and not highly predictive of response to a CM-free diet (CMFD). CMA-related GER seems
limited to the very young age groups. In older children, and mainly where a family history of allergy
is present, CMA symptoms are likely to evolve in cutaneous (atopic dermatitis), respiratory (wheezing,
asthma, rhinitis), or lower motility disturbance (constipation) [56].
CM protein and Beta-lactoglobulin IgG antibodies have been proposed to differentiate patients
with CMA–GER from GER unrelated to CMA, but with conflicting results [38]. Bradygastria and
tachygastria were found to be more frequent in patients with CMA than in GER or normal children [53].
In CMA, gastric dysrhythmia may cause delayed gastric emptying with vomiting and pain [57] and
increased of nonacid GER [58].
The prevalence of CMA is difficult to determine because most of the affected infants have negative
(or non-IgE) allergic tests. Conversely, data on the efficacy of a CM elimination diet are limited by
physiological improvement (with time), often lack of oral food challenge, to confirm the diagnosis
and effect of hydrolyzed formulas in gastric emptying. The National Institute for Health and Care
Excellence (NICE) guidelines on GER suggest that the likelihood of CMA is increased in presence of
regurgitation associated with chronic diarrhea, bloody stools, other atopic manifestations (i.e., eczema),
or positive family history for allergy [59].
In the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)
guidelines on allergy, [8] the diagnosis of CMA is likely if regurgitations are frequent and other
unexplained symptoms involving at least two different systems are present. The diagnosis of CMA
needs to be confirmed or excluded with an elimination diet, lasting 2–4 weeks, followed by food
challenge. In the recent review of Vandenplas, the authors proposed a new clinical score (CoMISS) to
identify infants with regurgitation and associated CM symptoms. However, this clinical score has not
as yet been validated [60].
CMA was first suggested as a cause of constipation in 1978 [43]. In an open study published
in 1995, Iacono et al. [61] reported that 21 (78%) out of 27 children affected by chronic constipation
improved after a CMP elimination diet. These early findings were later confirmed by prospective
studies, although different response rates were identified by other authors [2,26,45,62–65] and the
causal association between constipation and food allergy is not universally accepted [66,67].
The cause of constipation induced by CMA could be the result of increased resting anal sphincter
pressure and an abnormal relaxation of the anal canal related to the presence of allergic inflammation
of the rectal mucosa (characterized by an increased eosinophil and mast cell infiltration at rectal
biopsy) [63]. Both the inflammatory reaction and the motility abnormalities disappear after a CMP
elimination diet [63] It has been also suggested that abdominal and defecation pain in CMA-associated
constipation might be caused by visceral allodynia, which is characterised by an abnormal perception of
physiological stimuli, such as intestinal distention and peristalsis [68]. However, the pathophysiology
for the association between CMA and constipation is still being debated [69,70].
Nutrients 2018, 10, 1716 5 of 15

4. Functional Abdominal Pain/Irritable Bowel Syndrome

FAPDs [20] define a group of FGIDs with pain as the driving symptom. Within this group,
four subgroups have been defined: Irritable bowel syndrome (IBS), functional dyspepsia, functional
abdominal pain-not otherwise specified (FAP-NOS), and abdominal migraine [71] with the first three
diagnostic categories being more prevalent than the latter.
IBS is the most common FAPD, with most of the studies worldwide showing that 4–7% of all
school children qualify for this diagnosis [72–78].
There has been longstanding interest regarding the possible role of food allergies in IBS, but data
supporting this association are limited. Nevertheless, with the elevated prevalence of food allergies and
FGIDs, it is likely that patients might have allergies or hypersensitivity without a causal relationship in
all cases [9]. Although diet has traditionally been assigned a relatively minor role in the pathogenesis
of IBS, 50% of patients with IBS report postprandial exacerbations of symptoms, either as a direct or
deferred reaction [79–81]. However, a CM-free diet may ameliorate symptoms that are not exclusively
related to the absence of CM protein, but through the absence of lactose (hence decreasing fermentation,
distension, bloating, and diarrhea), reduced fat, and different protein source or size (accelerating gastric
emptying), all mechanisms that do not involve allergic or immune-mediated responses. However,
in some cases, the perception of the patients that CM triggers (and its elimination relieves) symptoms
is suggestive of CMA. As IgE-based allergy tests are often negative, the real prevalence of CMA is
unclear even after performing an oral challenge, as the reintroduction of nutrients may re-exacerbate
symptoms independently of the mechanism.
In the overall population, food allergies are reported in 12% of children, whereas the true prevalence
is only 3% [7]. Among patients with FAP/IBS, a similar overestimation of food allergies and intolerances
can be observed. The majority of patients with IBS/FAPDs develop symptoms after eating [82],
amplifying the idea that certain foods trigger their symptoms. Traditionally, clinical experience indicates
that families of children with FAP/IBS have come to the consultation suspecting milk intolerances
or allergies in their child. In 2004, Kokkonen et al. [83], conducted a population study in Finland
and almost half of the mothers with children ages 10 to 11 years experiencing frequent GI complaints
reported that these symptoms were related to milk, and most of them avoided mild products. However,
only 14% of those with GI symptoms were found to have CMA or lactose intolerance. Thus, two-thirds
of the children who avoided milk did not have CMA or lactose intolerance. In 2011, Gijsbers et al. [84]
conducted a study of 220 children with FAP (4–16 years old) and described that 20% of children
reported food intolerances, but only 2.3% of them had a confirmed food allergy. In an Italian study,
Grazioli et al. [85], showed that 70% of children (mean age of 4 years old) reported IBS symptoms with
meals, but in only 17% of these children could a food allergy be diagnosed. These data suggest that a
food allergy/intolerance can exist in conjunction with FAP/IBS, but it is unlikely the sole source of the
symptoms [86].
In functional dyspepsia, 10 atopic children showed a significant different pattern of gastric motility
(at electrogastrography) during oral challenge with CMP compared to 9 normal controls. Early-onset
neuroimmune interactions were associated with rapid disturbance of gastric myoelectrical activity and
dyspeptic symptoms [87].
Therefore, the diagnosis of either CMA or FAPDs and distinction between them is challenging
because of nonspecific and overlapping symptoms. CMA may be associated with FGIDs or may
manifest symptoms mimicking FGIDs. The GI symptoms associated with FAPs and IBS can also
manifest in cases of food allergies and intolerances. Since it is not possible to exclude conditions under
which both pathologies coexist, elucidating the pathogenesis and pathophysiology behind the patient’s
symptoms may be challenging [88], especially in non-IgE mediated reactions.

5. Cow’s Milk Allergy and Functional Gastrointestinal Disorders: Focus on Pathogenesis

In non-IgE CMA, there is evidence of pronounced T-cell-mediated inflammatory reactions,
causing increased gut permeability, which in turn allows a further activation of antigen-specific T-cells
Nutrients 2018, 10, 1716 6 of 15
Nutrients 2018, 10, x FOR PEER REVIEW 6 of 16

which is released
and subsequent during digestion
proinflammatory from the
cytokine A1 variant
production. Inof β-casein,
humans, butisnot
there from the
emerging A2 variant.
evidence for theIt
appears that peptide BCM-7 induces T-cell-mediated immune response and alterations to gut
proinflammatory role of A-1 β casein, probably mediated by the µ-opioid peptide BMC-7, which is
motility and transit
released during time from
digestion [13]. the
However,
A1 variant theofexact pathogenetic
β-casein, but not from mechanisms of non-IgE
the A2 variant. GI food
It appears that
allergies are still not fully known [89]. Similarly, the pathophysiology of FGIDs [16] is still not
peptide BCM-7 induces T-cell-mediated immune response and alterations to gut motility and transit
completely elucidated
time [13]. However, the[90].
exact pathogenetic mechanisms of non-IgE GI food allergies are still not fully
knownThe[89].
new definition
Similarly, theapproved by the Rome
pathophysiology of FGIDs IV [16]
committee and
is still not reflective elucidated
completely of current [90].
scientific
knowledge state that “FGIDs are the result of any combination of: Motility disturbance, visceral
The new definition approved by the Rome IV committee and reflective of current scientific
hypersensitivity,
knowledge statealtered mucosal are
that “FGIDs and the
immuneresultfunction,
of anyaltered gut microbiota,
combination and altered
of: Motility central
disturbance,
nervous hypersensitivity,
visceral system processing” [91].mucosal and immune function, altered gut microbiota, and altered
altered
Clearly,
central nervous thesystem
pathophysiology
processing” [91].of FGIDs is multifactorial (Figure 1). Genetic predisposition,
impaired
Clearly,pain regulatory systems,
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is multifactorial tissue1).damage,
(Figure intestinal distension),
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structure and/or function of organs and tissues (physical component), but also with illness, ofa
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patient’s
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tissues (physical unwell,
component), butsuffering
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a patient’s subjectivecomponent). Both
sense of feeling
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unwell, suffering experiences
disability may influence
(psychological an individual’s
component). susceptibility
Both genetics and earlyto copying
life style may
experiences and
FGIDs [92].
influence an individual’s susceptibility to copying style and FGIDs [92].

Figure
Figure 1.
1. The
The pathophysiology
pathophysiology of
of functional
functional gastrointestinal
gastrointestinal disorders (FGIDs) is
disorders (FGIDs) is multifactorial.
multifactorial.

Early
Early inin life,
life, the
the intestine
intestine is
is characterized
characterized byby an
an immature
immature immune
immune system,
system, altered
altered intestinal
intestinal
permeability,and
permeability, anda delicate
a delicate temporal
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with complex with complex
interactions
interactions
with the hostwith the host
[93,94]. [93,94].
Noxious Noxious
stimuli stimuli
in early in early
stages maystages
lead tomay the lead to the development
development of long-term of
long-term gastrointestinal
gastrointestinal hyperalgesia
hyperalgesia through various through various putative
putative mechanisms, includingmechanisms,
sensitization of including
primary
sensitization of neurons,
sensory or spinal primary altered
sensorystress
or spinal neurons,
response, and/or altered
impairedstress response,
descending and/orcontrol
inhibitory impaired
[95].
descending inhibitory is
GI inflammation control [95]. a risk factor for the development of FAPDs. It has been shown
considered
GI inflammation
that the development of is CMP-related
considered a allergic
risk factor for the development
proctocolitis [2] in the firstofmonths
FAPDs.ofItlifehasmight
been trigger
shown
that the development of CMP-related allergic proctocolitis [2] in the first months
persistent digestive symptoms, particularly IBS. Other sources of inflammation, such as infectious of life might
trigger persistent
gastroenteritis, may digestive symptoms,
also trigger particularly IBS.
FGIDs (postinfectious Otherparticularly
FAPDs, sources of IBS),
inflammation,
which cansuch as
last for
infectious
months to gastroenteritis, may also trigger
several years [41,42,96–99]. FGIDs (postinfectious
GI inflammation may also FAPDs, particularly
lead to visceral IBS), which
hypersensitivity
can last increased
through for months to several
mucosal yearspermeability
membrane [41,42,96–99]. to GI inflammation
antigens mayofalso
via alteration tightlead to visceral
junctions [100],
hypersensitivity through increased mucosal membrane permeability to antigens via alteration of
tight junctions [100], increased cytokines release [101], altered mucosal immune function,
Nutrients 2018, 10, 1716 7 of 15

increased cytokines release [101], altered mucosal immune function, microbiota [102], and receptor
sensitivity in the gut mucosa and myenteric plexus. Thus, visceral hyperalgesia may result from the
interaction of multiple factors, such as early adverse life events, sensitizing biological (distension,
inflammation due to infection or allergy, and motility disorders) and psychosocial factors, including
stressful events superimposed on a background of genetic predisposition [20]. Histological findings
associated with CMA include the presence of cellular infiltrates and marked increase in eosinophils in
the mucosa and submucosa with involvement of even deeper muscular layers in some cases [103,104].
Studies have linked the presence of T helper 2-associated eosinophilic inflammatory response to
GI allergic hypersensitivity and gastric dysmotility [105,106]. Eosinophil granule major basic protein
(MBP) decreases epithelial colonic barrier function [107]. Increased intestinal permeability has been
associated with both CMA and the pathogenesis of FGIDs [108]. A study [109] has shown higher
colonic permeability and GI inflammation in children with functional abdominal pain and IBS than in
healthy controls. It is likely that in patients with CMA, the detrimental effect of cellular infiltration
and their products on visceral nerve fibers is facilitated by the increased permeability. Sensitization of
the corresponding spinal segments may result in further amplification of afferent input. The combined
effect of these factors may explain the presence of short- and long-term alterations in sensation and
motor function that was found in this study.
The mechanisms of immune responses to specific CMP in GI and non-IgE CMA are likely to be
multiple, with more than one pathway involved [89]. Although few studies have been conducted on
the role of diet in IBS, recent research has suggested that an allergy or hypersensitivity to certain foods
may prompt the onset of and/or increase the severity of symptoms through immune activation [80].
Food allergy, traditionally denoted by an activation of immunoglobulin (Ig) E-mediated antibodies
to a food protein, has not been linked convincingly to IBS pathogenesis, although patients with
IBS have been shown to have a higher incidence of atopy [110–112]. Others have suggested a
role for IgG-mediated immune reactions. Two studies, conducted on adult patients (>18 years),
have demonstrated that when patients with IBS were given an exclusion diet to avoid foods that
were shown to promote elevated IgG antibodies (such as milk, eggs, cheese, wheat, rice, potatoes,
chicken, beef, pork, lamb, soya bean, fish, shrimps, yeast, tomatoes, and peanuts), a significant
decline in symptoms and a corresponding improvement in rectal function were reported [113,114].
Another 12-week study conducted on adult patients, who excluded specific IgG-associated foods,
resulted in a significant decrease in abdominal pain, abdominal distension, and diarrhea in patients
with IBS with diarrhea (IBS-D), compared to a healthy control group [115]. However, doubt remains
about the role of IgG in IBS. Zuo and colleagues found no significant relationship between IgG
antibodies and symptom intensity [116], and studies demonstrating positive results have been criticized
on the basis of study populations [117]. Thus, further studies on the relevance of IgG antibodies to IBS
symptoms are required to confirm a tentative link [80].

6. Cow’s Milk Allergy as Risk Factor for Development of Functional Gastrointestinal Disorders
Early-life allergic inflammatory triggers, especially if prolonged, may induce later digestive
symptoms meeting the criteria for FGIDs, supporting the concept of “post-inflammatory” FGIDs.
To date, few epidemiological studies have evaluated the association between preschool CMA
and subsequent risk of developing FGIDs later in childhood (Table 1). Saps et al. [68] conducted
a hospital-based case-control study including 52 subjects between 4 and 18 years of age who were
diagnosed with cow’s milk protein hypersensitivity within the first year of life; fifty-three healthy
siblings of the same age were selected as controls. Twenty-three of the 52 study subjects (44.2%)
reported GI symptoms that included abdominal pain, constipation, or diarrhea, compared to 11 of
the 53 controls (20.75%) (OR 3.03, p = 0.01). Ten of the 52 subjects (19.2%) met the Rome III criteria
for diagnosis of FGIDs (7 IBS, 2 functional dyspepsia, 1 functional abdominal pain), whereas none in
the control group did. In this study, not all of the children diagnosed with CMA developed FGIDs:
Possible suggested explanations include the fact that the inflammatory response and severity of
Nutrients 2018, 10, 1716 8 of 15

CMA may vary from child to child. Another birth cohort study conducted in Sweden revealed an
association between early allergic disease, including CMA, and recurrent abdominal pain at 12 years
of age [118]. Both of these studies seem to confirm previous findings focusing on the association
between CMA in infancy and FGIDs in childhood [119]. Di Nardo et al. [120] conducted a prospective
controlled cohort study assessing the association between allergic proctocolitis and new-onset FGIDs.
Sixteen of the 160 subjects (10.0%) included in this study met the Rome III criteria for FGIDs. Among
the 80 patients with allergic proctocolitis, 12 (15.0%) reported FGIDs, compared to 4 of 80 (5.0%)
controls (p = 0.035). They then found evidence suggesting that an inflammatory/allergic self-limiting
disorder occurring early in life, such as allergic proctocolitis, is a risk factor for the development later
in life of digestive symptoms meeting the Rome III criteria for FGIDs. This was due especially to
IBS, which accounted for 66% of the new FGIDs in the allergic proctocolitis group. The prolonged
release of inflammatory mediators during an early, vulnerable period of neural plasticity may lead
to altered enteric nervous system hypersensitivity and dysmotility. Furthermore, they identified the
duration of hematochezia as the only variable significantly associated with the development of FGIDs.
This suggests that even in postinflammatory FGIDs, the severity of the acute trigger is a determinant
of persistent digestive sequelae. An epidemiological study conducted in Taiwan on 11,242 children
(age range: 7–18 years) with IBS evaluated the association among six early allergic conditions and
subsequent IBS in childhood [121]. This study confirmed the existence of an association between food
allergy and the subsequent development of IBS in childhood; food allergy was associated with the
shortest time interval (2.35 years, SD 14 1.8 years) before to IBS development.

Table 1. Characteristics of pediatric studies evaluating cow’s milk allergy (CMA) as risk factor for
functional gastrointestinal disorders (FGIDs).
FGIDs Disorder Study and Patients Characteristics Pathogenetic Mechanisms Results References
Case-control Effect of eosinophils infiltration 23/52 CMA diagnosis (44.2%) vs.
Abdominal pain, n = 52 subjects and their degranulation products 11/53 controls (20.75%) developed
[68]
constipation, diarrhea Age 4–18 yrs on visceral nerve fibers; increased gastrointestinal symptoms
Diagnosis of CMA in the first year of life intestinal permeability (OR = 3.03)
Functional population-based prospective Possible shift in features of cow ’s
constipation at cohort (Generation R Study) milk allergy over time with OR: 1.57; 95% CI: 1.04–2.36
24 months (defined n = 4651 different clinical manifestations (after adjustment for [119]
according to Parental report diagnosis of CMA later in life compared to major confounders)
Rome II criteria) in the first year of life symptoms at the outset
Low-grade inflammation in the
gut resulting in barrier defects in
Birth cohort study 2610 children with complete
Recurrent abdominal the gastrointestinal tract;
n = 4089 children follow-up, 9% (n = 237) reported [118]
pain at 12 years of age increased colonic permeability;
Parents-based questionnaires abdominal pain at 12 years
increased mast cell counts and
increased tryptase release
Case-control study Subsequent risk of IBS: 1.54 for
n = 11,242 children Food Allergy (FA)
Visceral hypersensitivity and
(age range: 7–18 years) (95% CI, 1.15–2.05)
Irritable bowel alterations in intestinal mobility;
vs. 44,968 age- and sex-matched FA was associated with the [121]
syndrome (IBS) mucosal inflammation;
control subjects; shortest time interval (2.35 years,
dysregulated microbiota
Physician-based diagnosis Standard Deviation
(Rome II criteria) 1.8 years) before IBS development
Abnormal mucosal milieu;
Among the 80 patients with
prospective controlled cohort Abnormal neuroimmune
allergic proctocolitis, 12 (15.0%)
n = 160 interactions via mast cell
IBS, functional reported FGIDs, compared with
10% FGIDs activation and nerve growth
abdominal pain, 4 of 80 (5.0%) controls (p = 0.035); [120]
parental questionnaire on pediatric factor release;
constipation the OR for FGIDs in allergic
gastrointestinal symptoms, sensitizing medical factors
proctocolitis group was
Rome III version (distention, inflammation, and
4.39 (95% CI, 1.03–18.68)
motility disorders)

A prospective cohort study, the Generation R Study, aiming to assess the association between the
introduction of food allergens and gluten in the first year of life and the prevalence of constipation
at 24 months of age [119], showed that a history of CMA in the first year of life was significantly
associated with functional constipation in childhood (OR: 1.57; 95% CI: 1.04–2.36). The same authors,
however, outlined the limitations of the parental report of a doctor-made CMA diagnosis and the use
of Rome II criteria to define the outcome of the studies. Both of these limitations preclude drawing
Nutrients 2018, 10, 1716 9 of 15

definitive conclusions. Therefore, data supporting the role of CMA as a risk factor for the development
of FGIDs in children are limited and more studies are needed to fill this research gap.

7. Conclusions
There has been interest regarding the possible role of food allergies in the pathogenesis of FAPDs,
but data supporting this association are limited. Multiple studies suggest that GI inflammation is a
risk factor for the development of FAPDs. Inflammation of the GI mucosa may be due to an infectious
episode, but also due to an allergic condition. Alterations in the brain–gut interactions are likely to
underlie symptoms of chronic abdominal pain and associated GI dysfunction.
The majority of patients with IBS/FAPDs develop symptoms after eating, amplifying the idea that
certain foods trigger their symptoms. CMA usually presents more than one organ manifestation and
may be considered in persistent FGIDs, particularly when other allergic features occur. CMA may be
associated with FGIDs or may manifest symptoms mimicking FGIDs. The GI symptoms associated with
FAPs and IBS can also manifest in cases of food allergies and intolerances (e.g., lactose intolerance).
These symptoms include nausea, abdominal pain, abdominal cramping, bloating, and diarrhea.
Since it is not possible to exclude conditions under which both pathologies coexist, elucidating the
pathogenesis and pathophysiology behind the patient’s symptoms may be challenging, especially in
non-IgE mediated reactions. Oral challenge and CMP reintroduction should be planned to clarify the
etiology and allow proper management.

Author Contributions: L.P., S.S., E.D.A. and M.S. contributed to conception and design of the review,
interpretation of data, drafting the article, and final approval of the version to be published; F.P., D.C., O.B.,
N.T., A.S., and Y.V. contributed to interpretation of data, drafting the article, and final approval of the version to
be published.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest. S.S. has participated as consultant and/or
speaker for Deca, IMS-Health, Danone, Nestlé, and Menarini; N.T. has participated as an advisory board member
and/or speaker for Nutricia and Danone. A.S. has participated as a clinical investigator, advisory board member,
consultant, and/or speaker for D.M.G, Valeas, Angelini, Miltè, Danone, Nestlé, Sucampo, and Menarini. Y.V. has
participated as a clinical investigator, advisory board member, consultant, and/or speaker for Abbott Nutrition,
Aspen, Biocodex, Danone, Nestle Health Science, Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition,
Merck, Phacobel, Rontis, United Pharmaceuticals, Wyeth, and Yakult M.S. has served as a Scientific Consultant
for Forest, Quintiles, Ardelyx, IM HealthScience, QOL Medical, and Sucampo. The funders had no role in the
design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in
the decision to publish the results.

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