nutrients

Review
Nutrition in Patients with Lactose Malabsorption, Celiac
Disease, and Related Disorders
Michele J. Alkalay
Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition,
University of Texas Southwestern, Dallas, TX 75235, USA; [email protected];
Tel.: +001-469-497-2505

Abstract: Lactose malabsorption (LM), celiac disease (CD), non-celiac gluten sensitivity (NCGS),
and irritable bowel syndrome (IBS) are conditions associated with food triggers, improvement after
withdrawal, treatment with dietary restriction, and subsequent nutritional detriments. LM occurs
when there is incomplete hydrolysis of lactose due to lactase deficiency and frequently produces
abdominal symptoms; therefore, it can cause lactose intolerance (LI). A lactose-restricted diet is
frequently recommended, although it can potentially lead to nutrient deficiencies. Furthermore,
lactose is an essential component of fermentable oligo-, di-, and monosaccharides and polyols
(FODMAPs) and is subsequently associated with intolerance to these compounds, especially in IBS.
LM commonly presents in CD. Nutritional deficits are common in CD and can continue even on a
gluten-free diet (GFD). Conditions triggered by gluten are known as gluten-related disorders (GRDs),
including CD, wheat allergy, and NCGS. IBS can also be associated with a gluten sensitivity. A GFD
is the treatment for CD, GRDs, and gluten sensitive IBS, although compliance with this restricted diet
can be difficult. Strict dietary therapies can have a negative effect on quality of life. This review aims
to provide an overview of the difficult nutritional elements of these disorders, which are critical for
medical providers to recognize when managing these patients.





 Keywords: lactose malabsorption; lactose intolerance; celiac disease; gluten-related disorders; FODMAPs;
Citation: Alkalay, M.J. Nutrition in nutrition; diet adherence; gluten-free diet; non-celiac gluten sensitivity; irritable bowel syndrome
Patients with Lactose Malabsorption,
Celiac Disease, and Related
Disorders. Nutrients 2022, 14, 2.
https://doi.org/10.3390/ 1. Introduction
nu14010002
Lactose malabsorption (LM), celiac disease (CD), non-celiac gluten sensitivity (NCGS),
Academic Editor: Usai-Satta Paolo and irritable bowel syndrome (IBS) are disorders characterized by the onset of symptoms
from ingestion of a particular food and by relief after its elimination from the diet. Con-
Received: 30 November 2021
sequently, patients with these disorders are placed on restricted diets. However, this can
Accepted: 19 December 2021
lead to significant nutritional deficiencies. Lactose is a disaccharide that comprises the
Published: 21 December 2021
monosaccharides glucose and galactose, the primary carbohydrate found in mammalian
Publisher’s Note: MDPI stays neutral milk [1]. LM is caused by the incomplete hydrolysis of lactose due to lactase deficiency, the
with regard to jurisdictional claims in reduced expression of lactase enzyme in the small intestine. LM may occur as a primary or
published maps and institutional affil- a secondary disorder due to other intestinal diseases. LM leads to lactose intolerance (LI),
iations. the occurrence of gastrointestinal symptoms post-ingestion of lactose. A lactose-restricted
diet is typically recommended for symptom relief, although it may lead to nutritional dis-
advantages with reduced calcium and vitamin intake. The frequency of LI varies according
to ethnicity and has been reported as high as almost 100% in Southeast Asia, approximately
Copyright: © 2021 by the author.
80% in Southern Europe, and <5% in Northern Europe [2]. Furthermore, lactose is an
Licensee MDPI, Basel, Switzerland.
essential element of fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs)
This article is an open access article
distributed under the terms and
and is subsequently correlated to the broader intolerance of the absorption of these short
conditions of the Creative Commons
chain carbohydrates. FODMAPs can cause digestive discomfort, which has been com-
Attribution (CC BY) license (https:// monly reported in IBS patients. A low FODMAPs diet has been shown to improve IBS
creativecommons.org/licenses/by/ symptoms in 50–86% of patients. However, this diet is very restricted and risks nutritional
4.0/). insufficiency and encourages disordered eating [3].

Nutrients 2022, 14, 2. https://doi.org/10.3390/nu14010002 https://www.mdpi.com/journal/nutrients

Nutrients 2022, 14, 2 2 of 17

Furthermore, CD is a chronic autoimmune intestinal disorder triggered by gluten

consumption in genetically predisposed people, affecting 1% of the general population
worldwide. The ingestion of gluten in CD causes an inflammatory response with resultant
damage to the small intestine. LM occurs in CD due to the loss of lactase enzyme on the
damaged small intestinal villi [4]. LI occurs frequently in CD, estimated to be 10% and
increasing up to 50% in the presence of malabsorption [5]. Nutritional deficiencies occur
frequently in CD. During early diagnosis, at least one nutrient deficiency has been reported
in almost 90% of untreated adult celiac patients [6]. Nutrient deficits can persist despite
being placed on a gluten-free diet (GFD) [7,8]. Diseases caused by ingestion of gluten are
called gluten-related disorders (GRDs), which include CD, wheat allergy, and NCGS. GRDs
have an estimated 5% global prevalence [9]. In addition, approximately one-third of IBS
patients present with gluten sensitivity [10]. A GFD is the only effective treatment for CD,
GRDs, and IBS gluten sensitivity; however, adherence to the strict GFD can be problematic.
Furthermore, the restricted diet used to treat individuals with LM, GRDs, and IBS can
negatively impact their daily lives. Effects of nutrition on the health of patients with these
conditions are challenging and are important for health-care providers to recognize when
managing these diseases.
The aim of this review is to shed light on the nutritional aspects of LI, CD, NCGS, and
IBS with an overview of these diseases and emphasis on practical issues in the management
of patients. Treatment of these conditions involves dietary restriction; however, it is crucial
for clinicians to be aware that restricted diets can cause nutrient deficits, affect quality of
life, and pose difficulties with compliance. Disorders of lactose, gluten, and irritable bowel
currently present with evolving diagnostic measures, significant nutritional disadvantages,
advancing methods in measuring diet adherence, and rising challenges in the long-term
medical care of these patients.

2. Lactose Malabsorption and Intolerance

Absorption of lactose requires lactase enzyme activity in the small intestinal brush
border to split the two bound monosaccharides. Lactase is found in the small intestine
on the tips of the villi [1]. When there is low lactase enzyme activity, lactose absorption
is consequently reduced. LM is the imbalance between the amount of lactose ingested
and the ability for lactase to hydrolyze the disaccharide. If lactase enzymes are absent
or deficient, then unabsorbed lactose in the small intestine produces an osmotic load
with resultant secretion of fluid and electrolytes into the lumen. This also leads to the
fermentation of undigested lactose by the colonic microbiome, triggering the release of
hydrogen, carbon dioxide, and methane. The increase in osmotic load and gas production
in LM can cause gastrointestinal complaints [11]. LI is the clinical syndrome after lactose
ingestion, including one or more of the following symptoms: abdominal pain, diarrhea,
nausea, flatulence, and/or abdominal bloating. Primary lactase deficiency is the absence
of lactase and is the most common cause of LI. Secondary lactase deficiency is due to
small bowel injury, such as gastroenteritis, CD, Crohn’s disease, or chemotherapy [12].
As much as 70% of the world’s population have been estimated to have primary lactase
deficiency [13]. The amount of lactose consumed that causes symptoms is variable from one
individual to another and is dependent on several factors, including the amount of lactose
consumed, lactase expression, intestinal transit time, small bowel bacterial overgrowth,
and the composition of the enteric microbiome [14].
As LI is a clinical condition with symptoms post-ingestion of lactose, it can be di-
agnosed clinically and/or by various other methods. The hydrogen breath test (HBT)
involves the oral administration of lactose (usually 25 grams) and the measurement of
the quantity of exhaled hydrogen (recollected every 30 min after oral administration of
lactose). The HBT is positive when the hydrogen level is at least 20 parts per million greater
than the baseline value in the exhaled air. This study is considered the gold standard for
diagnosis of LI, with high sensitivity and specificity [15]. Testing lactase enzyme activity
in mucosal duodenal biopsies is considered the reference standard for lactase deficiency;
Nutrients 2022, 14, 2 3 of 17

however, it has limitations in the expression of lactase enzyme on the small intestinal villi
and the invasiveness of the test [16]. Genetic tests may be helpful in identifying groups of
people with lactase non-persistence [17–19]; however, genes and biopsies measuring lactase
enzyme do not address the clinical symptoms that lactose intolerant patients experience.
The treatment for LM and LI is a lactose-restricted diet, reducing the dietetic amount
of lactose until clinical symptoms disappear. Most lactose intolerant individuals can
tolerate less than 12 grams of lactose per single dose ingested in the diet [20,21]. However,
many countries do not have laws regulating commercialization of lactose-free products,
which poses the problem of mislabeling and causation of symptoms in lactose intolerant
individuals [22]. Furthermore, lactase enzyme replacement may be helpful in patients with
isolated LI when ingesting dairy products. Exogenous lactase breaks down lactose into
glucose and galactose to enable better absorption [23]. However, the lactase enzyme may
not completely relieve symptoms due to the incomplete digestion of lactose; therefore,
enzyme supplementation should not be the sole treatment for LI. Lactase enzyme should
rather be supplementary to dietary restriction [24]. Furthermore, studies suggest that
altering the intestinal microbiota by probiotic supplementation in lactose intolerant patients
can alleviate symptoms. A clinical trial involving probiotics (DDS-1 strain of lactobacillus)
in LI patients versus a placebo discovered that it decreased symptoms, including diarrhea,
abdominal pain, and emesis [25]. Another study used a mixture of probiotics, Bio-25,
lactase-producing bacteria that showed significant alleviation of gastrointestinal complaints
associated with LI; however, there was no reduction in hydrogen excretion to HBT of these
patients [26]. Systematic reviews have shown that probiotics have an overall positive effect
on LI [27,28]. As probiotics have no side effects and improve clinical symptoms, they
should be considered for the treatment of LI patients. Prebiotics have also been considered
in the treatment of LI in a few studies; however, further analyses are needed to investigate
the benefits in clinical trials that gather more evidence [29–31].

3. Lactose-Restricted Diet and Nutritional Disadvantages

Restricting lactose in the diet may reduce gastrointestinal complaints, although it can
predispose patients to nutritional risks. Dairy products are valuable sources of calcium,
Vitamin D, protein, and other minerals, including, magnesium, potassium, phosphorus,
and zinc. They can have positive effects on bone health, such as bone remodeling [32].
Although LM does not cause calcium malabsorption, dietary avoidance of milk products
can lead to sub-optimal bone mineralization [33].
During childhood, dairy products have been shown to be important for bone growth
and bone health. There is evidence of significant advances in height, body weight, bone
mineral content, and bone mineral density in children who consume dairy products [34–36].
Children who avoid milk products have been documented to ingest less than the recom-
mended amounts of calcium needed for normal bone growth and bone mineralization [37].
Avoiding milk has been linked to a lower bone mineral content and increased fracture risk
in children [38]. It is important to note that the association between LI and osteoporosis
remains unclear [39]. Some studies have shown a positive relationship between LI, low
bone mineral density, and osteoporosis [40,41]. Other studies have shown no significant
association between LI and bone mineral density [42,43].
Further studies are needed to account for LM and long-term health outcomes. How-
ever, if dairy products are eliminated, it is recommended that calcium intake from other
foods be increased or that calcium supplements be provided. Individuals with LI should
restrict lactose instead of avoiding lactose, so as not to lose the nutritional value of dairy
products in the diet. Therefore, consideration should be given to a temporary lactose-free
diet with the goal of reducing symptoms, followed by a gradual introduction of dairy
products as tolerated [44].
Nutrients 2022, 14, 2 4 of 17

4. Celiac Disease
CD is a common autoimmune enteropathy in genetically susceptible individuals,
precipitated by the consumption of gluten, the protein found in wheat, rye, and barley.
The immune-mediated reaction causes villous atrophy of the small intestine, specifically
in the duodenum, with subsequent malabsorption. There is complete resolution of CD
on a GFD; however, the duodenal inflammation relapses when gluten is reintroduced.
Regarding genetic susceptibility, 99% of celiac patients carry haplotype HLA DR3-DQ2
and/or DR4-DQ8, in comparison to approximately 40% of the general population [45]. CD
is usually detected by serologic testing of celiac specific antibodies, tissue transglutaminase
(TTG), endomysial antibody (EMA), and deamidated gliadin peptide (DGP), and the
diagnosis is confirmed by endoscopic duodenal mucosal biopsies when villous atrophy
is present [46,47]. Though antigliadin antibodies (AGAs) are prevalent in celiac patients,
they are not specific and have been replaced by the more specific antibodies (TTG, EMA,
and DGP) to detect CD. Small intestinal biopsy historically has been the gold standard for
diagnosis; however, a serology-based diagnosis for CD with the omission of endoscopic
biopsies has been an accepted approach in selected pediatric cases [48,49]. The treatment
for CD is a life-long GFD; the small intestinal damage recurs when gluten is re-ingested.

5. Nutritional Deficiencies in Celiac Disease

In untreated CD, the small intestinal villi atrophy on the apical enterocyte brush
border where lactase normally resides. This causes a partial deficiency in lactase enzyme,
with resultant LM and secondary LI. Lactase deficiency has been shown to be common
amongst celiac patients, and LI can be the sole initial manifestation of undiagnosed CD.
There is evidence that 24% of patients with LI determined by HBT have CD, diagnosed by
positive serology and biopsy [5]. LI symptoms can overlap with those of CD, including
abdominal pain, bloating, and diarrhea. Not only do LI and CD share common clinical
presentations, they also have a response to food withdrawal [4,21]. In fact, clinicians tend
to over-diagnose patients with LI and can possibly miss the diagnosis of CD, especially
in the pediatric population [50–52]. Once being placed on a GFD for CD treatment and
following the restoration of the mucosa, most patients can tolerate lactose one to two
months later [12]. HBT has been suggested for monitoring mucosal healing in treated
CD individuals [53]. However, LI has been frequently reported in CD patients who are
considered unresponsive to a GFD. Disaccharidase deficiency, specifically lactase, has been
notable in these individuals when biopsied. Nonresponsive celiac disease (NRCD) has
been described as occurring in approximately 20% of celiac patients. LI is a common cause,
reported in up to 8% of NRCD patients [54]. These individuals may require a long-term
lactose-restricted diet.
Due to the damage of the small intestinal villi that are important in the absorption
of micro- and macronutrients, the consequence of CD is predominantly malnutrition
secondary to malabsorption. Pediatric patients can present with failure to thrive, due to
chronic malabsorption. As there is an increased gut permeability from the autoimmune
inflammatory response in CD, this can lead to symptoms of diarrhea, steatorrhea, weight
loss, anemia, and even osteopenia [46]. CD is often a cause of low bone density, with an
increased fracture risk in celiac patients. This is due to impaired absorption of vitamin D
and calcium, likely resulting in hyperparathyroidism. During initial presentation of CD,
vitamin D levels are often lower and parathyroid levels are often higher than in healthy
controls [55–57]. Reduced bone mineral density, including osteopenia and osteoporosis,
occur in approximately 70% of celiac patients at diagnosis [58]. Common nutritional
deficiencies in newly diagnosed and untreated CD are iron, B12, calcium, Vitamin D, zinc,
and copper [8,59]. In most patients diagnosed with CD, a strict GFD should result in
complete resolution of their symptoms of the disease. However, despite a GFD, nutritional
deficiencies can persist in approximately 30% of CD patients [60–63].
Nutrients 2022, 14, 2 5 of 17

6. Irritable Bowel Syndrome

IBS is a functional bowel disorder characterized by chronic symptoms of abdominal
pain, changes in bowel habits, and bloating without a known organic cause. IBS affects
greater than 5% of the general population and is the most prevalent of functional gas-
trointestinal disorders. Diagnosis for IBS patients is based on their clinical assessment
using the Rome IV criteria (i.e., recurrent abdominal pain associated with defecation or
a change in bowel habits with symptom onset at least 6 months prior to diagnosis and
present for the last 3 months). IBS is classified into three main subtypes according to
the bowel pattern: IBS-C (constipation-predominant), IBS-D (diarrhea-predominant), and
IBS-M (mixed bowel habits) [64]. The exact pathophysiology of IBS is not well understood,
although proposed mechanisms include alterations in visceral hypersensitivity, disordered
gut-brain interaction, intestinal microbiome, enteric sensory and motor dysfunction, altered
pain processing, and immune dysregulation [65]. Diet plays a key role in IBS and has
been reported to be a symptom trigger in approximately 80% of patients. Individuals with
more severe IBS identify a greater number of food items as stimuli for their gastrointestinal
symptoms [66]. Subsequently, there is evidence for the utilization of dietary therapies
in IBS. Traditional dietary advice of healthy eating habits has been implemented to treat
IBS patients, and incorporates lifestyle management, eating regular meals, lowering fat
consumption, adequate liquid intake, and assessing the intake of fiber, alcohol, caffeine,
and spicy foods [67]. Two specific IBS dietary interventions that have been studied in
several randomized controlled trials are low FODMAPs diets and the GFD [68].

7. Nutritional Aspects of Irritable Bowel Syndrome, FODMAPs, and Gluten Sensitivity

Patients can have an intolerance to FODMAPs, which includes lactose, with symptom
improvement when placed on a low FODMAPs diet [69–71]. FODMAPs are short-chained
carbohydrates that are not well absorbed by the gastrointestinal tract, due to their in-
creased osmotic load and resultant excess gas production from bacterial fermentation. A
low FODMAPs diet is a 2-phase intervention, with strict avoidance of short-chain carbo-
hydrates followed by reintroduction of specific tolerated FODMAPs. Some studies show
an improvement in the quality of life in IBS patients on a low FODMAPs diet [71–73].
In contrast, other studies have shown a negative impact on quality of life due to strict
dietary restriction. A low FODMAPs diet may affect sleep patterns, energy, costliness,
and social functioning, with an increased risk of disordered eating behaviors [66,74,75].
Disordered eating patterns include skipping meals, binge eating, restricting certain foods,
or fasting, a deviation from the cultural standard of eating three meals a day. These
behaviors have been linked to orthorexia anorexia, an obsession focused on food choices,
planning, preparation, and consumption with the loss of pleasure when eating, affecting
an individual’s daily well-being [74].
Additional long-term studies assessing the quality of life in IBS patients when placed
on a low FODMAPs diet are necessary. It is important for healthcare providers to un-
derstand that any restrictive diet can lead to malnutrition. Certain nutrients are at risk
for depletion in a restricted FODMAPs diet, including fiber, calcium, protein, iron, and
Vitamin B12 [75,76]. Therefore, patients who are placed on a low FODMAPs diet should
be educated by a trained dietician to avoid nutritional depletion. Furthermore, there are
several studies that show the change in the gastrointestinal microbiota on a low FODMAPs
diet [77–80]; however, the exact implications on long-term health have yet to be discovered.
In addition to the intolerance of FODMAPs, many IBS patients suffer from gluten
sensitivity. Gluten has been reported to generate symptoms in up to 30% of individuals
with IBS [10]. Studies have demonstrated the improvement of IBS symptoms in individuals
who are on a GFD, such as constipation, abdominal pain, and especially diarrhea [81–83].
There is some evidence that small bowel permeability increases after a gluten challenge
in gluten sensitive IBS-D patients [81,84]. The exact mechanism is unclear and further
investigations with larger populations are needed to confirm this finding. In addition,
AGAs (non-specific antibodies prevalent in celiac patients) have been reported positive
Nutrients 2022, 14, 2 6 of 17

in IBS populations [83,85]. IBS patients with AGAs reported less diarrhea when placed
on a GFD than those patients without antibodies. This indicates the potential to predict
a clinical response to a GFD in IBS AGA-positive patients [83]. However, the AGA pos-
itivity of the general IBS population is unknown, and 7% of the general population has
AGA present [86]. The uncertain relevance of AGA testing in IBS warrants further studies.
Management of gluten sensitive IBS patients involves dietary therapy with a GFD. How-
ever, avoiding gluten in the diet can lead to micronutrient deficiency [87]. Despite being
exposed to some gluten, IBS gluten sensitive patients have shown clinical improvement
on a GFD [83]. Therefore, a gluten-reduced diet should be considered in lieu of a strict
GFD for IBS patients, potentially leading to symptom improvement and the avoidance of
nutritional complications [88].

8. Non-Celiac Gluten Sensitivity

NCGS is a GRD, a condition affected by the consumption of gluten. GRDs mainly
involve CD, NCGS, and wheat allergy. Sometimes referred to as non-celiac wheat sensitivity,
NCGS is recognized as a distinct clinical syndrome from IBS and other GRDs. These
patients present similarly to celiac patients who have no signs of intestinal damage [9,89].
NCGS is a condition characterized by symptoms related to the ingestion of gluten in
the absence of CD and wheat allergy. The diagnosis is often made by exclusion and
confirmed by improvement of symptoms after the removal of dietary gluten. Symptoms
can be gastrointestinal (bloating, abdominal pain, diarrhea, constipation, and nausea) or
extraintestinal (fatigue, headache, aphthous stomatitis, arthralgia, muscle pain, depression,
and reduced mental clarity). The re-introduction of gluten in the diet causes recurrence
of symptoms [89–92].
Regarding the genetics of NCGS, evidence reveals that there is no correlation be-
tween NCGS and the CD predisposing haplotypes, HLA-DQ2 and/or HLA-DQ8 [89,91].
The genetic background of NCGS has not yet been revealed. Furthermore, there are histo-
logic features in NCGS, including duodenal and colonic eosinophil infiltration [10], and
duodenal biopsies with Marsh 0 (normal) to I classification (infiltration of intraepithelial
lymphocytes (IELs)) without villous atrophy [91,93,94]. Potential predisposing factors
for NCGS are autoimmune and functional gastrointestinal disorders, female sex, neuro-
logical disorders, eating disorders, first-degree relatives with CD, and adverse reactions
to foods [95].
The pathophysiology of gluten sensitivity in non-celiac patients is not well understood.
NCGS potentially involves an innate immune response activated by gluten and other wheat
proteins. Wheat components other than gluten, such as FODMAPs and amylase-trypsin in-
hibitors, have been shown to trigger clinical manifestations of NCGS [95–97]. Upregulated
levels of toll-like receptor 2 and downregulated levels of the T-regulatory cell marker factor
forkhead box P3 have been found in intestinal biopsies of NCGS patients, in comparison to
CD patients and healthy controls [98]. Studies reveal an increased expression of transform-
ing growth factor α, interleukin 10, CD14, granulocyte-macrophage colony-stimulating
factor, C-X-C motif chemokine ligand 10, and lipopolysaccharide-binding protein in NGCS
patients [81,99,100]. However, the production of tumor necrosis factor and IL-17 in rectal
tissue of NCGS subjects suggests an adaptive immune response [101]. AGA positivity in
NCGS patients also supports the involvement of an adaptive immunopathology [90,91].
In addition to the activation of the innate and adaptive immune systems, recent evidence
suggests that the pathogenesis of NCGS involves alterations at the intestinal level (inflam-
mation, dysbiosis, and altered barrier function) and the translocation of microbial and
dietary products [95,102–104].
There are currently no diagnostic tests for gluten sensitivity in non-celiac patients. Due
to the absence of NCGS biomarkers, a double-blind placebo-controlled gluten challenge
is the only method to confirm the diagnosis [10]. This test requires providing the patient
with a blind administration of increasing doses of gluten and a placebo, while recording
the results. The procedure is complicated and, therefore, impractical for routine clinical
Nutrients 2022, 14, 2 7 of 17

practice. In addition, AGA has been proposed to serve as a potential marker for NCGS.
Studies on serologic testing in NCGS patients have revealed prevalent positive AGAs,
particularly immunoglobulin G anti-gliadin, with negative EMA, TTG, and DGP antibod-
ies [90]. However, AGA is not specific and is increased in both CD and gluten sensitive
IBS patients.
Interestingly, the prevalence of AGA positivity in NCGS patients has been reported as
being similar to that in individuals with gluten sensitive IBS [10,83,90,91]. Furthermore,
several biomarkers have been suggested for NCGS, such as T helper lymphocytes, mast
cells, cytokine levels, serum antibody levels, intraepithelial CD3+ T cells, evaluation of
eosinophils, RNA transcripts, and miRNA signatures [10,105–109]. However, these markers
are not specific for NCGS. Diagnosing NCGS without sensitive and specific markers can
be challenging.
Further complicating the diagnosis, NCGS can have overlapping symptoms with IBS
and other GRDs, specifically CD and wheat allergy. Obtaining a serum Immunoglobulin
E (IgE) antibody against wheat protein can help distinguish between wheat allergy and
gluten sensitivity. Wheat allergen specific IgE is not detected in NCGS. Furthermore, NCGS
patients do not express celiac-specific autoantibodies, distinguishing the two diagnoses [89].
On duodenal biopsy, both NCGS and CD may display an increased infiltration of IELs
(class I histologic Marsh classification); however, CD can only present with villous atrophy
(Marsh III classification) [110].
Additionally, distinguishing NCGS from gluten sensitive IBS can be complex. Neither
disorder has a well-known pathophysiology, making their differentiation more difficult. In
addition, NCGS and gluten sensitive IBS can share a similar clinical presentation. NCGS
patients commonly present with IBS symptoms, such as bowel habit changes, abdominal
pain, and bloating. Over 20% of patients with self-reported NCGS fulfill the IBS Rome
III criteria (i.e., abdominal pain or discomfort for at least 3 months, with onset at least
6 months prior in relation to defecation) [111]. The difference between these two conditions
is that NCGS patients self-report symptoms when ingesting gluten and identify it as a
symptom trigger. In contrast, IBS patients do not report gluten as a specific culprit for their
symptoms. However, wheat is commonly reported as a food intolerance in IBS patients.
Without sensitive markers, it can be difficult to set apart gluten sensitivity of non-celiac
patients from those with IBS. Three notable differences between NCGS and IBS are the
more frequent presence of extraintestinal symptoms in NCGS than in IBS, the absence of
IELs in endoscopic biopsies in IBS cases, and the reaction of NCGS patients solely to gluten
and not to other foods. Some NCGS patients continue to complain of symptoms despite
a strict GFD, and a low FODMAPs diet can potentially alleviate their symptoms [112]. A
GFD and a low FODMAPs diet can reduce symptoms in individuals with both IBS and
NCGS [10], again making it difficult to separate NCGS from IBS cases. Therefore, further
studies are needed to assess the relationship between GRDs and gluten sensitive IBS.
The treatment for gluten sensitivity is a GFD, together with the guidance and support
of a registered dietician [113]. Currently, therapeutic intervention for NGCS is life-long
avoidance of gluten. NCGS patients have been reported to have wheat as a trigger even
after 8 years on a strict GFD [114]. However, it is debated whether prolonged restriction
is necessary. Evidence reveals that NCGS patients have gluten tolerance thresholds [115].
Consideration should be given to a gluten rechallenge in NCGS after one year of following
a strict GFD, followed by a determination of the dose of gluten that is tolerable in each
patient [116]. Therefore, patients may require a gluten-reduced diet in NCGS.

9. The Gluten-Free Diet and Diet Adherence

The nutrient deficits observed in CD may be caused by the disease itself, with small
intestinal damage and/or the consequence of a GFD. Accumulation of heavy metals has
been reported in individuals on a GFD [117]. CD patients with over 2 years of good
compliance with a long-term GFD have shown micronutrient deficiency in up to 30% of
subjects for vitamin B12, 40% for iron, 20% for folic acid, 25% for Vitamin D, 40% for zinc
Nutrients 2022, 14, 2 8 of 17

oxide, 3.6% for calcium (in children), and 20% for magnesium (in children) [118]. If dietary
changes are inadequate in correcting these nutrient deficiencies, supplementation may
be necessary. Therefore, it is crucial for clinicians to continue to monitor for nutritional
deficiencies in CD patients and to provide access to a skilled dietician for these individuals.
Celiac patients should be differentiated from those who are non-celiac with gluten
sensitivity to identify the risk for complications of CD and to determine the necessary degree
and duration of adherence to a GFD. Unlike NCGS, CD has the comorbidities of increased
risk of osteoporosis, infertility, increased mortality, and certain types of malignancies [119].
Furthermore, there is evidence that NCGS patients eat differently than healthy individuals,
and consume less protein, carbohydrate, fiber, and polyunsaturated fatty acids. Therefore,
their diets should be also guided by a registered dietician to potentially correct and avoid
nutritional deficits [120].
With the growing awareness and increase in reported gluten sensitivity, many non-celiac
individuals are on a GFD, which can result in nutritional detriments. Studies find up to 5%
of the Western population follow a GFD, and 13% self-report gluten sensitivity [110,121,122].
Some studies have shown an increased risk of obesity and metabolic syndrome on a GFD,
although other studies have shown no associated risk of coronary heart disease on a GFD,
and possible prevention of diabetes [123–125]. In addition, an increase in body mass index
in children on a GFD has been observed, which may be due to improvement of nutrient
absorption in CD or to the consumption of starchy gluten-free replacement foods [126].
Many studies have shown that gluten-free products can have low nutritional value. Some
gluten-free products have been reported to have an increased total of saturated fat, higher
glycemic index, low protein, low fiber, and lower levels of micronutrients (Vitamin D, E, B12,
iron, magnesium, potassium, and sodium) [7,120,127,128]. Naturally gluten-free foods are
preferred over manufactured products, as natural foods have a higher nutritional value in
lipid composition, vitamin content, and energy. Leafy green vegetables, legumes, fish, and
meat are rich in iron and folic acid. Amaranth, quinoa, and buckwheat are healthy gluten-free
pseudocereals, alternatives to wheat, and good sources of protein, fiber, carbohydrates, and
polyunsaturated fatty acids. They are also rich in vitamins, such as folic acid, riboflavin,
Vitamin E and C [128].
Furthermore, the GFD changes the gut microbiome. In children, it has been reported
that CD patients have a decrease in lactobacilli and an increase in enterobacteria [129].
Studies have shown a depletion in the probiotic species (Lactobacillus and Bifidobacteria)
and improvement of pro-inflammatory bacteria of CD patients on a GFD. In addition,
NCGS patients show depletion of beneficial species (Bifidobacteria) and increasing pro-
inflammatory bacteria (Enterobactericeae and Escherichia coli) [130]. Further studies are
needed to determine the significance of the changes in the intestinal microbiota when
avoiding gluten.
Many individuals have trouble adhering to a GFD. Several factors have been reported
to affect adherence to a GFD in CD. Facilitators in complying with the strict GFD include
the understanding of the diet itself, membership of a CD advocacy group, the perception of
the ability to maintain compliance despite stress, mood changes, and travel [131], cognitive,
emotional, and socio-cultural influences, and regular follow-up with a dietician [132].
Another important determinant of adherence to a GFD in celiac patients is the presentation
of classical symptoms at diagnosis, such as diarrhea and weight loss [133]. However, the
factors of young age at diagnosis, adolescence, long duration of disease, non-academic
education, below-average income, and no gastroenterology follow-up have been shown to
be barriers to GFD adherence [134,135]. In addition, anemia and dermatitis herpetiformis
have indicated poor long-term compliance [133]. Furthermore, there are positive predictors
of long-term GFD compliance, including classical CD symptoms at diagnosis and upon
initial adherence to the diet. Although GFD adherence changes minimally over time, the
trend of change is improvement [133,135].
Approximately 40% of children with CD experience ongoing gluten exposure even
after starting a GFD [136]. In Europe, pediatric adherence to a GFD is approximately 50%,
Nutrients 2022, 14, 2 9 of 17

and unintentional contamination is common [137]. Pediatric GFD non-compliance has been
attributed to poor palatability, difficulties in dining outside the home, poor availability of
gluten-free products, and asymptomatic disease diagnosed by screening [138]. In addition,
pediatric patients with newly diagnosed CD have been found to have a lower quality of
life compared to healthy children and to report physical and emotional impairment, with
difficulties in school and social functioning [139]. Children require regular assessment
by an experienced dietician for nutritional needs, and continual clinical follow-up by a
pediatric gastroenterologist.
Gluten exposure is the most common cause of NRCD in adult patients, reported at a
prevalence rate of up to a 50%; however, it is difficult to distinguish between purposeful
versus accidental gluten exposure [140]. Up to two-thirds of adult patients claimed never to
have intentionally consumed gluten. Furthermore, they also expressed negative emotions
of isolation and frustration due to the restrictions of the GFD, especially with respect to
difficulties related to food labelling and eating away from home; however, these negative
emotions are notably experienced less often when a person is on a diet for more than five
years [141]. Noncompliance with the GFD is the leading cause of failure to respond in
patients with CD.
Non-adherence to the GFD increases the risk of morbidity and mortality, including
infertility, skeletal disorders, and malignancy in CD [8]. Therefore, counseling at the time
of celiac diagnosis and ongoing long-term medical follow-up are essential in the care of
CD patients.
The vital role of the dietician in CD is to provide proper instruction to patients on
how to follow a GFD. Patients who identify themselves as having poor food knowledge
are at a higher risk for noncompliance [142]. A qualified registered dietician educates
celiac patients on the GFD, evaluates for nutrient depletion, and supports nutritional
status at initial diagnosis and throughout the disease [143]. Similarly, an experienced
dietician is recommended when treating patients with a GFD in NCGS and gluten sensitive
IBS, and when placing IBS patients on a low FODMAPs diet [72]. A specialist dietician
is important in educating patients when implementing strict dietary therapies, to help
prevent nutritional deficiencies.
There are several methods to assess GFD adherence in patients. Clinicians can follow
celiac autoantibodies for normalization in monitoring response to a GFD, although serologic
tests can often take 6–24 months to decrease after gluten has been eliminated from the
diet [144]. In children, the measurement of the negative TTG antibody did not correlate
well with good compliance [145]. In addition, questionnaires have been developed to
measure GFD adherence. The Biagi score entails four fast and simple questions to monitor
GFD compliance that has been associated with both persistent villous atrophy and EMA
antibodies [146]. The validated Celiac Dietary Adherence Test (CDAT) is a standardized
evaluation of GFD adherence by a clinically relevant, easy survey [142,147]. The CDAT
can be used as a fast tool for screening for compliance with a GFD in patients with CD.
As compared to the CDAT, the Standardized Dietician Evaluation (SDE) score has been
found to correlate better with serologic and histologic findings [148]. Recent studies reveal
the measurement of gluten immunogenic peptide (GIP) in human samples to determine
gluten ingestion. Testing GIP in both urine and stool samples has been reported to detect
gluten consumption in celiac patients and was concordant with over 65% of dietary reports.
Testing was performed by enzyme-linked immunosorbent assay (ELISA) for stool and
point-of-care tests (POCTs) for GIP excretion in urine and stool [149]; however, the lack
of standardization in urinary GIP makes it an unreliable tool to assess adherence to the
GFD [150]. Measuring GIP in stool of celiac patients may be helpful for monitoring GFD
compliance [151,152]. In addition, GIP in stool has been measured in gluten sensitive IBS
patients and found to correlate with a decreased level when a patient is placed on a GFD.
However, GIPs were found in all subjects at baseline [83]. Therefore, further studies are
necessary to develop reliable GIP controls to accurately assess GFD compliance in CD and
other GRDs.
Nutrients 2022, 14, 2 10 of 17

Strict adherence to a rigid diet can negatively impact the quality of life for patients
with food sensitivity. These negative factors are important for clinicians to be aware of
when caring for these patients. Any restrictive diet, such as lactose-free, low FODMAPs,
or gluten-free, can exacerbate eating disorder behaviors. Individuals can develop food
aversion or anxiety regarding the preparation of their food, or avoid social situations related
to eating, leading to orthorexia nervosa, a condition in which people restrict their diet based
on its quality. There is evidence that patients diagnosed with CD, IBS, and inflammatory
bowel disease have high prevalence rates of disordered eating practices. Individuals may
develop food aversions, with the development of fear of foods being contaminated, and
subsequently become too afraid and anxious to consume a variety of foods with a resultant
dietary restriction. There is also a relationship between disordered eating and psychological
distress, associated with maladaptive coping mechanisms, depression, and stress [74,153].
In addition to disordered eating and adherence difficulties with gluten-free restric-
tion, many studies have demonstrated that a GFD significantly increases the cost of food,
with prices up to three times greater than for similar non-gluten-free products [154,155].
Gluten-free products are generally more expensive, and perceived costs remain a barrier
to adherence [156]. There are many reasons that may contribute to difficulty with compli-
ance of the GFD, including social exclusion, fewer food choices, accidental contamination,
and cost.

10. Conclusions
Any individual on a restricted diet, whether avoiding lactose, gluten, or FODMAPs,
should be screened for nutritional deficiencies. Patients on these diets have shown signif-
icant nutrient deficits that may require supplementation. Eliminating gluten in the diet
is the treatment for GRDs and gluten sensitive IBS, although compliance with the GFD is
challenging. Consequently, access to an educated dietician is essential to ensure a nutri-
tionally balanced diet while being carefully monitored by a gastroenterologist to ensure
long-term compliance. Furthermore, the dietary restriction used to treat IBS, lactose condi-
tions, CD, and NCGS, can negatively impact quality of life. Therefore, medical providers
managing and treating these conditions should be aware of the persistent challenging
effects of nutrition on the overall health of these patients. As LI patients can tolerate small
amounts of lactose, and NCGS and IBS patients have shown tolerance to some exposure to
gluten, a reduced diet instead of strict avoidance may be adequately effective for symptom
relief while preventing nutritional complications. Clinicians should consider a temporary
restricted diet in these patients, with the goal of reducing symptoms followed by a gradual
introduction of dairy or gluten products as tolerated. Subsequently, a prolonged dietary
restriction may not be required for treatment in these conditions.
Future studies should examine the effects of diet reduction versus elimination in
patients with LI, IBS, and NCGS. In addition, research should focus on the relationship
between LI in adults and osteoporosis, as the relationship between low bone mineral
density and osteoporosis remains unclear. There are conflicting studies on whether the
FODMAPs diet positively affects the quality of life in IBS individuals; therefore, additional
long-term examination of these patients is necessary. Furthermore, novel testing of GIP in
the urine and stool has been used to detect gluten ingestion; however, the development of
a reliable GIP control is necessary for the accurate evaluation of GFD adherence in GRDs.
In addition, changes in the intestinal microbiome on a GFD have been reported, although
additional longer studies are needed to assess the impact of this change on patients’ health.
Conclusive data is essential for the study of the actual prevalence of IBS in patients with
CD, for a better understanding of the relationship between these two conditions. Finally,
more data is required to uncover the pathophysiology of NCGS and IBS and to establish
the precise association between IBS and GRDs.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Nutrients 2022, 14, 2 11 of 17

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.
Conflicts of Interest: The author declares no conflict of interest.

Abbreviations
AGA: anti-gliadin antibody; CD, celiac disease; CDAT, Celiac Dietary Adherence
Test; DGP, deamidated gliadin peptide; EMA, endomysial antibody; FODMAPs, fer-
mentable oligo-, di-, and monosaccharides and polyols; GFD, gluten-free diet; GIP, gluten
immunogenic peptide; GRDs, gluten-related disorders; HBT, hydrogen breath test; IBS,
irritable bowel syndrome; IBS-D, irritable bowel syndrome diarrhea-predominant; IELs,
intraepithelial lymphocytes; IgE, immunoglublin E; LI, lactose intolerance; LM, lactose
malabsorption; NCGS, non-celiac gluten sensitivity; NRCD, nonresponsive celiac dis-
ease; TTG, tissue transglutaminase.

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