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A High-Sodium Diet Modulates the Immune Response of Food Allergy in a Murine Model

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Mounting evidence demonstrates that a high-salt diet (HSD) not only affects hemodynamic changes but also disrupts immune homeostasis. The T helper 17 (Th17) and regulatory T cells (Tregs) are susceptible to hypersalinity. However, research on the influence of sodium on Th2-mediated food allergies remains scarce. We aimed to investigate the effect of dietary sodium on the immune response to food allergies. Mice maintained on an HSD (4% NaCl), low-salt diet (LSD; 0.4% NaCl), or control diet (CTRL; 1.0% NaCl) were orally sensitized with ovalbumin (OVA) and a cholera toxin (CT) adjuvant, and then subjected to an intragastric OVA challenge. OVA-specific immunoglobulin G (IgG), IgG1, IgG2a, and IgE antibodies were significantly higher in the HSD group than in the CTRL group (p < 0.001, p < 0.05, p < 0.01, and p < 0.05, respectively). Mice on HSD had significantly higher interleukin (IL)-4 levels than the CTRL group (p < 0.01). The IL-10 levels were significantly lower in the HSD group than in the CTRL group (p < 0.05). The serum levels of interferon-γ (IFN-γ), sodium, and chloride did not differ among the three groups. This study indicates that excessive salt intake promotes Th2 responses in a mouse model of food allergy.
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Nutrients 2021, 13, 3684. https://doi.org/10.3390/nu13113684 www.mdpi.com/journal/nutrients
Article
A High-Sodium Diet Modulates the Immune Response of Food
Allergy in a Murine Model
Zheying Liu 1,2,3,4, Shih-Kuan Li 4,5, Chih-Kang Huang 4,6 and Ching-Feng Huang 4,7,*
1 Emergency Department, Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei
Medical University, Taipei City 11696, Taiwan; 102230@w.tmu.edu.tw
2 Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University,
Taipei City 11031, Taiwan
3 Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei City 11696, Taiwan
4 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Taipei
Veterans General Hospital, Taipei City 11217, Taiwan; calm2577@gmail.com (S.-K.L.);
follyfolly25@yahoo.com.tw (C.-K.H.)
5 Department of Pediatrics, Yonghe Cardinal Tien Hospital, New Taipei City 23445, Taiwan
6 Department of Pediatrics, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan City 33052, Taiwan
7 National Defense Medical Center, School of Medicine, Taipei City 11490, Taiwan
* Correspondence: h-cf@yahoo.com.tw; Tel.: +886-2-2875-7019; Fax: +886-2-2873-9019
Abstract: Mounting evidence demonstrates that a high-salt diet (HSD) not only affects
hemodynamic changes but also disrupts immune homeostasis. The T helper 17 (Th17) and
regulatory T cells (Tregs) are susceptible to hypersalinity. However, research on the influence of
sodium on Th2-mediated food allergies remains scarce. We aimed to investigate the effect of dietary
sodium on the immune response to food allergies. Mice maintained on an HSD (4% NaCl), low-salt
diet (LSD; 0.4% NaCl), or control diet (CTRL; 1.0% NaCl) were orally sensitized with ovalbumin
(OVA) and a cholera toxin (CT) adjuvant, and then subjected to an intragastric OVA challenge.
OVA-specific immunoglobulin G (IgG), IgG1, IgG2a, and IgE antibodies were significantly higher
in the HSD group than in the CTRL group (p < 0.001, p < 0.05, p < 0.01, and p < 0.05, respectively).
Mice on HSD had significantly higher interleukin (IL)-4 levels than the CTRL group (p < 0.01). The
IL-10 levels were significantly lower in the HSD group than in the CTRL group (p < 0.05). The serum
levels of interferon-γ (IFN-γ), sodium, and chloride did not differ among the three groups. This
study indicates that excessive salt intake promotes Th2 responses in a mouse model of food allergy.
Keywords: food allergy; ovalbumin; IgE; high salt diet; Th2 response
1. Introduction
Globalization has caused rapid changes in people’s eating habits, leading to an
increased consumption of processed and packaged foods, and a lifestyle that is based on
a high-salt diet (HSD). Excessive salt consumption can pose a threat to human health.
High dietary salt intake has been linked to many well-recognized diseases, such as
cardiovascular complications, hypertension, and metabolic syndromes [1]. Mounting
evidence on the effects of HSD has demonstrated that it not only mediates hemodynamic
changes but also disrupts immune homeostasis. It is well established that excessive salt
augments the differentiation of naïve T cells into T helper 17 cells (Th17), resulting in the
onset and exacerbation of autoimmune conditions in animal models of multiple sclerosis,
lupus nephritis, rheumatoid arthritis, and Crohn’s disease [2–4]. There is a fine balance
between Th17 and regulatory T cells (Tregs). Furthermore these T-helper subsets are
reciprocally regulated, which enables the transition between pro- and anti-inflammatory
states [5]. Therefore, the enhanced differentiation of Th17 cells after exposure to high
concentrations of salt may further dampen Treg phenotypes. Moreover, excessive salt was
Citation: Liu, Z.; Li, S.-K.;
Huang, C.-K.; Huang, C.-F. A
High-Sodium Diet Modulates the
Immune Response of Food Allergy
in a Murine Model. Nutrients 2021,
13, 3684. https://doi.org/10.3390/
nu13113684
Academic Editor: Albertino Bigiani
Received: 10 September 2021
Accepted: 14 October 2021
Published: 20 October 2021
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Attribution (CC BY) license
(https://creativecommons.org/license
s/by/4.0/).
Nutrients 2021, 13, 3684 2 of 10
shown to exert a direct effect on the suppressive functions of Tregs and exacerbate
experimental graft-versus-host diseases [6]; Th2 and Tregs also share such a relationship.
A change in the equilibrium between allergen-specific Th2 and Treg cells can either result
in the development of allergic diseases or in the recovery from allergy [7,8]. A previous
study demonstrated that the failure to induce oral tolerance, or the breakdown of oral
tolerance as a result of the impaired generation or functioning of the suppressive Tregs,
could contribute to food allergy [9]. Newly discovered evidence revealed that the
epigenetic modifications, caused by decreased or increased levels of histone acetylation at
key Th cell loci, contributed to the allergy to cow’s milk protein or the allergy-protective
effect of raw milk [10,11]. While it is well known that sodium is an immunomodulator of
Th17 cells and Tregs [12], our understanding of the direct effect of sodium on Th2-
dependent allergic diseases, such as food allergies, remains scarce.
The expression of food allergies is multifactorial and is affected by the genetic
background of an individual, environmental factors, and interactions between the
genome and environment, including the epigenetic effects. The prevalence of food
allergies has been constantly increasing over the last three decades [13]. As evidenced by
the epidemiologic studies, up to 10% of the population is affected by food allergies [14].
The present standards for treating food allergy include allergen avoidance and immediate
access to medication in the event of anaphylaxis [13]. These are relatively safe and effective
measures for controlling symptoms but not for curing the disease. Food allergies are
characterized by an overriding Th2 response. The increasing prevalence of food allergies,
together with a rise in human urbanization may indicate a correlation between the two.
Moreover, urbanization leads to changes in lifestyle and diet is one of the most rapid of
these changes. The limited evidence on the impact of dietary components, such as food
additives and vitamin D n-3/n-6 polyunsaturated fatty acids, on the homeostasis of the
immune system suggests that these components may hinder or facilitate the development
of food allergies [15–17]. However, the impact of HSDs or low-salt diets (LSDs) on food
allergy has not yet been ascertained. Since sodium chloride (NaCl) has been shown to
affect immune homeostasis, we hypothesized that a high salt intake might have an effect
on food allergies. Here, we aimed to investigate the effect of dietary salt intake on the
immune response in a mouse model of food allergy.
2. Materials and Methods
2.1. Animals and Ethics Statement
Eight-week-old female BALB/c mice were purchased from the National Animal
Center (Taipei, Taiwan). All mice were housed in cages under conventional conditions of
controlled temperature and relative humidity with a regular 12 h light/dark cycle in the
Animal House of the National Defense Medical Center (Taipei, Taiwan). All animal
experiments were approved by the Institutional Animal Care and Use Committee of the
National Defense Medical Center (Ethical approval number: IACUC-13-121).
2.2. Antigen Preparation
Ovalbumin (OVA) grade V was acquired from Sigma-Aldrich (St. Louis, MO, USA).
Cholera toxin (CT; Calbiochem, San Diego, CA, USA) was used as an adjuvant. Briefly,
360 mL of 1 mg/mL OVA and 90 μL of 2 mg/mL CT were dissolved in 9 mL phosphate-
buffered saline (PBS).
2.3. Experimental Design
After an acclimatization period of one week, the mice were randomly divided into
the following three groups: HSD, LSD, and control (CTRL) (n = 6 mice/group). In the HSD
group, naïve mice were exposed to HSD (TestDiet®, St. Louis, MO, USA) that was
supplemented with 4% NaCl. In the LSD group, naïve mice were administered chow with
0.4% NaCl (TestDiet®), whereas mice from the control group were fed a normal salt diet
Nutrients 2021, 13, 3684 3 of 10
(TestDiet®) containing 1.0% NaCl. One-percent, NaCl-containing water was provided to
mice from the HSD group, and distilled water was provided to the mice in the LSD and
control groups. All mice were maintained on a specialized rodent diet and water ad
libitum for 10 weeks (weeks 0 to 10).
All mice were first sensitized and thereafter challenged with OVA intragastrically.
Briefly, the mice were intragastrically administered 20 mg of OVA in the presence of 10
μg of CT adjuvant, which was suspended in 500 μL of PBS, once a week for six weeks. In
the week after the last sensitization, mice were challenged with 50 mg OVA suspended in
200 μL of PBS via intragastric gavage after overnight fasting. All mice were euthanized
one day after the OVA challenge, and blood and spleen samples were harvested for
further analyses. The experiments were performed in duplicates to obtain representative
data. The experimental scheme is illustrated in Figure 1.
Figure 1. Experimental protocol. Three different experimental protocols were used for priming. Mice were fed a high- or
low-salt diet or control diet ad libitum for 10 weeks. After 4 weeks of exposure to different sodium concentrations, all mice
were intragastrically sensitized with 20 mg of ovalbumin (OVA) and 10 μg of cholera toxin (CT) once every week, for six
weeks. After sensitization, mice were challenged with 50 mg of OVA via intragastric gavage. All mice were euthanized
for blood and spleen sampling 1 day after the OVA challenges. Ovalbumin: OVA, cholera toxin: CT, intragastrically: i.g.
2.4. Measurement of OVA-Specific Immunoglobulin G (IgG), IgG1, and IgG2a Antibodies
Blood samples were collected after challenge. The levels of OVA-specific IgG, IgG1,
and IgG2a were measured using enzyme-linked immunosorbent assays (ELISA) (R&D
Systems, Minneapolis, MN, USA), as described previously [18]. Briefly, microtiter plates (96
wells; Nunc, Kamstrup, Roskilde, Denmark) were coated overnight at 4 °C with 100 μL of
OVA (100 μg/mL) in 0.05 M sodium carbonate (pH 9.6). On the next day, the plates were
blocked with 3% skimmed milk in PBS-Tween 20 by incubation for 1 h. Serum samples (1/30
1/1000) and standards (pooled hyperimmune sera after monthly treatment with OVA
emulsified in complete Freund’s adjuvant) were added to the plates in duplicates. The plates
were then incubated for 5 h at room temperature. An amount of 100 mL horseradish
peroxidase conjugated with goat anti-mouse IgG (1/4000; Jackson, West Grove, PA, USA),
IgG1 or IgG2a (1/4000 for both; SBA, Birmingham, AL, USA) were added to each well and
incubated overnight at 4 °C. Between each incubation, the plates were washed with PBS
containing 0.05% Tween 20. Color was developed by adding orthophenyleldiamine (0.5
mg/mL; Sigma) in citrate-carbonate buffer containing 0.015% hydrogen peroxide and
incubated in the dark at room temperature. Finally, the reaction was stopped with 4 N sulfuric
acid. A SPECTRAmax 250 reader (Molecular Devices, Sunnyvale, CA, USA) was used to
measure the absorbance at 492 nm, and unknowns were interpolated.
2.5. Measurement of OVA-Specific IgE Antibody
OVA-specific IgE antibodies in mouse serum were detected by in vivo passive
cutaneous anaphylaxis (PCA) assay, as described previously [18]. Briefly, Sprague
Nutrients 2021, 13, 3684 4 of 10
Dawley rats were purchased from the Animal Center, National Yang-Ming University,
Taipei, Taiwan. Aliquots (100 μL) of 2-fold dilutions of mouse serum samples (1/50–1/800)
were intradermally injected into the rats. They were then challenged after 48 h via an
intravenous injection of 2 mg of OVA and 5 mg of Evans Blue in 1 mL PBS. Thirty minutes
after the challenge, the rats were sacrificed and the diameter of the cutaneous reaction was
measured. A positive IgE response was recorded if the challenge resulted in a blue lesion
≥5 mm on the skin of 50% or more recipient animals. The antibody titer was expressed as
the highest dilution of the serum sample to give a positive PCA reaction.
2.6. Analysis of Cytokine Production in OVA-Stimulated Spleen Cells
Cytokine production in spleen cells was analyzed as described previously [18]. A day
after the oral OVA challenge, spleen cells from the six BALB/c mice of each group were
gently crushed and cultured (2 × 106 cells per well) in 24-well flat-bottomed microtiter
plates (1 mL per well; Costar, Cambridge, MA, USA) with OVA, in duplicates, and in
complete Roswell Park Memorial Institute 1640 (RPMI) medium (1 mg/mL) supplemented
with 10% fetal calf serum and antibiotics. Culture supernatants were harvested after 1–3
days of incubation. The levels of interleukin (IL)-4, IL-10, and interferon-γ (IFN-γ) from
the harvested supernatants were measured using sandwich, enzyme-linked
immunosorbent assay (ELISA) kits (e-Bioscience, San Diego, CA, USA) according to the
manufacturer’s instructions.
2.7. Statistical Analysis
All the experiments were performed in duplicates. Experimental data were expressed
as box-and-whisker plots with individual data points. Statistical comparisons between the
two groups were made by the non-parametric Mann–Whitney U-test. Differences were
considered significant at p < 0.05. Analysis was performed using GraphPad Prism version
9.1.1 (223) for Mac (GraphPad Software, San Diego, CA, USA).
3. Results
3.1. HSD Induces High Levels of OVA-Specific Serum IgG, IgG1, IgG2a, and IgE in Mice
To investigate the impact of salt intake on the humoral response in sensitized mice,
we measured plasma levels of OVA-specific IgG, IgG1, IgG2a, and IgE antibodies after an
oral challenge with the OVA-antigen (Figure 2). OVA-specific IgG, IgG1, IgG2a, and IgE
levels were significantly higher in the HSD group than in the CTRL group (p < 0.001 for
Figure 2a; p < 0.05 for Figure 2b; p < 0.01 for Figure 2c; p < 0.05 for Figure 2d). Conversely,
there were no statistical differences between the levels of OVA-specific IgG1, IgG2a, and
IgE serum antibodies between the LSD and CTRL groups.
(a) (b)
Nutrients 2021, 13, 3684 5 of 10
(c) (d)
Figure 2. Effect of different concentrations of dietary sodium on the production of OVA-specific immunoglobulin G (IgG)
(a), IgG1 (b), IgG2a (c), and IgE (d) antibodies in mice with OVA-induced food allergy. Serum was collected after challenge
with the OVA antigen. IgG (a), IgG1 (b), and IgG2a (c) levels were examined by the enzyme-linked, immunosorbent assay
(ELISA) and IgE (d) levels by the in vivo passive cutaneous anaphylaxis (PCA) test. Data are expressed as box-and-whisker
plots with individual data points. The boxes represent the inner quartiles value range with the median indicated as black
line. The whiskers represent minimum to maximum interval. * p < 0.05, ** p < 0.01, and *** p < 0.001. High-salt diet: HSD,
Low-salt diet: LSD, Control diet: CTRL
3.2. High IL-4 and Low IL-10 Production in Splenocytes of Mice Maintained on HSD
Next, we evaluated the effect of sodium intake on the cytokine production in the
spleens of mice with food allergies. The concentration of IL-4 was significantly higher in
the HSD group than in the CTRL group, after the stimulation with OVA (p < 0.01 for Figure
3a). In contrast, the IL-10 levels were markedly lower in the HSD group than in the CTRL
group (p < 0.05 for Figure 3b). No significant difference were observed in the IFN- levels
between the HSD and CTRL groups (Figure 3c). On the contrary, LSD did not significantly
change IL-4, IL-10, and IFN- production in the spleen cells of OVA-sensitized mice.
Nutrients 2021, 13, 3684 6 of 10
(a) (b)
(c)
Figure 3. Effect of different concentrations of dietary sodium on the production of cytokines by splenocytes. Splenocytes
were isolated from the spleens after OVA challenge and incubated in culture medium containing fetal bovine serum (FBS)
and OVA for 1 to 3 days. Interleukin (IL)-4 (a), IL-10 (b), and interferon- (IFN-) (c) were measured by sandwich ELISA.
Data are expressed as box-and-whisker plots with individual data points. The boxes represent the inner quartiles value
range with the median indicated as black line. The whiskers represent minimum to maximum interval. * p < 0.05 and ** p
< 0.01. High-salt diet: HSD, Low-salt diet: LSD, Control diet: CTRL
3.3. HSD Causes No Change in the Serum Levels of Sodium and Chloride
To determine the effect of the different salt concentrations on electrolyte homeostasis,
plasma concentrations of sodium (Na) and chloride (Cl) were evaluated after the
administration of a special salt diet for 10 weeks (Figure 4). Dietary salt had no effect on
plasma levels of Na and Cl for all mice from the three groups.
(a) (b)
Figure 4. Effect of different concentrations of dietary sodium on the levels of serum sodium (Na; (a)) and chloride (Cl; (b)).
Mice were fed a high- or low-salt diet, or a control diet ad libitum for 10 weeks. Blood samples were collected 1 day after
administering the specialized diet. Data are expressed as box-and-whisker plots with individual data points. The boxes
represent the inner quartiles value range with the median indicated as black line. The whiskers represent minimum to
maximum interval. High-salt diet: HSD, Low salt diet: LSD, Control diet: CTRL.
Nutrients 2021, 13, 3684 7 of 10
4. Discussion
HSD is suggested to be an environmental factor that modulates T cell differentiation,
and which may promote the differentiation of naïve T cells into effector cells that are
associated with autoimmune disease, such as Th17 cells. Our present knowledge about
the effect of sodium on Th2-mediated allergic diseases, such as food allergies, is largely
limited. In this study, mice from the HSD and LSD groups were administered a diet
supplemented with 4% or 0.4% NaCl, and compared to mice from the control group,
which received chow containing 1% NaCl. All mice were sensitized with OVA and the CT
adjuvant, and thereafter subjected to an intragastric challenge. We observed a significant
increase in the levels of serum OVA-specific IgG1, IgE, and splenic IL-4, and a significant
decrease in the splenic IL-10 levels of mice from the HSD group (Figures 2 and 3). This
indicated that the intake of a diet supplemented with excessive dietary sodium altered
immune homeostasis and promoted Th2 immune responses in a mouse model for OVA-
induced food allergy. This is the first report to provide experimental evidence for the effect
of sodium exposure on food allergy. Our results provide evidence that, in addition to its
well-described effect on the induction of proinflammatory Th17 cells and the abrogation
of the suppressive capacity of Tregs, excessive salt intake skews T cell differentiation
towards Th2 responses in a mouse model of food allergy.
Food allergy is an immunologically aberrant reaction to food allergens, mainly
proteins. The immunoglobulins, IgG1 and IgE, are both associated with Th2-type immune
responses. Numerous animal studies have already demonstrated that OVA, as a common
allergen, can increase the production of OVA-specific IgG1 and IgE serum antibodies after
sensitization, thereby suggesting the induction of a Th2 response [19–21]. The reports on
the role of NaCl in food allergies are sparse and controversial. One study reported that
cultivating murine CD4+ T cells, in the presence of hypertonic NaCl (40 mM), showed
impaired Th2 cell differentiation [22]. In contrast, another recently published pilot study
demonstrated that hypersalinity enhanced the production of signature Th2 cytokines,
namely IL-4 and IL-13, in memory T cells from healthy human donors [23]. Furthermore,
NaCl could facilitate the differentiation of human and mouse-derived naïve T cells into
Th2 cells, independent of Th2-polarizing cytokines, via the osmosensitive transcription
nuclear factor of activated T-cells 5 (NFAT5) and the enzyme serum/glucocorticoid
regulated kinase 1 (SGK-1) [23]. In line with this previously published data, our study
revealed that the levels of serum OVA-specific IgG1, IgE, and splenic IL-4 were
significantly elevated in mice from the HSD group, suggesting that a high-sodium intake
potentiated dysregulated immune responses and directly enhanced the Th2
differentiation in mice. Anti-OVA IgG levels are relatively non-specific parameters and
represent indicators for frequent OVA exposure [24]. Previous studies showed that some
strains of mice failed to mount a significant IgE antibody response to ovalbumin despite
the presence of an adjuvant [25]. In this study, we measured both IgE and IgG to confirm
the successful elicitation of an allergen’s immune response to the ovalbumin. Our findings
showed that anti-OVA IgG levels were significantly higher in the HSD and LSD group
than in the CTRL groups. The markedly elevated levels of IgG and IgE indicated a
potentiated allergic response in the HSD group. In the contrary, OVA-specific IgG was
significantly reduced in the CTRL group compared to the LSD group. However, OVA-
specific IgE, IgG1 and IgG2a did not significantly differ. It is possible that there may be
other IgG subclasses that may have contributed to the decrease in OVA-specific IgG to
induce the potential tolerance in the CTRL group. However, due to no difference in the
OVA-specific IgE, IgG1, and IgG2a between LSD and the CTRL group, further studies will
be needed to investigate the effect of low salt diet on the food allergy. Based on these
results, we suggest that the intake of chow supplemented with high sodium upregulates
antigen-specific, Th2-related antibody responses in mice.
Functional Tregs are important for maintaining tolerance to innocuous exogenous
antigens and self-antigens. IL-10 is a key cytokine secreted by Tregs that can limit T cell
responses. In addition to the existing evidence that Tregs limits the pathogenesis of
Nutrients 2021, 13, 3684 8 of 10
autoimmune diseases and prevents allograft rejection, accumulating evidence suggests
that Tregs might play a critical role in controlling the expression of allergic diseases. In a
mouse model of peanut allergy, CD4+ CD25+ T cell-depleted mice showed impaired oral
tolerance upon the exposure to peanuts and induced an IgE-mediated food
hypersensitivity response after an oral challenge [26]. In the case of rare diseases, such as
X-linked autoimmunity–allergic dysregulation syndrome
(XLAAD)/immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX), the
patients lack CD25+ Tregs and could develop severe eczema, eosinophilia, elevated IgE,
and food allergies, which indicated that Tregs were crucial for the development of allergic
diseases [27]. Our results showed a significant decrease in the IL-10 levels of mice from
the HSD in comparison to the control, suggesting that the function of Tregs was impaired.
Moreover, this functional impairment of Tregs could further promote a type 2 immune
response due to the loss of suppression, which was also observed in the present study
with the markedly elevated IgG1, IgE, and IL-4 levels in the HSD group. This was
consistent with previous studies, which showed that excessive dietary salt had a negative
effect on the suppressive function of Tregs via inducing SGK1-mediated FOXO1
phosphorylation, which further led to the destabilization of FOXP3 [6,28]. The low IL-10
levels in our study implied that excessive sodium may indirectly skew Th2 polarization
by attenuating the Treg function in the mouse model of food allergy. Existing studies
demonstrated how epigenetic mechanisms affected Tregs by decreased levels of histone
acetylation in the allergy to cow’s milk [11]. Whether high-sodium condition also plays a
role in epigenetic modifications by regulating the severity of food allergy should be
investigated in follow-up studies.
The results regarding the effect of salt on the differentiation of Th1 cells are barely
comparable with previous studies. A study in mice showed that HSD had no effect on Th1
cell differentiation [22]. The levels of IgGa2 in OVA-allergy mouse models varied greatly
between studies. Previous studies reported that CT could induce a weak Th1 response
characterized by elevated IgGa2 levels [29–31]. In line with previous studies, we observed
a significant increase in IgG2a levels in the HSD group, which suggested that HSD
affected the frequency of Th1 cells. However, there was no significant change in IFN-γ
levels between mice from the HSD and control groups. The inability of high salt to induce
IFN-γ production is in accordance with the previous findings and could be explained by
the low levels of SGK1 expression in the Th1 cells [3].
Concerning the effect of LSD on the adaptive immune response, we did not observe
any significant influence on Th1- or Th2-related antibodies and cytokines in our study.
This suggested that HSD could have a detrimental effect on human health in many
aspects, while the extreme restriction of salt intake may not have a definite benefit against
food allergy. With regard to the effect of the sodium on electrolyte homeostasis, we found
no differences in plasma levels of sodium and chloride from the three groups. The
accumulating evidence has shown that sodium could distribute at a different
concentration throughout the human body and may reach hypersalinity in the
interstitium regardless of the circulating levels [28,32,33]. A previous study demonstrated
that sodium was concentrated in the colons of mice on an HSD, indicating the direct
impact of salt within the colon [34]. In the tissue microenvironment, sodium could
regulate the differentiation and function of immune cells via modulating signaling
pathways and contributing to protective or proinflammatory immunity.
There are several limitations in the present study. First, it was performed in an animal
model and the numbers of animals were limited. We selected a small sample size because
of the effect of a high-salt diet on food allergy was evaluated in vivo for the first time in
the present study, and thus the initial intention was to gather basic evidence regarding
the use of this experimental protocol in more complex experimental designs. Further
research was necessary to investigate involving larger groups of animals to validate
reproducibility. Second, whether HSD exacerbated the severity of the clinical
manifestations of food allergy was not investigated in the current study and should be
Nutrients 2021, 13, 3684 9 of 10
investigated in the follow-up study. Moreover, we measured Th cell-dependent immune
responses but did not analyze the types of differentiated T cells which may provide
further information on the effect of sodium on T cell polarization.
5. Conclusions
In conclusion, our findings suggest that HSD may play an essential role in type 2
immune responses in a given microenvironment and extend the pre-existing evidence on
the ability of HSD to affect type 2 driven diseases, such as food allergies. Our findings
provide putative evidence that, although it warrants further research, controlling the
intake of dietary salt by targeting NaCl-induced signaling may be a promising therapeutic
strategy for improving adjuvant therapy in patients with food allergy.
Author Contributions: Conceptualization, C.-F.H.; methodology, C.-F.H.; validation, S.-K.L. and
C.-K.H.; formal analysis, Z.L.; investigation, C.-F.H.; resources, C.-F.H.; data curation, S.-K.L.;
writing—original draft preparation, Z.L.; writing—review and editing, Z.L.; visualization, Z.L.;
supervision, C.-F.H.; project administration, C.-F.H.; funding acquisition, C.-F.H. All authors have
read and agreed to the published version of the manuscript.
Funding: This research was funded by Taipei Veterans General Hospital, grant number V108C-182,
and National Science Council, grand number NSC 102-2314-B-016 -054 -MY3.
Institutional Review Board Statement: The study was conducted according to the animal care and
use guidelines of the Institutional Animal Care and Use Committee of the National Defense Medical
Center (Ethical approval number: IACUC-13-121).
Informed Consent Statement: Not applicable.
Data Availability Statement: The data that support the findings of this study are available from the
corresponding author upon reasonable request.
Conflicts of Interest: The authors declare no conflict of interest.
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... These effects were dependent on NFAT5 and SGK1. 65 Consistently, an HSD augmented Th2 responses in food allergy mice, 136 while the high-salt formulation of Al(OH) 3 enhanced the ovalbumin (OVA)induced Th2 response in mice. 109 In addition, high NaCl can significantly increase the polarization of human Tfh cells. ...
... These responses were associated with Th17 cell activation in the kidney. 163,164 Moreover, an HSD might exacerbate food allergy in mice, 136 while sodium may participate in the progression of atopic dermatitis by regulating Th2 responses. 65 ...
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