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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.
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;
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; (S.-K.L.); (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:; 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.
Academic Editor: Albertino Bigiani
Received: 10 September 2021
Accepted: 14 October 2021
Published: 20 October 2021
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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)
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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Background: The adverse effect of excessive salt intake has been recognized in decades. Researchers have mainly focused on the association between salt intake and hypertension. However, studies in recent years have proposed the existence of extra-renal sodium storage and provided insight into the immunomodulatory function of sodium. Objectives: In this review, we discuss the modulatory effects of high salt on various innate and adaptive immune cells and immune-regulated diseases. Methods: We identified papers through electronic searches of PubMed database from inception to March 2022. Results: An increasing body of evidence has demonstrated that high salt can modulate the differentiation, activation and function of multiple immune cells. Furthermore, a high-salt diet can increase tissue sodium concentrations and influence the immune responses in microenvironments, thereby affecting the development of immune-regulated diseases, including hypertension, multiple sclerosis, cancer and infections. These findings provide a novel mechanism for the pathology of certain diseases and indicate that salt might serve as a target or potential therapeutic agent in different disease contexts. Conclusion: High salt has a profound impact on the differentiation, activation and function of multiple immune cells. Additionally, an HSD can modulate the development of various immune-regulated diseases.
Scope: This study assessed whether oleuropein prevented ovalbumin (OVA)-induced food allergy (FA) and investigated the underlying mechanisms. Methods and results: A Balb/c FA mouse model was established and maintained for seven weeks. The subjects were administered OVA by oral gavage to induce FA and supplemented with different oleuropein doses (1.00-20.00 mg/kg per day) to evaluate its preventative efficacy. The results indicated that oleuropein effectively alleviated OVA-induced allergy symptoms and promoted temperature elevation in sensitized mice. The secretion of serology-specific OVA-immunoglobulin (Ig)E, OVA-IgG, and histamine was inhibited in the sensitized mice. Oleuropein dramatically upregulated the expression of intestinal tight junction (TJ) proteins, regenerating gene (Reg) IIIγ, and interleukin (IL)-22, enhancing the physical and biochemical barrier function of the intestinal epithelium. Additionally, oleuropein improved the immune homeostasis of the intestinal epithelium by affecting the function of mucosal mast cells and regulatory T (Treg) cells. The disordered intestinal flora of the sensitized mice also improved after oleuropein administration. Conclusions: These findings suggest that oleuropein prevents FA by enhancing intestinal epithelial barrier function and improving immune homeostasis and intestinal flora in sensitized mice. Therefore, diets rich in oleuropein should be recommended for people with FA. This article is protected by copyright. All rights reserved.
Evolutionary biology informs us that the living world is a product of evolution, guided by the Darwinian mechanism of natural selection. This recognition has been fruitfully employed to a number of issues in health and nutrition sciences; however, it has not been incorporated into education. Nutrition and dietetics students generally learn very little or nothing on the subject of evolution, despite the fact that evolution is the process by which our genetically determined physiological traits and needs were shaped. In the present paper, three examples of topics (inflammatory diseases, nutrition transition, and food intolerance) that can benefit from evolutionary information and reasoning are given, with relevant lines of research and inquiry provided throughout. It is argued that the application of evolutionary science to these and other areas of nutrition education can facilitate a deeper and more coherent teaching and learning experience. By recognizing and reframing nutrition as an aspect and discipline of biology, grounded in the fundamental principle of adaptation, revelatory light is shed on physiological states and responses, contentious and unresolved issues, genomic-, epigenomic-, and microbiomic features, and optimal nutrient status and intakes.
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T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.
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The Western diet is rich in salt, and a high salt diet (HSD) is suspected to be a risk factor for cardiovascular diseases. It is now widely accepted that an experimental HSD can stimulate components of the immune system, potentially exacerbating certain autoimmune diseases, or alternatively, improving defenses against certain infections, such as cutaneous leishmaniasis. However, recent findings show that an experimental HSD may also aggravate other infections (e.g., pyelonephritis or systemic listeriosis). Here, we discuss the modulatory effects of a HSD on the microbiota, metabolic signaling, hormonal responses, local sodium concentrations, and their effects on various immune cell types in different tissues. We describe how these factors are integrated, resulting either in immune stimulation or suppression in various tissues and disease settings.
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Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.
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Immunoglobulin E (IgE)-mediated allergy against cow’s milk protein fractions such as whey is one of the most common food-related allergic disorders of early childhood. Histone acetylation is an important epigenetic mechanism, shown to be involved in the pathogenesis of allergies. However, its role in food allergy remains unknown. IgE-mediated cow’s milk allergy was successfully induced in a mouse model, as demonstrated by acute allergic symptoms, whey-specific IgE in serum, and the activation of mast cells upon a challenge with whey protein. The elicited allergic response coincided with reduced percentages of regulatory T (Treg) and T helper 17 (Th17) cells, matching decreased levels of H3 and/or H4 histone acetylation at pivotal Treg and Th17 loci, an epigenetic status favoring lower gene expression. In addition, histone acetylation levels at the crucial T helper 1 (Th1) loci were decreased, most probably preceding the expected reduction in Th1 cells after inducing an allergic response. No changes were observed for T helper 2 cells. However, increased histone acetylation levels, promoting gene expression, were observed at the signal transducer and activator of transcription 6 (Stat6) gene, a proallergic B cell locus, which was in line with the presence of whey-specific IgE. In conclusion, the observed histone acetylation changes are pathobiologically in line with the successful induction of cow’s milk allergy, to which they might have also contributed mechanistically.
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Specific and adequate nutrition during pregnancy and early life is an important factor in avoiding non-communicable diseases such as obesity, type 2 diabetes, cardiovascular disease, cancers, and chronic allergic diseases. Although epidemiologic and experimental studies have shown that nutrition is important at all stages of life, it is especially important in prenatal and the first few years of life. During the last decade, there has been a growing interest in the potential role of epigenetic mechanisms in the increasing health problems associated with allergic disease. Epigenetics involves several mechanisms including DNA methylation, histone modifications, and microRNAs which can modify the expression of genes. In this study, we focus on the effects of maternal nutrition during pregnancy, the effects of the bioactive components in human and bovine milk, and the environmental factors that can affect early life (i.e., farming, milk processing, and bacterial exposure), and which contribute to the epigenetic mechanisms underlying the persistent programming of immune functions and allergic diseases. This knowledge will help to improve approaches to nutrition in early life and help prevent allergies in the future.
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Epidemiological studies identified raw cow’s milk consumption as an important environmental exposure that prevents allergic diseases. In the present study, we investigated whether raw cow’s milk has the capacity to induce tolerance to an unrelated, non-milk, food allergen. Histone acetylation of T cell genes was investigated to assess potential epigenetic regulation. Female C3H/HeOuJ mice were sensitized and challenged to ovalbumin. Prior to sensitization, the mice were treated with raw milk, processed milk, or phosphate-buffered saline for eight days. Allergic symptoms were assessed after challenge and histone modifications in T cell-related genes of splenocyte-derived CD4+ T cells and the mesenteric lymph nodes were analyzed after milk exposure and after challenge. Unlike processed milk, raw milk decreased allergic symptoms. After raw milk exposure, histone acetylation of Th1-, Th2-, and regulatory T cell-related genes of splenocyte-derived CD4+ T cells was higher than after processed milk exposure. After allergy induction, this general immune stimulation was resolved and histone acetylation of Th2 genes was lower when compared to processed milk. Raw milk reduces allergic symptoms to an unrelated, non-milk, food allergen in a murine model for food allergy. The activation of T cell-related genes could be responsible for the observed tolerance induction, which suggested that epigenetic modifications contribute to the allergy-protective effect of raw milk.
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The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (TH17) cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes TH2 cell responses on multiple regulatory levels. Sodium chloride enhanced interleukin-4 (IL-4) and IL-13 production while suppressing interferon-γ (IFN-γ) production in memory T cells. It diverted alternative T cell fates into the TH2 cell phenotype and also induced de novo TH2 cell polarization from naïve T cell precursors. Mechanistically, sodium chloride exerted its effects via the osmosensitive transcription factor NFAT5 and the kinase SGK-1, which regulated TH2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained elevated sodium compared to nonlesional atopic and healthy skin. These results suggest that sodium chloride represents a so far overlooked cutaneous microenvironmental checkpoint in atopic dermatitis that can induce TH2 cell responses, the orchestrators of atopic diseases.
Sodium intake is undoubtedly indispensable for normal body functions but can be detrimental when taken in excess of dietary requirements. The consequences of excessive salt intake are becoming increasingly clear as high salt consumption persists across the globe. Salt has long been suspected to promote the development of hypertension and cardiovascular diseases and is now also recognized as a potential modulator of inflammatory and autoimmune diseases through its direct and indirect effects on immune cells. The finding that, in addition to the kidneys, other organs such as the skin regulate sodium levels in the body prompted new hypotheses, including the concept that skin- resident macrophages might participate in tissue sodium regulation through their interactions with lymphatic vessels. Moreover, immune cells such as macrophages and different T cell subsets are found in sodium rich interstitial microenvironments, where sodium levels modulate their function. Alterations to the intestinal bacterial community induced by excess dietary salt represent another relevant axis whereby salt indirectly modulates immune cell function. Depending on the inflammatory context, sodium might either contribute to protective immunity (for example, by enhancing host responses against cutaneous pathogens) or it might contribute to immune dysregulation and promote the development of cardiovascular and autoimmune diseases.
During tissue inflammation, immune cells infiltrate the interstitial space of target organs, where they sense and adapt to local environmental stimuli. Such stimuli include not only pathogens but also local factors such as the levels of oxygenation, nutrients and electrolytes. An important electrolyte in this regard is sodium (Na⁺). Recent in vivo findings have shown a role of Na⁺ storage in the skin for electrolyte homeostasis. Thereby, Na⁺ intake may influence the activation status of the immune system through direct effects on T helper cell subsets and innate immune cells in tissues such as the skin and other target organs. Furthermore, high Na⁺ intake has been shown to alter the composition of the intestinal microbiota, with indirect effects on immune cells. The results suggest regulatory roles for Na⁺ in cardiovascular disease, inflammation, infection and autoimmunity. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Autoimmune diseases are a group of heterogeneous condition that occur secondary to the intrinsic loss of tolerance to self- antigens. In genetically susceptible individuals, the complex interplay of environmental factors and epigenetic deregulations have been proposed to drive disease etiopathogenesis. Various environmental variables have been identified including viral infections, exposure to pollutants, stress and dietary factors. Sodium, a major constituent of salt is essential for mammalian physiology. However, high salt intake may play a role in the development of autoimmune diseases. Several lines of evidence point toward the role of high sodium intake in reversing the suppressive effects of Regulatory T cells (Tregs) and instead promoting cellular shift toward T-helper (Th)-1 and Th17 pro-inflammatory phenotypes. These effects have been attributed to cascade of events that ultimately results in downstream activation of serum glucocorticoid kinase 1 (Sgk1). In vivo, various autoimmune animal models have confirmed the role of high sodium diet in the emergence and the exacerbation of autoimmune conditions including for instance Experimental Autoimmune Encephalomyelitis model for multiple sclerosis, MRL/lpr mouse model for lupus nephritis, collagen induced arthritis model for rheumatoid arthritis, and dextran sulfate sodium induced colitis, and TNBS-induced colitis models for Crohn's disease. Clinical epidemiological studies are scarce. High sodium intake was associated with increased risk of rheumatoid arthritis disease emergence. In multiple sclerosis, some studies suggest a relation to clinical exacerbation rates however other studies did not corroborate these results. Taken together, high dietary salt intake plays a role in the spectrum of autoimmune disease etiology. Further research is warranted to better characterize such relationship and assist in identifying individuals that would benefit from dietary salt restriction.