Modulation of the immune response to allergies using alternative functional foods

Citation: López-Enríquez, S.; Múnera-Rodríguez, A.M.; Leiva-Castro, C.; Sobrino, F.; Palomares, F. Modulation of the Immune Response to Allergies Using Alternative Functional Foods. Int. J. Mol. Sci. 2024, 25, 467. https://doi.org/ 10.3390/ijms25010467 Academic Editor: Soo-Jin Choi Received: 15 November 2023 Revised: 14 December 2023 Accepted: 28 December 2023 Published: 29 December 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). International Journal of Molecular Sciences Review Modulation of the Immune Response to Allergies Using Alternative Functional Foods Soledad López-Enríquez 1,2,* , Ana M. Múnera-Rodríguez 1, Camila Leiva-Castro 1, Francisco Sobrino 1 and Francisca Palomares 1,2,* 1Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, University of Seville, Avenue Sanchez Pizjuan s/n, 41009 Seville, Spain; [email protected] (A.M.M.-R.); [email protected] (C.L.-C.); [email protected] (F.S.) 2Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, Virgen Macarena University Hospital, University of Seville, CSIC, 41013 Seville, Spain *Correspondence: [email protected] (S.L.-E.); [email protected] (F.P.) Abstract: Modulation of the allergic immune response through alternative therapies is a field of study that aims to address allergic reactions differently from traditional approaches. These therapies encompass the utilization of natural functional foods, which have been observed to exert an influence on the immune response, thus mitigating the severity of allergies. Indeed, some studies suggest that the incorporation of these nutraceuticals can regulate immune function, leading to a reduction in histamine release and subsequent alleviation of allergic symptoms. Moreover, certain herbs and dietary supplements, such as curcumin, are believed to possess anti-inflammatory properties, which may serve to moderate allergic responses. Although the results remain somewhat mixed and require further research, these alternative therapies exhibit the potential to impact the allergic immune response, thereby providing complementary options to conventional treatments. Therefore, in this review, we aim to provide an updated account of functional foods capable of modulating the immune response to allergies. In that sense, the review delves into functional foods sourced from plants (phytochemicals), animals, and marine algae. Emphasis is placed on their potential application in the treatment of allergic disorders. It also provides an overview of how these foods can be effectively utilized as functional foods. Additionally, it explores the molecular mechanisms and scientific validity of various bioactive natural compounds in the management of allergies. Keywords: allergic immune response; functional foods; immune modulation; rhinitis allergic; food allergy and atopic dermatitis 1. Introduction The majority of healthy individuals do not exhibit reactions to common and typically innocuous environmental substances. However, an increasing proportion of the population responds abnormally to one or more of these substances [ 1 , 2 ], resulting in the development of allergic reactions with an immunological basis. In such cases, this abnormal response occurs because the immune system is incapable of distinguishing between harmless and pathological substances. These hypersensitivity reactions to innocuous molecules give rise to tissue damage in allergic individuals due to multiple and complex inflammatory processes. Allergic diseases encompass a range of conditions triggered by the immune system’s hypersensitivity to various environmental allergens. Within allergies, we can determine different types such as food allergy (FA), allergic asthma (AA), atopic dermatitis (AD), allergic rhinitis (AR), conjunctivitis, chronic rhinosinusitis with or without nasal polyposis (CRS or CRSwNP), drug allergy (DA), and venom allergy [ 3 – 5 ]. Allergic reactions can manifest in a variety of ways, ranging from mild discomfort to severe and life-threatening responses [ 6 ]. Moreover, the prevalence of allergies and allergic skin reactions has been on the rise [7]. Int. J. Mol. Sci. 2024,25, 467. https://doi.org/10.3390/ijms25010467 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2024,25, 467 2 of 20 These allergic reactions typically involve a sensitization and memory phase as well as an effector phase [ 8 ]. Briefly, the key cells in the allergic response include B and T lymphocytes, basophils, eosinophils, and mast cells. Upon first exposure to the allergen, T cells, specifically T helper type 2 (Th2) cells, become activated and release cytokines, such as interleukin (IL)-4 and IL-13. These cytokines stimulate B lymphocytes to generate specific immunoglobulin E (IgE) antibodies against that particular allergen [ 9 ]. Thus, in this proinflammatory microenvironment, it has been demonstrated that functional foods can act upon the immune system by modulating or balancing the exacerbated inflammatory response [10]. Nutraceuticals, known for providing health benefits and influencing disease prevention and treatment, can also modulate epigenetic changes [ 11 , 12 ]. Due to this, these compounds act as cellular and functional modulators, contributing to the homeostasis of physiological processes [ 11 ]. These compounds have been identified as having healthpromoting properties and the potential for therapeutic or preventive applications. In the context of regulating allergic responses, some nutraceuticals can play a significant role due to their anti-inflammatory, antioxidant, and immune system-modulating properties. This review aims to elucidate the anti-inflammatory and anti-allergic effects of nutraceuticals on hypersensitivity reactions, paying special attention to effects on allergic reactions (AR, FA, and AD) and the underlying mechanisms involved in these processes. 2. Allergic Diseases Allergies are complex systemic diseases arising from defects in the immune system [ 13 ]. As we have previously described, these pathologies encompass FA, DA, AR, conjunctivitis, CRS or CRSwNP, AA, and AD [ 6 ]. The prevalence of allergic diseases, once diagnosed, continues to escalate significantly over time, affecting between 10 and 30% of the global population [ 2 ]. Although most allergies may not be reversed, treatments can help to alleviate allergy symptoms. These treatments include antihistamines, nasal steroids, leukotriene receptor antagonists, bronchodilators, topical calcineurin inhibitors (TCI), and immunotherapy, such as monoclonal antibodies and vaccines [14]. Hypersensitivity reactions were classified into I-IV pathophysiologic types by the Gell and Coombs classification [ 15 ], re-classified by Rajan [ 16 ], and revised by Johansson and collaborators [ 17 ]. This classification includes immediate or immunoglobulin (Ig) E-mediated (Type I), antibody-mediated cytotoxic reactions (Type II), immune complexmediated reactions (Type III), and delayed-type hypersensitivity (Type IV) [18]. Immunological Mechanism of Allergic Reactions The immune system responds to antigens, inducing strong immune responses. Both genetic and environmental factors can influence the development of allergic reactions in individuals. Thus, the principal immune cells and molecular mechanisms involved in immune-mediated hypersensitivity reactions [ 8 , 14 ] are as follows: (a) Type I reactions primarily involve mast cells, basophils, and eosinophils, which possess high-affinity FcRI receptors that bind to allergen-specific IgE secreted by plasmatic cells. This binding leads to degranulation and the release of histamine and other inflammatory mediators, such as vasoactive amines and lipid mediators, among others. (b) Type II reactions are characterized by IgG and IgM production by plasma cells, targeting cell surface or extracellular matrix self-antigens. Thus, through opsonization, these antibodies activate the complement system and select cells for phagocytosis by neutrophils and macrophages, ultimately recruiting inflammatory cells and inducing tissue damage. (c) Type III reactions are mediated by IgM and IgG antibodies specific to blood-soluble antigens. The recruitment of immune complexes is facilitated by the complement system and Fc receptor and leukocyte activation. Subsequently, immune complexes are deposited into tissue’s vascular endothelium to cause inflammation, thrombosis, and tissue damage. (d) Type IV reactions represent delayed responses mediated by T cells after antigen-professional cells, such as dendritic cells (DCs), present antigens. Tissue injury may result from CD4+ T lymphocytes, which secrete Int. J. Mol. Sci. 2024,25, 467 3 of 20 cytokines inducing inflammation and macrophage activation, or CD8+ cytotoxic T cells, which kill target cells while producing inflammatory cytokines. To further categorize and achieve a better definition of the complex diversity of these reactions, Lerch and Pichler proposed a subclassification of these type IV reactions into four groups: Type IVa, in which cytotoxicity is produced preferentially by the recruitment and activation of monocytes, such as FA. However, in Type IVb, eosinophils are responsible for cytotoxicity, such as DA, whereas CD4+ and CD8+ T lymphocytes recruit and actively induce cytotoxicity in Type IVc, such as autoimmune diseases. Finally, marked by the activation and preferential recruitment of neutrophils attracted by the chemokine CXCL-8 and the granulocyte-monocyte colony-stimulating factor (GM-CSF), T lymphocytes characterize toxicity in Type IVd, such as coeliac disease [19]. 3. Functional Foods (Nutraceuticals) Nutraceuticals play a crucial role in the context of allergies, given their potential to modulate the immune response and reduce inflammation associated with allergic reactions. Derived from various sources, including foods, herbs, specific nutrients, or natural products, these compounds possess properties that can impact the body’s physiology and, in some cases, mitigate allergic symptoms while downregulating mast cell degranulation [ 10 , 20 ]. Some nutraceuticals exhibit anti-inflammatory and antioxidant effects, which can be advantageous in the management of allergies. For instance, certain herbs, such as curcumin, contain compounds that can help mitigate inflammation associated with allergic responses. This review aims to provide an in-depth exploration of the immunological mechanisms of key nutraceuticals known for their modulatory effects on allergic reactions. Therapeutic Nutraceuticals and Their Immunomodulatory Mechanisms Nutraceuticals have demonstrated their effectiveness in regulating the heightened inflammatory response characteristic of allergic reactions. This approach involves intervention in the signaling pathways activated in this type of response, either using nutraceuticals independently or in combination with conventional medications. This strategy presents an attractive opportunity to induce significant alterations in allergy-related immunocellular properties (Table 1). The signaling pathways modulated by nutraceuticals primarily encompass nuclear factor erythroid 2-related factor 2 (Nrf2), mitogen-activated protein kinases (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF κ B) (Figure 1). Sesamin, a natural polyphenolic compound with potent antioxidant effects, has been demonstrated to significantly reduce inflammation in the ovalbumin (OVA)-induced murine model. This reduction is accompanied by a decrease in the expression of cytokines typically associated with a Th2 response pattern, such as IL-4, IL-5, IL-13, and serum IgE levels. In addition, the number of total inflammatory cells and eosinophils decreased in animals treated with sesamin. Furthermore, it was able to reverse the activation of the NFκB signaling pathway [21]. Another study demonstrated that naringenin, a flavanone compound from citrus fruits, significantly reduced OVA-induced airway inflammation and airway reactivity in an animal model. This study showed that, after administering naringenin to these mice, the levels of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid (BALF) and the total IgE levels in the blood decreased. Naringenin was observed to inhibit the NF κ B signaling pathway at the lung level [ 22 ]. Similarly, another study demonstrated that naringenin exhibited antioxidant and anti-inflammatory effects in rats with OVA-induced asthma. They described that treatment with this nutraceutical significantly decreased malondialdehyde (MDA), but on the contrary, it highly increased glutathione (GSH) levels and notably reduced the IL-4 and IL-13 levels in lung tissue. Furthermore, the total eosinophil count was significantly reduced [23]. Int. J. Mol. Sci. 2024,25, 467 4 of 20 Int. J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 4 of 21 Figure 1. Main signaling pathways modulated by nutraceuticals. Sesamin, a natural polyphenolic compound with potent antioxidant effects, has been demonstrated to significantly reduce inflammation in the ovalbumin (OVA)-induced murine model. This reduction is accompanied by a decrease in the expression of cytokines typically associated with a Th2 response pattern, such as IL-4, IL-5, IL-13, and serum IgE levels. In addition, the number of total inflammatory cells and eosinophils decreased in animals treated with sesamin. Furthermore, it was able to reverse the activation of the NFκB signaling pathway [21]. Another study demonstrated that naringenin, a flavanone compound from citrus fruits, significantly reduced OVA-induced airway inflammation and airway reactivity in an animal model. This study showed that, after administering naringenin to these mice, the levels of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid (BALF) and the total IgE levels in the blood decreased. Naringenin was observed to inhibit the NFκB signaling pathway at the lung level [22]. Similarly, another study demonstrated that naringenin exhibited antioxidant and anti-inflammatory effects in rats with OVA-induced asthma. They described that treatment with this nutraceutical significantly decreased malondialdehyde (MDA), but on the contrary, it highly increased glutathione (GSH) levels and notably reduced the IL-4 and IL-13 levels in lung tissue. Furthermore, the total eosinophil count was significantly reduced [23]. The oral administration of Cyanidin-3-O-β-glucoside (C3G), a metabolite produced by Saccharomyces cerevisiae, in IgE-sensitized mice before antigen inoculation suppressed passive cutaneous anaphylaxis reaction. The mechanism involved in this suppression was the inhibition of β-hexosaminidase (𝛽-Hex) and the release of histamines mediated by IgE, thus preventing mast cell degranulation. These results suggest the potential of C3G for the prevention or treatment of type I allergies [24]. Musa paradisiaca inflorescence (MPI), a banana product with immune bioactivity, has demonstrated immunomodulatory capabilities in a mouse model of combined AR and AS. MPI inhibits type 2 immune cells through the NFκB pathway and decreases the expression levels of the CD86 and HLA-DR markers on human M1 macrophages independent of M2 modulation [25]. Figure 1. Main signaling pathways modulated by nutraceuticals. The oral administration of Cyanidin-3-O- β -glucoside (C3G), a metabolite produced by Saccharomyces cerevisiae, in IgE-sensitized mice before antigen inoculation suppressed passive cutaneous anaphylaxis reaction. The mechanism involved in this suppression was the inhibition of β -hexosaminidase ( β -Hex) and the release of histamines mediated by IgE, thus preventing mast cell degranulation. These results suggest the potential of C3G for the prevention or treatment of type I allergies [24]. Musa paradisiaca inflorescence (MPI), a banana product with immune bioactivity, has demonstrated immunomodulatory capabilities in a mouse model of combined AR and AS. MPI inhibits type 2 immune cells through the NF κ B pathway and decreases the expression levels of the CD86 and HLA-DR markers on human M1 macrophages independent of M2 modulation [25]. Recently, resveratrol, a natural phenol from different plants, has been shown to inhibit mast cell degranulation by decreasing β -Hex release through the inhibition of phosphatidylinositol (PI) 4-kinase type II in animal models [ 10 ]. Moreover, resveratrol inhibits STAT3 and MAPK (ERK1/2) pathways in human mast cells activated by IgE [ 10 ]. Furthermore, resveratrol has also shown, at low concentrations, to exert anti-inflammatory properties through the arachidonic acid pathway, inhibiting prostaglandin D2 (PGD2) biosynthesis and enhancing the release of TNF from human mature mast cells after IgE-dependent activation [ 26 ]. In this line, resveratrol decreased the release of β -Hex and histamine in rat basophilic leukemia-2H3 cells, decreasing serum blood-specific IgE. Moreover, resveratrol inhibited the release of β -hex and histamine in bone marrow-derived cells and alleviated mast cell-mediated passive cutaneous anaphylaxis reactions [ 27 ]. Another study indicated that oral administration of resveratrol inhibited the immune response in mice with OVA- induced asthma. They demonstrated that the mechanism of action was mediated by an increase in FOXP3+ cells, and subsequently alteration of the miRNAs profile, specifically, resveratrol induced a regulation of miR-34a in lung infiltrating cells [28]. Carnosol, a diterpenoid found in rosemary extracts, exhibits anti-inflammatory and antioxidant effects. Its impact was investigated in an asthma murine model, revealing that carnosol treatment effectively inhibited t mast cell degranulation and decreased eosinophils in the BALF of the asthma murine model. Moreover, carnosol also inhibited inflammatory responses by decreasing IL-4 and IL-13 in both BALF and lungs [ 29 ]. In association with this, the main polyphenolic constituent of rosemary extract, carnosic acid (CA), demonstrated the ability to mitigate the allergic response in early and late phases of bone marrow-derived mast cells (BMMCs) sensitized with IgE and stimulated with the allergen. The results showed an inhibition of Syk phosphorylation and a reduction in Akt phosphorylation, along with the blockade of the NF κ B pathway. Additionally, CA blocked intracellular Ca 2+ mobilization, allergen-induced reactive oxygen species (ROS) production, and subsequent mast cell degranulation. Furthermore, CA decreased the release of proinflammatory cytokines and chemokines (IL-6, TNF, IL-13, CCL1, CCL2, CCL3, and CCL9) by selectively inhibiting the activity and phosphorylation of Syk, Akt, and the NF κ B pathway in animal models of allergic inflammation [30]. Int. J. Mol. Sci. 2024,25, 467 5 of 20 Curcumin, the active compound in the curry spice turmeric, possesses anti-inflammatory properties. In fact, it has been demonstrated that ingestion of curcumin during exposure to oral allergens inhibits mast cell activation and intestinal anaphylaxis in OVA-allergic mice. In this case, what was blocked was the signaling pathway that inhibits phosphorylation of the p56 subunit of NFkB [31]. Piperine, the major alkaloid present in long pepper and black pepper, demonstrates anti-allergic effects. This nutraceutical has been shown to inhibit eosinophil infiltration and the Th2 response in an OVA-induced asthma model [ 32 ]. In addition, oral administration of pepper nigrum extract (PNE) in an OVA-induced AR mouse model inhibited early phase allergic nasal symptoms. PNE also blocked the infiltration of inflammatory cells, such as eosinophils, in both nasal lavage fluid (NLF) and nasal tissue. Furthermore, PNE prevented the activation of STAT3 and NF κ B signaling pathways, leading to an increased synthesis of Th1 cytokines and the suppression of Th2 and Th17 cytokines [33]. Quercetin, a common polyphenol found in various natural sources like onions and shallots, is an aglycone bioflavonoid. This nutraceutical inhibits the release of allergic mediators (IgE-mediated), such as histamine, TNF- α , IL-1 β , IL-6, and IL-8, in rats and human cell lines, such as RBL-2H3 and HMC-1 mast cells, and it also inhibits Ca 2+ entry and the NF κ B signaling pathway [ 34 ]. Quercetin has been proposed as a natural treatment for AR [35]. Baicalin is a flavonoid compound present in plants of the genus Scutellaria (Lamiaceae), specifically in leaves and stem bark. Moreover, this compound exhibits anti-allergic and anti-inflammatory activities. Baicalin inhibits the release of histamine, β -hex expression, and the JAK2-STAT5 and NF-kB signaling pathways in human HMC-1 mast cells stimulated with lipopolysaccharide (LPS), blocking the inflammatory response [ 36 ]. Furthermore, this nutraceutical has been employed to regulate the immune response in a mouse model of FA [37]. Berberine, a quinoline alkaloid found in plants, possesses anti-inflammatory properties. Berberine has been shown to reduce allergic inflammation in a house dust mite AR mouse model, decreasing levels of specific IgE and transcriptional factors such as GATA-3 and T- bet. Furthermore, this nutraceutical has been shown to increase Treg cells [ 38 ]. Additionally, it reduces the release of β -hex, histamine, IL-4, and TNF- α in RBL-2H3 cells and blocks the activation of the MAPK pathway in mouse models of passive cutaneous anaphylaxis [39]. Omega-6 and omega-3 fatty acids, along with their metabolites, have demonstrated positive effects in AS models and allergic diseases [ 40 ]. Among them, Fat-1 was employed as a mouse model with increased n-3 or n-6 polyunsaturated fatty acids (PUFA) in tissue. They demonstrated that transgenic Fat-1 mice with OVA-induced allergic airway reaction modulated the Th2-cell response with a decrease in IL-5, IL-9, and IL-13 in BALF [ 41 ]. In addition, alpha-linolenic acid (ALA) has been found to decrease AR in an animal model by increasing the production of 15-hydroxyeicosapentaenoic acid (15-HEPE), a metabolite of eicosapentaenoic acid (EPA). In fact, the intranasal injection of 15-HEPE inhibited mast cell degranulation in this animal model [42]. Short-chain fatty acids (SCFAs), such as butyrate and propionate, obtained through microbial fermentation of dietary intake fibers, have demonstrated protective effects against allergic reactions [ 43 , 44 ]. It has been shown that butyrate decreases the activation of human eosinophils. Additionally, this nutraceutical has improved allergen-induced eosinophilia in the pulmonary system and reduced the production of Th2 cytokines (IL-4 and IL-13) in BALF from an OVA-induced pulmonary inflammation mouse model [45]. Dietary fiber, resistant starch (RS), positively influences biomarkers such as glucose metabolism and blood [ 46 , 47 ]. Additionally, RS supplementation can enhance satiety, and its prebiotic effects contribute to a positive impact on the gut microbiome, promoting increased microbial diversity [ 48 ]. In vitro studies suggest that fibers like inulin and arabinoxylan hydrolysates can influence the secretion of cytokines and chemokines by epithelial cells, macrophages, and DCs. Fibers can also directly affect immune cells through the activation of pattern recognition receptors (PRRs), including C-type lectin receptors Int. J. Mol. Sci. 2024,25, 467 6 of 20 (CLRs), galectins, and Toll-like receptors (TLR-2 and TLR-4). Some fibers, like pectin, may inhibit PRR activation, as demonstrated by its blocking of TLR-2-induced cytokine secretion [49]. Astaxanthin (ASX) is a xanthophyll carotenoid found in various sources, including algae, fungi, plants, seafood, and certain bird species like flamingos. This nutraceutical possesses anti-inflammatory and antioxidant properties [ 11 ]. ASX decreases the inflammatory response while reducing the imbalance of Th1/Th2 cells and modulating the production of IL-4, IL-5, and IFN-γin the BALF in a mouse OVA-induced asthma model [50]. Sulforaphane (SFN), an isothiocyanate of vegetable origin with potent antioxidant and anti-inflammatory properties, regulates the immune response (including the modulation of DCs activity with the specific proliferative response of Treg cells) [ 51 ]. Preliminary results from our group determined that SNF inhibits the inflammatory reaction induced by LPS in innate cells through MAPKs (p38, p44, and p42) along with the NKkB signaling pathways. In fact, SFN administration in patients with asthma has shown an improvement in bronchoprotection response, accompanied by increased expression levels of NADH- quinone oxidoreductase 1, indicating the involvement of Nrf2-mediated gene pathways [ 52 ]. SFN administration has also reduced neutrophil-induced airway inflammation, inhibited myeloperoxidase, and suppressed Th17 proinflammatory responses. The signaling pathway involved was Nrf2. However, the combination of corticosteroids and SFN has inhibited both innate (neutrophilic and eosinophilic) and adaptive Th17/Th2 responses in the airways, decreasing inflammatory cytokines IL-6, IL-23, and IL-17A during treatment in a mouse model of asthma [ 53 ]. Finally, SFN has reversed chronic inflammation by activating the Nrf2 antioxidant signaling pathway, leading to reduced pulmonary mRNA expression of TNF α , SMAD2, IL6, IL-1 β , IL-8, and MIP-1 β in a chronic allergic disease model induced by OVA in mice [54]. In the following section, the review will discuss the most relevant nutraceutical remedies used in managing patients with AR, FA, and AD. Table 1. Immunomodulatory effect of nutraceuticals in vitro and in vivo models. Nutraceuticals Study Design Immunomodulatory Effect Refs. Sesamin Asthma murine model ↓NFκB and ↓(IL-4, IL-5, and IL-13) ↓IgE [21] Naringenin Asthma/Inflammatory murine model ↓NFκB and ↓(IL-4 and IL-13) [22] ↓MDA, ↓(IL-4 and IL-13) in lung tissues, and ↓total eosinophils ↑GSH [23] C3G Cutaneous reaction in murine model ↓β-Hex and ↓histamine release IgE-mediated. ↓Mast cell degranulation [24] MPI Murine model, combining AR and asthma and human M1 macrophages ↑Th1 profile ↓Type 2 immune cells ↓NFκB pathway ↓CD86 and ↓HLA-DR [25] Resveratrol Murine model ↓Mast cells degranulation with ↓β-Hex by ↓PI 4-kinase ↓IgE-mediated histamine release [10] Human mast cells from AR patients ↓IgE- mediated β-Hex release ↓pSTAT3 and pERK1/2 ↓Nasal symptoms in AR patients with ↓(IgE, IL-4, and TNF-α) ↓Eosinophils in blood Human mast cells from AR patients ↓PGD2 ↑TNF in mast cells after IgE-dependent activation [26] Rat basophilic leukemia-2H3 cells and AR murine model ↓β-Hex ↓IgE-mediated histamine ↓(DCs and B and mast cells) ↓TXNIP pathway ↓(PGD2, LTC4, ECP, IL-4, IL-5, IL-6, IL-33, and TNF) [27] Asthma murine model ↑FOXP3+ cells ↓miR-34a in lung infiltrating cells [28] Int. J. Mol. Sci. 2024,25, 467 7 of 20 Table 1. Cont. Nutraceuticals Study Design Immunomodulatory Effect Refs. Carnosol Asthma murine model ↓Mast cells degranulation ↓Eosinophils ↓(IL-4 and IL-13) [29] Allergic inflammation model ↓(Syk, Akt phosphorylation, and NFκB). ↓Intracellular Ca2+ mobilization ↓ROS production and β-Hex release ↓Mast cells degranulation, and ↓(IL-6, TNF, IL-13, CCL1, CCL2, CCL3, and CCL9) [30] Curcumin Allergic inflammation model ↓Mast cell activation and ↓NFκB signaling pathway [31] Piperine Asthma and AR murine model ↓Eosinophil infiltration ↓Th2 response and ↑Th1 cells ↓STAT3 and NFκB signaling pathways [32,33] Quercetin Human HMC-1 mast cells from AR patients ↓(Histamine, TNF-α, IL-1β, IL-6, and IL-8) and Ca2+ ↓NFκB signaling pathway ↓Allergic symptoms in AR patients [34] Baicalein AR and FA murine model ↓(Histamine, OVA-IgE, IL-1β, IL-6, IL-8, and TNF) ↑Treg in a mouse [36] Human HMC-1 mast cells ↓(Histamine and β-hex) ↓JAK2-STAT5 and NF-kB signaling pathways [37] Berberine House dust mite AR murine model ↓(sIgE, GATA-3, and T-bet mRNA levels, L-10) ↓Eosinophil infiltration and ↑Treg [38] Cutaneous anaphylaxis murine model ↓Mast cell activation by ↓(β-hex, histamine, IL-4 and TNF) ↓MAPK signaling pathway [39] PUFAs Transgenic Fat-1 murine model (allergic airway) ↓Th2-cell response [41] AR animal model ↓degranulation mast cells [42] SCFAs Keratinocyte humans Protection and reprogramming of skin barrier function and metabolism [43] Pulmonary inflammation murine model ↓Eosinophils ↓Th2 (IL-4 and IL13) [45] Fiber (RS) In vitro model: HEK-Blue™ TLR cells and macrophage cells RAW264.7 ↑Modulation of immune cells and chemokine secretion via CLRs or TLRs [49] ASX Asthma murine model ↓Th1/Th2 cells ↓(IL-4 and IL-5) and ↑IFN-γ) and ↓IgE [50] SFN Asthma patients ↑Bronchoprotective response ↓Nrf2 signaling pathway [52] Asthma animal model ↑antioxidant effects ↓Th17 responses [53] mRNA ↓(TNF-α, SMAD2, IL6, IL-1β, IL-8, and MIP-1β) expression [54] Abbreviations: AR, allergic rhinitis; MDA: malondialdehyde; β -Hex: β -hexosaminidase; PI 4-kinase: phosphatidylinositol 4-kinases; PGD2: prostaglandin D2; TXNIP: thioredoxin-interacting protein; SYK: Tyrosineprotein kinase SYK; ROS: Reactive oxygen species; PUFAs: polyunsaturated fatty acids; SCFA: Shortchain fatty acids; SFN: Sulphoraphane; ASX: Astaxanthin; C3G: Cyanidin-3-O- β -glucoside; MPI: Musa paradisiaca inflorescence; RS: Resistant starch; CLRs: C-type lectin receptors; TLRs: Toll-like receptors. ↓(reduction). ↑(increase). 4. Nutraceuticals and Allergic Rhinitis (AR) AR is a chronic inflammatory respiratory disorder associated with IgE [ 55 ]. The immunological response in AR involves a variety of inflammatory cells, including mast cells, T cells, B cells, macrophages, and eosinophils. Recent research has identified immune cells such as ILC2s, Th2 cells, DCs, and epithelial cells as important players in AR pathogenesis [ 56 ]. Exposure to allergens activates DCs, initiating a cascade that involves Th2 cells, cytokine release, production of allergen-specific IgE by B cells, and the triggering of allergic responses through mast cells and basophils [57,58]. There are different treatments for AR that control the exaggerated immune response to allergens and alleviate symptoms, such as antihistamines, nasal corticosteroids, an- Int. J. Mol. Sci. 2024,25, 467 8 of 20 tileukotrienes (montelukast), and specific allergen immunotherapy (AIT) [ 56 , 59 ]. However, these treatment approaches may prove ineffective in certain instances. Consequently, both in vitro and in vivo research have been conducted to create AR models, and these investigations also evaluate the impact of various nutraceuticals (Table 2). Quercetin and SFN have been investigated for their ability to reduce the allergic response by inhibiting the release of inflammatory mediators, thereby helping to relieve the symptoms of the pathology [ 60 , 61 ]. One study examined the impact of quercetin on the production of nitric oxide (NO) in human nasal epithelial cells (HNEpC) following IL-4 stimulation. The findings of the study suggested that quercetin may have a therapeutic effect on AR by influencing the behaviour of HNEpC cells [ 62 ]. Thioredoxin (TRX) is a protein known for regulating oxidative metabolism and neutralizing reactive oxygen species, which play a role in suppressing allergic inflammation [ 63 ]. A study determined quercetin’s impact on AR symptoms and TRX production in nasal cells both in vitro and in vivo . Results showed that taking quercetin orally notably decreased nasal symptoms and raised TRX levels in nasal fluids. This boost in TRX production by quercetin might enhance its effectiveness in treating AR [ 64 ]. Recently, it has been investigated the anti-allergic effects of the oral intake of quercetin as a supplement on allergen-induced reactions in AR adult subjects in a randomized controlled trial. Their results showed that allergic symptoms improved after 4 weeks of repeated oral administrations [ 65 ]. In a clinical study conducted with a randomized, double-blind design and a placebo control group, SFN demonstrated its effectiveness in reducing type 2 cytokines such as IL-4, IL-5, and IL-13 found in the mucus of the nasal cavity in AR patients compared to the control group. Furthermore, nasal symptoms (TNSS) and peak nasal inspiratory flow (PNIF) showed notable improvements after 3 weeks of treatment with SFN [66]. Subsequently, in a clinical trial featuring a double-blind, randomized, and placebocontrolled design, AR patients who received resveratrol exhibited a reduction in nasal symptoms, serum IgE, IL-4, TNF- α , and eosinophil levels, as compared to the AR patients in the placebo group [ 28 ]. In fact, resveratrol also presented anti-allergic and antiinflammatory effects by inhibiting the thioredoxin-interacting protein (TXNIP), decreasing specific IgE levels, and reducing inflammatory mediators in an AR model [27]. In an animal model of OVA-induced AR, the potential therapeutic benefits of a piper nigrum extract were explored. The mice that were treated with piper nigrum extract presented a notable reduction in histamine release from mast cells, a decrease in nasal symptoms, and a reduction in eosinophil infiltration. Furthermore, the extract played a protective role in preventing nasal epithelial barrier dysfunction by elevating the expression of the active form of Nrf2, thereby promoting the synthesis of the anti-inflammatory enzyme HO-1 [33]. Similar results were found for baicalin, which showed an inhibitory effect on allergic response in OVA-induced AR pigs and in LPS-stimulated human mast cells [ 36 ]. Berberine reduced allergic inflammation in a house dust mite AR mouse model, decreasing the specific-IgE levels and increasing the regulatory response [38]. Omega-3 fatty acids (EPA) are found in fatty fish and have anti-inflammatory properties that could help reduce inflammation in AR [ 67 ]. In an in vivo study using an animal model of AR, it was found that linseed oil, abundant in ALA, lessens AR by encouraging eosinophils to produce 15-HEPE, an EPA metabolite. Notably, 15-HEPE, generated by eosinophils, suppressed allergic symptoms by hindering mast cell degranulation through peroxisome proliferator-activated receptor gamma. This suggests a promising treatment for AR [42]. In the study of dietary fiber, a single-blinded randomized controlled trial investigated the impact of a 15 mg dose of dried Ma-al-Shaheer (a traditional Iranian medicine based on barley, Hordeum vulgare) compared to a twice-daily dosage of 60 mg fexofenadine (an antihistamine) in AR patients over a 21-day period. Both groups exhibited improved AR control, and symptoms were significantly reduced in both sets of participants. However, the reduction in nasal congestion, post-nasal drip, and headache appeared slightly more pronounced in the Ma-al-Shaheer group [68]. Int. J. Mol. Sci. 2024,25, 467 9 of 20 Table 2. Achievements of nutraceuticals as alternative therapies in AR. Nutraceuticals Refs. Source of Nutraceuticals Phase of Allergic Reaction Achievements Limitations Quercetin [62–65]Isolated from a natural source. Commercially obtained In vitro models under specific IL-14 stimulation. Onset phase in animal model, after sensitization phase. Clinical trial in AR patients in the sensitization phase. Suppressive effect on NO production from nasal epithelial cells. Increase of TRX production in nasal epithelial cells and animal models. Significant decrease in allergy nasal symptoms (seizing and rubbing). Lack of food matrix Low bioavailability Lack of research on dosage and forms of administration Limited research in humans and clinical trials Lack of studies of possible interactions with other drugs Sulforaphane [66]Broccoli sprout extract, including sulphoraphane. Clinical trial in AR patients in the sensitization phase. Anti-inflammatory and anti-allergic properties in AR patients, with the improvement of nasal symptoms. Resveratrol [27,28]Isolated from natural sources (for example, Abies georgei). Onset phase in animal model, after sensitization phase. Reduction of nasal symptoms. Anti-allergic and anti-inflammatory properties. Piper [69] Piper nigrum extract. Reduction of nasal symptoms and inflammatory mediators. Baicalin [36]Isolated from natural sources. Commercially obtained. Anti-allergic response in OVA-induced AR pigs and in LPS-stimulated human mast cells. Berberine [38]Isolated from natural sources. Commercially obtained. Reduction of the inflammatory and increase in regulatory response. Omega-3 fatty acids [67]Dietary fatty acids on allergic models. Before the sensitization phase in animal models. Suppression of the allergic symptoms. Fiber [68]Natural formulation from Hordeum vulgare. Clinical trial in AR patients in the sensitization phase. All symptoms of AR except cough were significantly reduced. 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