Dietary xenobiotics and their role in immunomodulation

Abstract

Within our daily dietary intake, lies an intriguing and frequently overlooked dimension— the realm of dietary xenobiotics. These chemical compounds originate from different food sources like grilled or processed meat (animal-origin), flavonoids, preservatives, beverages(plant-origin) and so on. Numerous studies have explored the oncogenic properties. Additionally, these compounds also result in interrupting the humoral and cellular immune response. This review specifically concentrates on elucidating the regulatory functions of these dietary xenobiotics within the human immune system. While some, like heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), are predominantly deemed harmful, certain other compounds, such as specific phenolic compounds and nitrates, have exhibited therapeutic benefits. Furthermore, the review notes the immunomodulatory role of two relatively underexplored compounds, acrylamide and maltol. This underscores the necessity to broaden the scope of investigation surrounding these compounds and this review gives a brief overview of these xenobiotics interfering with the immune system.

Graphical abstract

Introduction

The word "xenobiotics," which refers to foreign things in living form, is derived from the Greek words "xenos" (foreign) and "bios" (life). They are mostly natural as well as synthetic compounds which are typically not involved in metabolic pathways and are adventitious in nature. Most of these compounds are directly introduced into the ecosystem by anthropogenic activities like industrial processes, urbanization, waste disposal, agriculture, breeding, etc. The various natural and synthetic compounds used during these activities have the crucial common feature of being foreign to the biological system. Along with that the physicochemical structures of these compounds makes them extremely challenging to identify, quantify, and eliminate. Some of which include small molecular size, ionizability, water solubility, lipophilicity, polarity, and volatility (de Oliveira et al., 2020). Thus, all biological systems are inevitably exposed to these chemical substances throughout life, from conception to adulthood, and as a result, may experience unprecedented negative effects (Kreitinger et al., 2016). Research shows some of these compounds can be extremely hazardous to most life forms, from primitive prokaryotes to highly complex organisms, including humans. Even modest quantities may show toxic, mutagenic, or teratogenic effects with prolonged exposure according to various research groups.

Food products contain a variety of xenobiotics, including substances like flavorings, preservatives, thickeners, and colorants, which collectively fall under the term "dietary xenobiotics." Depending on their source, these items can be categorized as either of animal or plant origin. In the case of food derived from animals, meat products are a major source of these xenobiotic compounds. While these foods inherently contain nutritional and bioactive components, additional chemicals are often introduced through cooking, processing, and preservation methods to enhance their taste, safety, and digestibility. Notably, certain compounds like heterocyclic amines (HAs) and polycyclic aromatic hydrocarbons (PAHs) are formed during high-temperature cooking processes, even though they are not naturally present in the original foods. Nitrites and nitrates, commonly associated with food, also play a role in this context (Bertel-Sevilla et al., 2020; Greer and Shannon, 2005). Heterocyclic amines (HAs) are generated through the Maillard reaction, which involves the interaction of muscle creatine and/or creatinine, sugars, and amino acids (Dennis et al., 2015). The existing literature indicates that the primary dietary origins of HAs are meat and meat products (Table 1). Another significant compound, categorized by the International Agency for Research on Cancer (IARC) as a probable human carcinogen (Group 2A), is acrylamides (Zapico et al., 2022). It results from the Maillard reaction in carbohydrate-rich foods, like potatoes or cereals, through the condensation of reducing sugars (glucose or fructose) and free amino acids (e.g., asparagine) during baking or frying (Dybing et al., 2005; Xu et al., 2014). As discussed previously, PAHs are generally absent in raw foods but have been detected in foods from industrialized regions due to atmospheric contamination (Aravind and Kamaraj, 2022). On the other hand, high levels of PAHs, found in smoked products and grilled meats, are formed by the pyrolysis processes at high temperatures. These processes can include direct contact of lipids with an open flame or heat source, exposure to cooking smoke, or incomplete combustion of wood or charcoal during cooking. Once formed, these compounds deposit on the surface of the cooking meat (Miller et al., 2013). Another major group of dietary xenobiotic compounds is phenolic compounds, including flavonoids and isoflavones, which are detected in raw vegetables and other plant products (Table 1) (Kong et al., 2001; Rezai-Zadeh et al., 2008). These compounds are recognized to possess potential beneficial effects under various circumstances. However, further in-depth studies are necessary to firmly establish their benefits with a higher degree of certainty. Maltol, an alternative food flavor enhancer, has also been subject to study and has demonstrated potential beneficial effects. Despite the limited research conducted on this compound, there exists a significant scope for conducting novel and comprehensive studies to further explore its potential benefits and hazards (Mi et al., 2018; Park et al., 2021).

Table 1.

Sources of different dietary xenobiotics and their detrimental effect on the host

Characteristics	Classification	Xenobiotics detected	Threat possessed	References
Origin: 1. Animal origin:	Chicken breast (cholesterol, MUFA, PUFA,proteins, iron)	PhIP, DiMeIQx (HA)	Intestinal polyp and Mutagenecity, Oxidative stress Forestomach tumor	Zapico et al. (2022), Ruiz-Saavedra et al. (2022) Carvalho et al. (2015) Ushijima et al. (1995)
	Pork loin and beef	MeIQx (HA)
	Fried beef Processed and cooked ham	DiMeIQx, MeIQx (HA) Nitrites and nitrosamines	Non- hodgkin lymphoma Pancreatic cancer	Murray et al. (1988), Aschebrook-Kilfoy et al. (2012), Coss et al. (2004)
2. Plant origin:	Alcoholic beverages (beer and wine)	DMBA, BaP (PAH)	Malignancy in prostate	Kooiman et al. (2000)
	Vegetables (fibres, cellulose, hemicellulose, flavanoids)	Nitrates	Methemoglobinemia in infants, Tachycardia	Greer and Shannon (2005)
		Green tea polyphenols (GTP) (2)-epigallocatechin-3-gallate (EGCG) (from flavonoids)	Necrosis or apoptosis	Kong et al. (2001)
	Cereals, potatoes, white bread and cookies	Acrylamide	Cognitive dysfunction in diabetic individuals Carcinogenic	Quan et al. (2022) Xu et al. (2014)
Processing of meat	Sausages and preserved meat	Nitrites	Carcinogenic	EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) et al. (2017)
	Grilled chicken	PhIP (HA)	Squamous cell carcinoma of the esophagus	Carvalho et al. (2015) Stefani et al. (2012) Zimmerli et al. (2001)
	Fried chicken	PhIP level increases as the temperature increases (HA)
Processed food	Food preservatives	Potassium nitrate	In high doses results in carcinogenic	Maguire et al. (2017)
		Butylated hydroxyanisole (BHA) de-methylated metabolite t-butyl hydroquinone (tBHQ) (phenolic antioxidants) (flavonoids)	Tissue necrosis	Kong et al. (2001)
		Allyl isothiocyanate (AITC)	Cytotoxic and tumorigenic at high doses	Jiao et al. (1994)
		Maltol	Carcinogenic	Anwar-Mohamed and El-Kadi (2007)

The fate of dietary xenobiotics in the human body

The process by which xenobiotics are metabolized and absorbed in humans vary from compound to compound and hence several pathways have been identified in various studies.

For xenobiotic compounds that are of animal origin like HA and PAH, several microsomal enzymes like p450 isoenzymes play a very pivotal role in their metabolism either in the small intestine or liver. One such enzyme is CYP1A1 which is present in the enterocytes, while they lack CYP1A2 (another isoenzyme). A study stated that the consumption of chargrilled meat led to a significant induction of liver CYP1A2 activity in all participants and at the same time had profound effects on small intestinal CYP1A1 expression (Fontana et al., 1999) (Fig. 1). However, recent research has shown that the intestinal metabolism of HA is predominantly catalyzed by CYP3A enzymes rather than CYP1A1 (McKinnon et al., 1992). Other CYP3A enzymes, particularly CYP3A4, are the primary cytochrome P450 isoenzymes responsible for generating 3-OH benzo[a]pyrene (B(a)P), a significant metabolite of B(a)P found in humans (Yun et al., 1992) (Fig. 1). Liver and kidney are also the major sites of xenobiotic detoxification by a group of enzymes called the UGT, which stands for UDP glucosyltransferase superfamily. These help by adding a sugar residue to small lipophilic chemicals. UGTs may also be expressed in the gut, where they metabolize dietary xenobiotics as well as endobiotics. The UGT1 and UGT2 enzyme families utilize UDP-glucuronic acid, while UGT3 enzymes employ UDP-N-acetylglucosamine, UDP-glucose, and UDP-xylose as co-substrates for conjugating xenobiotics. This metabolic process enhances the polarity of the substrate, making it more easily excreted from the body and potentially rendering it functionally inactive (Meech et al., 2015). The aforementioned xenobiotic compounds are typically eliminated through the urinary tract, but in certain cases, fecal elimination may also occur (Fig. 1). The liver plays a crucial role as the central hub for phase II metabolism and transport of xenobiotics, facilitated by the action of multidrug resistance protein 2 (Mrp2). It is an ATP-binding cassette transporter protein and helps in the biotransformation of these xenobiotic compounds. Within the gastrointestinal tract, the proximal portion of the small intestine harbors a notable concentration of phase II enzymes and the protein Mrp2, primarily located at the apex of the villi. This process leads to the excretion of conjugated metabolites into bile and is followed by fecal elimination (Arana et al., 2014; Moscovitz et al., 2016) (Fig. 1).

Fig. 1.

Fate of certain animal source-derived dietary xenobiotics in human body: In the small intestine, P450 isoenzymes, including CYP1A1 and CYP3A4, break down xenobiotic compounds such as PAH and HCA. Notably, CYP3A4 plays a crucial role in biotransforming B(a)P by introducing an (OH) group. Within the liver, Phase II metabolism enzymes aid in the biotransformation of these compounds. The multidrug-resistant protein (MrP2) facilitates enzyme activation, leading to the elimination of transformed compounds through feces. UGT superfamily enzymes also actively participate, converting the compounds into a polar form for rapid excretion through urine

Many of the plant-derived phenolic compounds like flavonoids exist as β-glycosides, which are hydrolyzed to enable further metabolism, conjugation, and elimination. Traditionally, it was believed that glycoside hydrolysis primarily occurred in the colon, facilitated by microbial β-glucosidases (McIntosh et al., 2012). However, emerging evidence suggests that absorption through the colon is not the sole route for dietary xenobiotics to enter the bloodstream. Certain glycosides can be actively transported inside the enterocytes by hexose transporters like the sodium-dependent glucose transporter (SGLT1) (Passamonti et al., 2009) (Fig. 2). Other pharmacokinetic studies reveal that the absorption of numerous xenobiotic glycosides may take place rapidly after ingestion, indicating uptake before these compounds reach the colon (Hollman et al., 1996).

Fig. 2.

Fate of certain plant source-derived dietary xenobiotics in human body: phenolic compounds, such as flavonoids and isoflavones, undergo diverse metabolic processes upon ingestion. While some, like quercetin, are absorbed even before reaching the small intestine, the majority exists in the form of β-glucosides. These β-glucosides undergo breakdown facilitated by β-glucosidases, released by gut microbiota, or by lactase phlorizin hydrolase located on the epithelial surfaces. Subsequently, the resulting aglycones are transported into enterocytes through the sodium-dependent glucose transporter (SGLT1)

Dietary xenobiotics and human lymphatic system

The lymphatic system is a crucial component of the human body's immune and circulatory systems, playing a pivotal role in maintaining tissue fluid balance, filtering harmful substances, and facilitating immune responses. Comprising a network of vessels, nodes, and organs, the lymphatic system transports lymph, a clear fluid containing white blood cells and waste products, throughout the body (Margaris and Black, 2012; Charman and Stella, 2019). It serves as a dynamic highway for immune cells, allowing them to surveil and defend against invading pathogens and abnormal cells (Swartz et al., 2008). In addition to its immunological functions, the lymphatic system aids in the absorption of dietary fats and fat-soluble vitamins from the intestines (Charman and Stella, 1991). Given its intricate involvement in immune responses and metabolic processes, it is essential to explore how dietary xenobiotics, which include foreign chemical compounds, may impact the function and integrity of the lymphatic system. The uptake of some xenobiotic compounds, into the lymphatic system is heavily influenced by the absorption of lipids (Shibamoto and Bjeldanes, 2009). Each villus contains a central lacteal that transports fluid through lymphatic capillaries to the mesenteric lymph duct. Following the digestion of dietary lipids, chylomicrons, which are large lipoproteins (ranging from 200–800 nm), are secreted within enterocytes. Due to their size, chylomicrons cannot be absorbed directly into the bloodstream and instead are taken up by the lymphatic system (Tso and Balint, 1986). Xenobiotics which may be either lipophilic or non-lipophilic, behave differently based on their solubility. Non lipophilic are more likely to be soluble into the aqueous milieu of Gastrointestinal lumen, allowing for direct absorption. While lipophilic xenobiotics such as phytochemicals like carotenoids, are hydrophobic and not soluble in the aqueous environment of the gastrointestinal tract. Therefore, they require the co-consumption of lipids to aid in their dissolution and to form micelles, lipoproteins, or chylomicrons for effective absorption alongside lipids into the lymphatic system (Neilson et al., 2017; Shibamoto and Bjeldanes, 2009). There has been limited research on the immunomodulatory effects of these xenobiotics, and this review paper explores the immunomodulation induced by these dietary xenobiotics and sheds light on potential implications for the well-being of human beings.

Effect of dietary hetero amines in the immune system of the host

Dietary heterocyclic amines (HCAs) are a group of compounds that are formed during the cooking process of certain foods, particularly those that are high in protein and exposed to high temperatures (Carvalho et al., 2015). These compounds are considered heterocyclic because of their ring-like structure, which contains at least one nitrogen atom (Nadeem et al., 2021). HCAs have gained significant attention in recent years due to their potential association with adverse health effects, including an increased risk of certain types of cancer. Understanding the formation, sources, and potential health implications of dietary heterocyclic amines is important for developing strategies to minimize their intake and mitigate any potential risks.

A study on food-borne heterocyclic amine called 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) has shown that it has immune inhibitory response on tumor necrosis factor-alpha (TNF-α). The study clearly showed that on treatment of PhlP on Lipoteichoic acid (LTA) (a virulence factor released by Gram-negative bacteria) stimulated macrophage (RAW 264.7 cells), resulted in suppression of TNF-α expression (Im et al., 2009) which is typically involved in apoptosis of tumor cells (Tian et al., 2014). Similarly, another study showed that PhIP can also affect the proliferation of invitro-stimulated murine thymocytes or T Cells. In this study when thymocytes were treated with PhIP, it was observed that it decreased the activation of transcription factors like NF-κB, AP-1 and NF-AT which resulted in the decrease of the IL-2 mRNA synthesis and ultimately limited the expression of IL-2. As a result of this, there was a decrease in ROS generation (Yun et al., 2006). In addition to its immunoregulatory effects, co-treatment of PhIP and Triclocarban (TCC), which is an antimicrobial agent used in personal products, resulted in significant cellular changes associated with breast cancer. These changes included increased production of reactive oxygen species (ROS) and activation of the Erk-Nox pathway which in turn can cause abnormal cell proliferation as well as evasion of the normal host immune response (Sood, 2013).

Other heterocyclic amines such as 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MexIQ) can have detrimental effects on lymphocytes. It was observed that on treating lymphocytes in vitro with MexIQ there was an imbalance between antioxidants and ROS thereby causing DNA damage in the treated cells (Najafzadeh et al., 2009). Some studies have shown that the interactions between the host's gut microbiota and dietary HCAs can have an immunomodulatory effect on the host. One such study showed a significant increase in genome damage in Hp-positive (Helicobacter) patients compared to those without the infection. Furthermore, when Hp-infected cells were exposed to highly active mutagens like N-methyl-N'-nitro-N-nitrosoguanidine and other heterocyclic amines (IQ, MeIQx, and PhIP), there was a notable increase in DNA damage. The authors hypothesized that the presence of Hp enhances the metabolic activation of these amines, resulting in the production of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-8. This leads to oxidative stress and DNA damage in the infected mucosa, promoting genomic instability and the initiation of cancer (Poplawski et al., 2013).

Effect of dietary polycyclic aromatic hydrocarbons in the immune system of the host

PAHs (polycyclic aromatic hydrocarbons) are ubiquitous environmental contaminants. These compounds have a high hydrophobicity and low aqueous solubility, which allows them to readily adsorb onto soil and sediment particles. Thus, deposition of PAHs in soil can lead to their uptake by plants, where they get transferred to the edible parts of these plants and enter the food system. In addition to soil deposition, PAHs can also be introduced into the food system through atmospheric and industrial processes. During the combustion of organic materials, such as fossil fuels and biomass, PAHs are generated and released into the atmosphere, which can also be deposited on the plants. Flavored drinks, such as tea, coffee, and alcohol, are also susceptible to PAH contamination due to the processing and production methods involved (Aravind and Kamaraj, 2022). For example, high temperatures in the black tea manufacturing process may reduce the essential oil content, which could facilitate the absorption of polycyclic aromatic hydrocarbons (PAHs) and their release into the aqueous infusion. Additionally, tea leaves may absorb smoke scents containing PAHs that are released from the combustion of biomass during the production of tea products (Phan Thi et al., 2020). Similarly while roasting of coffee at high temperature also generates PAH (Da Costa et al., 2023).

Benzo[a]pyrene (BaP) is a Polycyclic aromatic hydrocarbon (PAH) that is generated by the incomplete combustion of organic substances such as tobacco smoke, exhaust fumes, and grilled or charred foods. An extensive investigation revealed that when immunocompetent cells are exposed to BaP (benzo[a]pyrene), various immunomodulatory effects occur. These effects include reduction in the antigen presentation to the T Cells, overall number of T lymphocytes, inhibition of their proliferation, and disruption of the balance between different subsets of T cells, specifically helper T cells (Th) and cytotoxic T cells (Tc) [Fig. 3(A)]. BaP exposure may also interfere with B cell development, antibody production, and the process of immunoglobulin class switching, potentially compromising the effectiveness of humoral immune responses (Blanton et al., 1988). Furthermore, BaP exposure has been shown to suppress the activity of natural killer (NK) cells, which play a critical role in eliminating infected or cancerous cells, and impair the maturation and function of dendritic cells [Fig. 3(A)]. These dendritic cells are antigen-presenting cells which play a very essential role in initiating and regulating immune responses by activating T cells and coordinating immune cell interactions (Blanton et al., 1988).

Fig. 3.

Immunomodulatory roles of Polyaromatic Hydrocarbons (PAH) and Nitrates: (A) Benzo[a]pyrene (BaP) acts as a ligand for the Aryl hydrocarbon receptors (AhR) present on both T cells and B cells. This interaction is associated with a decline in the proliferation of T cells, interference with B cell development, and a reduction in Immunoglobulin production. Additionally, BaP impacts the antigen-presenting capability of macrophages, contributing to a decrease in Natural Killer (NK) cell production. (B) In contrast, 7,12-dimethylbenz[a]anthracene (DMBA) also exhibits binding to AhR receptors on hematopoietic stem cells (HSC), resulting in a diminished generation of mature neutrophils. (C) Nitrates reduce CRP, IL-6, and TNF-α in venous blood, exhibiting anti-inflammatory effects and lowering Type 2 diabetes (T2D) risk. They also lower MIF associated with cardiovascular diseases. Symbiotic bacteria convert nitrates to nitric oxide (NO), which decreases Th1 cytokines like IFN-γ but increases Th2 cytokines, potentially causing hypersensitivity reactions

Another study showed binding of the PAH compounds like BaP and 1,2 benz(a)anthracene (BA), to the Aryl hydrocarbon (AhR) receptors resulting in release of certain metabolites such as reactive epoxides that can interact with key proteins like tyrosine kinase or ATPase and can modulate the immune system (Ataria et al., 2007). AhR are also expressed in immune cells like B-cells, T cells, NK cells and macrophages. The activation of AhR by different ligands, whether persistent or short-acting, can have contrasting effects [Fig. 3(A)]. In the case of persistent ligands, AhR activation promotes the regulation of regulatory T (Treg) cells, leading to the suppression of autoimmunity. On the other hand, with short-acting ligands, AhR activation can upregulate the expression of Th17 cells, resulting in the production of proinflammatory cytokines. These differential effects of AhR activation on T lymphocytes play a critical role in immune modulation and the balance between immune tolerance and inflammation. (Abel and Haarmann-Stemmann, 2010) On injecting (intraperitoneal) BaP in C57BL/6 mice, there was a significant increase in the liver microsomal EROD (ethoxy resorufin O-deethylase) activity which in turn is associated with the decrease of the splenic plaque-forming cells in the organism. This evidence also proves the immunosuppressive nature of these aromatic compounds (Ataria et al., 2007).

It has also been observed that on exposure of BaP there is a significant B-cell suppression in the host immune system which results in alteration in the host resistance to tumors and bacterial challenge (Frederick et al., 2007). The adverse effects of PAH also include changes in serum immunoglobulin and cytokine levels, alterations in T-cell, B-cell proliferation and variation in natural killer (NK) cell numbers- affecting the calcium homeostasis (Karakaya et al., 2004), altered phagocytic activity in monocytes, and evidence of DNA damage in peripheral lymphocytes (Zaccaria and McClure, 2013).

Research studies involving murine models have demonstrated that 7,12-dimethylbenz[a]anthracene (DMBA), another dietary polycyclic aromatic hydrocarbon (PAH), can suppress natural killer (NK) cells. These studies involved the administration of varying dosages of DMBA to the organisms and the results showed a decrease in NK cell activity, indicating the immunosuppressive effects of DMBA on these specific immune cells (Dean et al., 1986; Kimber et al., 1986).

A study was designed to understand DMBA-induced myelotoxicity, mainly affecting the bone marrow and its cellular components [Fig. 3(B)]. The findings of the study indicate that AIRmin mice (mice with low acute inflammatory response) exhibit greater susceptibility to DMBA-induced toxicity compared to AIRmax mice (mice with high inflammatory response). This susceptibility is characterized by an increase in immature myeloid precursors and a significant decrease in mature neutrophils in the bone marrow, thus showing a direct impact on the acute inflammatory response. The increased susceptibility observed in AIRmin mice may be influenced by the activation of the aryl hydrocarbon receptor (AhR) through its high affinity binding to DMBA. This activation leads to an imbalance in the cellular differentiation process within the bone marrow, which subsequently affects the production of functional cells for the immune system (Katz et al., 2014).

Histological study of the salivary glands of DMBA induced rats revealed the presence of an inflammatory reaction characterized by the infiltration of various inflammatory cells, including polymorphonuclear leukocytes (PMNs), macrophages, lymphocytes, and plasma cells. The authors hypothesize that the observed inflammatory response may be attributed to the release of reactive oxygen species (ROS), which in turn activates the NF-κB signaling pathway. NF-κB is known to be an enhancer of activated B cells and also acts as a key transcription factor of M1 macrophages. (Liu et al., 2017) Thus activation of NF-κB signaling can subsequently lead to the induction of an inflammatory response (Abdul Khalik and Elkammar, 2019).

Effect of dietary nitrates in the immune system of the host

Nitrates, aside from their role as a source of nitric oxide in the body, are also generated from L-arginine found in the food we ingest (Jones, 2014). For many years, there has been a belief that nitrates (NO3⁻) and nitrites (NO2⁻) hurt human health. This perception stemmed from the association between nitrates and the risk of N-nitrosation, which leads to the formation of highly carcinogenic compounds known as N-nitrosamines, such as NDEA (N-nitrosodiethylamine), NMEA (N-nitrosoethylmethylamine), NPYR (N-nitrosopyrrolidine), and NPIP (N-nitrosopiperidine) (Lv et al., 2016). However, recent research has shed new light on nitrates and many studies validate the fact that nitrates (NO3⁻) and nitrites (NO2⁻) obtained from vegetables and drinking water do not pose an increased risk of cancer, rather they challenge the previous notion that nitrates are universally harmful (Nicikowski and Reguła, 2021). Thus, it is realized to highlight the importance of differentiating between naturally occurring nitrates from dietary sources and those associated with N-nitrosamine formation. Studies have shown that intake of nitrate-rich vegetables like spinach, lettuce, parsley etc. has an impact on inflammatory markers in the body. Following the consumption of vegetables abundant in nitrates there has been a decrease in the concentrations of proteins like C-reactive protein (CRP) and cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in venous blood. These are well-known markers of inflammation, often linked to various chronic diseases like T2DM (Type 2 diabetes mellitus) (Lainampetch et al., 2019) [Fig. 3(C)]. The ability of nitrate-rich vegetables to lower the levels of these markers suggests a potential anti-inflammatory effect. The mechanisms underlying this anti-inflammatory response are believed to be linked to the conversion of nitrate to nitric oxide (NO) in the body. Nitric oxide acts as a signaling molecule that helps regulate immune responses and blood vessel function (Carter et al., 2020).

Another study implemented the effect of nitrates intake on Macrophage Migratory Inhibition Factor (MIF). MIF is an inflammatory cytokine and is overexpressed in the aorta of patients with coronary atherosclerosis. Thus, it has a significant role to play in atherosclerosis through its effects on immune cells (Gong et al., 2015) [Fig. 3(C)]. To mitigate this issue a study demonstrated that on daily administration of nitrate (as sodium nitrate) for four weeks to a subject with moderate cardiovascular risk, there was a significant lowering of MIF in plasma level demonstrating its beneficial side as well (Raubenheimer et al., 2019).

Another nitrogen compound, Nitric Oxide is also produced in different ways inside the human body. Among these, the most important one is the conversion of nitrates to nitric oxide by the symbiotic bacteria in the oral cavity and stomach (Ma et al., 2018). Nitric oxides (NO) also exert a regulatory influence on the functioning of lymphocytes and monocytes by providing potential signal transducers between innate and acquired immunity. NO generated by endothelial NO synthase (eNOS) is a key regulator of endothelial function. It relaxes blood vessels, prevents platelet aggregation and adhesion, and decreases the expression of pro-inflammatory genes that contribute to atherogenesis (Mir and Maurya, 2022). Because of its vasodilating nature and bronchodilatory effect, NO has the potential to decrease the viral load of SARS-Cov2 (Martel et al., 2020).

In contrast, one study concluded that NO can repress the production of Th1 cytokines like IFN-γ while activating Th2 cytokines, leading to hypersensitivity reactions. NO also exerts its inhibitory effect on the cytokine genes, such as IL-1β, TNF-α, IL-6, and INF-γ, in various immune cells like lymphocytes, eosinophils, and monocytes. This regulation is achieved through nitrosylation of different transcription factors, including JAK/STAT and NF-κβ (Nosalski and Guzik, 2017).

Effect of dietary phenolic compounds like flavonoids in the immune system of the host

Bioactive compounds are primarily abundant in plant-based foods, such as whole grains, fruits, and vegetables (Patra, 2020). These compounds encompass polyphenols, phytosterols, carotenoids, tocopherols, and organosulfur compounds, including isocyanates and diallyl sulphate compounds (Handique and Baruah, 2002). Among them, polyphenols are the most prevalent and widely distributed group of bioactive molecules. Polyphenols contain one or more benzene rings, along with varying numbers of hydroxyl (OH), carbonyl (CO), and carboxylic acid (COOH) groups. They are commonly found with one or more attached sugar residues. Based on their chemical structure, polyphenols are traditionally categorized into two main groups: flavonoids and non-flavonoids. The flavonoid group consists of compounds with a C6-C3–C6 structure, such as flavones, flavanones, dihydroflavonols, flavanols, flavan-3-ols, anthocyanidins, isoflavones, and proanthocyanidins. On the other hand, the non-flavonoid group is classified based on the number of carbons it contains and includes subgroups of simple phenols, phenolic acids, and aldehydes (Watson and Preedy, 2019).

Studies show that flavonoids can have an influence on the secretion of inflammatory mediators from macrophages and other leukocytes. In a recent study conducted by Kenny (Kenny et al., 2007) the impact of two distinct fractions of purified cocoa flavonoids on lipopolysaccharide-stimulated human peripheral blood mononuclear cells (PBMC) was studied. The short-chain flavanol fraction, comprising monomers to pentamers, and the long-chain fraction, encompassing hexamers to decamers, were found to increase the secretion of cytokines like TNF-α, IL-1, IL-6, and IL-10 from the stimulated human PBMC, where the most significant increase was seen under the influence of long chain fraction (Kenny et al., 2007).

Flavonoids from cocoa have also been tested to affect B cell proliferation, the effects of a 10% cocoa diet on B lymphocyte differentiation were investigated and the results showed that the diet led to a significant increase in the proportion of B cells in the spleen. However, despite the increased B cell proportion, spleen immunoglobulin (Ig) secretion was down-regulated, and serum Ig levels were also reduced, suggesting that cocoa interferes with B lymphocyte differentiation into Ig-secreting cells (Ramiro-Puig et al., 2007).

Beneficial effects of isoflavones were detected in postmenopausal women. Intake of soy-based isoflavone like daidzein, equol, and genistein, there was a significant increase in the B-cell proliferation and a decrease in plasma concentration of 8-hydroxy -2 deoxy-guanosine which is an oxidative marker from DNA damage (Ryan-Borchers et al., 2006).

Another study investigated the effects of two flavonoids, apigenin and luteolin, on immune responses in microglial cells. The results showed that both apigenin and luteolin suppressed the expression of CD40, a cell surface protein involved in immune responses, in a concentration-dependent manner when induced by IFN-γ. Furthermore, these flavonoids also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6 in microglial cells that were stimulated by IFN-γ and subjected to CD40 ligation. This indicates that apigenin and luteolin have anti-inflammatory properties and can reduce the inflammatory response of microglial cells under certain conditions. Moreover, apigenin and luteolin were found to significantly inhibit the phosphorylation of STAT1, a key signaling molecule involved in immune responses that is activated by IFN-γ. Thus, the authors could conclude that these flavonoids have a therapeutic effect on different neurodegenerative diseases (Rezai-Zadeh et al., 2008).

The effects of EGCG (Epigallocatechin gallate), a major component of green tea, on inflammatory processes in human cartilage and chondrocytes (cartilage cells) were studied. The results showed that at micromolar concentrations, EGCG effectively inhibited the IL-1β-induced release of glycosaminoglycan (GAG) from human cartilage explants in vitro. This is an important component of cartilage that gets degraded during inflammation. Apart from this, EGCG also inhibited the IL-1β-induced expression of two matrix-degrading enzymes, MMP-1 and MMP-13, at both mRNA and protein levels in human chondrocytes, which play a role in breaking down cartilage in inflammatory conditions like arthritis (Ahmed et al., 2004). Additionally, EGCG also showed a similar differential dose-dependent inhibition of two transcription factors, NF-κB and AP-1. These transcription factors are known to regulate the expression of various inflammatory genes, including MMPs. Inhibition of these transcription factors may also contribute to EGCG's anti-inflammatory effects (Ahmed et al., 2004).

Another study by Qin (Qin et al., 2010) has also shown that on consumption of GTP (Green Tea Polyphenols) there was an inhibition in the expression of certain inflammatory biomarkers in both plasma and cardiac muscle, which showed a reduction in the chance of developing CVD (cardiovascular disease). These biomarkers include proinflammatory cytokines like TNF-α and IL-6, which can promote insulin resistance, dyslipidemia, and endothelial dysfunction thereby resulting in development of certain CVD (Qin et al., 2010).

Effect of dietary acrylamide in the immune system of the host

Acrylamide (C₃H₅NO) is a highly reactive and odorless crystalline compound with a high solubility in water and significant chemical reactivity. It is recognized as a toxic carbonyl compound. Notably, various inadvertent sources of acrylamide are present in daily life, particularly in processed foods. The formation of acrylamide arises from the Maillard reaction between monosaccharides and proteins when these foods are subjected to high temperatures (> 120 °C) during cooking. This reaction is particularly evident in carbohydrate-rich foods like potato chips, bread, biscuits, cereals, toasted bread, roasted coffee beans, crisps, malt beverages, fish, and chicken nuggets. In 1994, the International Agency for Research on Cancer classified acrylamide as a class 2A substance, signifying that it is likely carcinogenic to humans (Zamani et al., 2018).

Another research showed chronic consumption of dietary acrylamide from sources like potato chips leads to oxidative stress in humans by activating leukocytes and causing an elevated production of reactive oxygen radicals. As a result, notable increases were observed in concentrations of oxidized Low-Density Lipids (ox-LDL), high sensitivity Interleukins 6 (hs IL-6), and high sensitivity C- reactive protein (hs CRP)—factors, known to potentially accelerate the progression of atherosclerosis. They also showed this acrylamide resulted in a reduction of a crucial cellular antioxidant like Glutathione (GSH) (Naruszewicz et al., 2009).

Acrylamide demonstrated activity in in vitro mammalian gene mutation assays as well, particularly affecting the tk locus in mouse lymphoma cells (Knaap et al., 1988). Further elaborate studies are required to understand the role of Acrylamide in our immune system.

Effect of dietary maltol in the immune system of the host

Maltol (3-hydroxy-2-methyl-4-pyrone), recognized as a secure and dependable flavor enhancer, food preservative, and natural antioxidant, is generated as a result of the Maillard reaction during the breakdown of starch and sucrose through pyrolysis. (Li et al., 2015) It is also present in various food items, including baked goods, red ginseng root, coffee, chicory, soybeans, bread crusts, and caramelized foods (Zhang et al., 2012).

Maltol was found to have immune-modulating effects on lipopolysaccharide (LPS) stimulated cells. The expression of pro-inflammatory cytokines like IL-1β, IL-6, and IL-8 increased significantly after LPS treatment in intestinal epithelial cells (IEC) and chicken macrophage cells (CMC). The authors concluded from this that maltol showed a dose-dependent influence on cytokine expression, with its effects varying between different doses and cell types (Park et al., 2021). The upregulation of these cytokines can also be linked with inflammation and could be associated with pathological pain (Zhang and An, 2007).

Conversely, contrasting studies suggest that maltol may mitigate the toxicity of other therapeutic compounds, such as cisplatin commonly used in cancer treatment. Reports have highlighted the nephrotoxic nature of cisplatin (Goldstein and Mayor, 1983; Peres et al., 2013), prompting investigations into the potential therapeutic effects of maltol in reducing its toxicity. In a study conducted on HEK293 cell lines, pretreatment with maltol demonstrated positive outcomes. These included a reduction in the overproduction of cytokines like TNF-alpha and IL-1 beta, leading to decreased inflammation associated with cisplatin treatment. Additionally, the study observed a lower expression of the AMPK pathway, promoting cell survival and inhibition of apoptosis (Mi et al., 2018). Therefore, given the limited research specifically addressing the immunomodulatory effects of maltol, it is too hasty to draw definitive conclusions about its efficacy. Further, more in-depth research dedicated exclusively to examining the immunomodulatory impacts of maltol in humans is essential for a better comprehensive understanding.

Discussion

These xenobiotic compounds exhibit both carcinogenic and immunological responses in the human body. This review emphasizes the adverse or beneficial immunological responses they induce. The dietary heterocyclic amines (HCAs), such as PhIP, demonstrated immunosuppressive responses, impacting crucial factors like TNF-α expression and T cell proliferation. Polycyclic aromatic hydrocarbons (PAHs), represented by compounds like Benzo[a]pyrene (BaP), exhibited immunosuppressive effects on various immune cells, including T lymphocytes, B cells, and natural killer (NK) cells. Nitrates, sourced from both dietary and endogenous pathways, displayed a complex role, with some studies indicating anti-inflammatory effects through the modulation of cytokines, while others suggested potential immunosuppression. Moreover, phenolic compounds like flavonoids showcased intricate interactions with immune responses. Flavonoids from cocoa and green tea polyphenols displayed both pro-inflammatory and anti-inflammatory effects, highlighting the complexity of their impact on immune cells. Acrylamide, formed during the cooking process of certain foods, demonstrated potential oxidative stress and inflammatory responses, emphasizing the need for further research in this area. Maltol, known for its flavor-enhancing properties, exhibited both immune-enhancing and mitigating effects, particularly in reducing the toxicity of therapeutic compounds like cisplatin. While these findings shed light on the immunomodulatory roles of xenobiotic compounds, it is crucial to emphasize the necessity for further extensive research. This is essential to fully comprehend the specific mechanisms and implications of these compounds on human health. Such in-depth investigations are pivotal for developing strategies to mitigate potential harm, identifying safer alternatives, and implementing measures to reduce exposure. The intricate interplay between these compounds and the immune system underscores the complexity of their impact, necessitating a nuanced exploration. This comprehensive understanding not only contributes to scientific knowledge but also guides regulatory and public health efforts in minimizing any adverse effects on individuals and populations.

Funding

This work received no external funding.

Declarations

Conflict of interest

The authors declare no conflict of interest.