Immunomodulatory Effects of Food Additives

1School of Biological Sciences, Dr. Harisingh Gour Central University, Sagar (MP)-470003, India 2Institute of Bioinformatics & Biotechnology, Savitribai Phule Pune University, Pune (MH)-411007, India 3School of Biochemical Engineering, Indian Institute of Technology-BHU, Varanasi (UP)-221005, India 4Department of Molecular Biology, National Institute for Research in Environmental Health, Bhopal (MP)462001, India


Introduction
Food items that are unprocessed and do not contain preservatives, artifi cial colours, chemicals, fi llers, artifi cial fl avours etc are called as Natural foods. Natural foods are the best source of nutrition and health. Substances added to natural food to preserve fl avour and increase their life are named as food additives. When food is to be stored for a long period, additives and preservatives are required to maintain the quality and fl avour of the food items. The additives and preservatives prevent bacterial and fungal growth due to excess water in the foods [1]. Additives are defi ned by the United States Food and Drug Administration (FDA) as "any substance, the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food." Direct additives are those that are intentionally added to foods for a specifi c purpose. Indirect additives are those to which the food is exposed during processing, packaging, or storing. Preservatives are additives that inhibit the growth of bacteria, yeasts, and moulds in foods [2].
The drastic changes in agricultural and industrial practices over the past decades have increased the world's capacity to provide food through increased productivity and diversity, decreased seasonal dependency and seasonal prices [3].
Increased consumption has been facilitated by rising income, urbanization, food industry marketing, media advertisement and trade liberalization, mainly in developed countries. Major shifts in dietary patterns are continually occurring, even in basic staples, consumption towards a more diversifi ed and industrially processed food products. Living in westernized countries has a strong impact on nutritional patterns collectively termed as "Western diet" including high fat, trans fatty acids, cholesterol, proteins, sugars, salt intake, as well as frequent consumption of processed and "fast food" [4].
Infl uenced by this reality, populations of developing countries are undergoing a rapid change towards "transition nutrition".
Thus the traditional dietary pattern is gradually being replaced by the Western one [5].
Additives are used to provide a smooth and consistent texture, preserve the nutrient value and reduce the spoilage of food. Additives also control the acid-base balance of foods.
Preservatives slow the process of product spoilage caused by mould, air, bacteria, fungi or yeast. Food additives are of great help in various techniques employed for food preparation and preservation, such as pickling, salting, and smoking, which were developed to deal with the emerging problems of storage, waste, and food-borne illnesses. The effects of food additives may be immediate or may be harmful in the long run on constant exposure. Sometimes immediate effects may also include headaches, change in energy levels and alteration in mental concentration, behaviour and immune response. Longterm effects of food additives had also been linked to increased risk of cancer. Some widely used food additives are Sodium benzoate (E211), Tartrazine (E102), Quinoline yellow (E104), Sunset yellow (E110), Carmosine (E122) and Allura red (E129) to name a few. Depending on the test protocol followed, it has been found that between 10-40% of aspirin-sensitive patients are indeed usually also affected by tartrazine, the reactions include asthma, urticaria, and rhinitis and childhood hyperactivity [6]. Sunset Yellow (E110), used in biscuits, has been found to damage kidneys and adrenals when fed to laboratory rats [7].
Benzoates (E210-E219), used mainly in marinated fi sh, fruitbased fi llings, jam, salad cream, soft drinks and beer have been found to provoke urticaria, angioedema and asthma [7]. Sulphites (E220-E227) fed to animals have also been found to have mutagenic action [7]. Monosodium glutamate (MSG) a fl avour enhancer, used in savoury foods, snacks, soups, sauces and meat products, has been associated with a conjunction of symptoms in susceptible individuals, such as severe chest and/or facial pressure and overall burning sensations, not unlike a feeling that the victim is experiencing a heart attack [6]. Consumption of artifi cial sweeteners has also been linked to various behavioural problems, hyperactivity, allergies and possibly carcinogenesis. Aspartame, sodium cyclamate and saccharine are used as artifi cial sweeteners with low calorie in fruit juices, jam & jelly. Corn starch, waxes and gums are used as food stabilizers. Incidental additives is the term applied to any substances that come into contact with food during its growth, processing or packaging. Intentional additives are those substances of known composition that are added to food to serve some useful purpose [8]. The FDA maintains a list of over 3000 ingredients in its database "Everything Added to Food in the United States", many of which we use at home every day (e.g., sugar, baking soda, salt, vanilla, yeast, spices and colours, table 1. Food additives added to food for a specifi c purpose for example xanthan gum -used in salad dressings, chocolate milk, bakery fi llings, puddings and other foods to add texture are called as direct food additives. Most direct additives are identifi ed on the ingredient label of foods [12].
Food additives that become part of the food in trace amounts due to its packaging, storage or other handling, for instance minute amounts of packaging substances which fi nd their way into foods during storage are called as indirect food additives. Food packaging manufacturers must prove to the U.S. FDA that all materials coming in contact with food are safe before they are permitted for use in such a manner [9].

Types of food additives
Preservatives: Food preservatives prevent the growth of microbes or spoilage and help in preserving fl avour, texture, edibility and nutritive value of the food. Natural food preservatives come in the form of salt, sugar, alcohol, vinegar etc. These are the traditional preservatives in food that are also used at home while making pickles, jams, juices etc. Sugar and salt are the earliest natural food preservatives that very effi ciently prevent the growth of bacteria in food [9]. To preserve meat and fi sh, salt is still used as a natural food preservative. During the past few decades the use of chemical food additives has increased tremendously. They seem to be the best and most effective for longer shelf life and are generally fool proof for preservation purposes [9]. Examples of chemical food preservatives are: Sodium Nitrate (251), Benzoic acid (210), Sodium Benzoate (211) and Sodium Sulphite (221). Artifi cial preservatives are the chemical substances that stop or delay the growth of bacteria thereby preventing spoilage and its discoloration. These artifi cial preservatives can either be added or sprayed on the food [9].
Sweeteners: Sweeteners provide sweet taste similar to that of sugar with or without any extra calories. Caloric sweeteners.
Artifi cial sweeteners are synthetic sugar substitutes, but may

Anti-caking agents
Anti-caking agents are a type of food additive that are added to keep ingredients from clumping together after being packaged [8]. Anti-caking agents act either to absorb moisture or act as a sealant and repel water and oil [11]. Anticaking agents reduce the stickiness of the chunked, diced, or

Emulsifi ers
When water and oil are mixed together and vigorously shaken, oil droplets disperse in water and upon stopping of shaking, the phases start to separate. However, when an emulsifi er is added to the system, the droplets remain dispersed, and a stable emulsion is obtained. The emulsifi er may be an aerating agent, starch complexing agent and/ or crystallisation inhibitor [12]. Nature is good at making emulsions, and the classic example is milk, where a complex mixture of fat droplet is suspended in an aqueous solution.

pH controlling agents
The pH is the negative logarithm of the hydrogen-ion concentration in aqueous solution. The pH of a food is the measure of that product's acidity or alkalinity which maintains fl avour of food. The acid ingredients maintain a constant acid level by lowering the pH and thus preserve foods by inhibiting microbial growth. Natural acids include acetic acid or vinegar and citric acid from citrus, malic acid and tartaric acid (a weak acid) [13]. Commonly used acidulants are Lactic acid (E270),

Antioxidant
Antioxidants prevent foods from oxidising or going rancid.
Oxidation is a real problem for food products which causes raw apples and potatoes to go brown. Antioxidants are used as food additives to preserve food for a longer period of time. They act as oxygen scavengers, as the presence of oxygen in the food helps the bacteria to grow that can ultimately harm the food [14]. Antioxidants are classifi ed into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytosol and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation [15]. Different kind of antioxidants acts in different ways to delay or minimize the process of oxidation in food. BHT is another synthetic antioxidant. It works in the same way as butylated hydroxyanisole, but has caused controversy, as it has produced adverse effects in dogs. However, it also has anticancer effects [15]. It is used in margarine, oils, crisps and cheese. This antioxidant helps in preventing the reactions leading to the breakdown of fats [14]. Ascorbic acid (vitamin C) used in beers, cut fruits, dried potatoes and jams helps in preventing the discoloration of food by preventing the oxidation and also act as a substitute of vitamin C in potatoes that is lost during processing [14]. Some commonly used antioxidants are; Butylated hydroxyanisole (320), Ascorbyl palmitate (304), Calcium ascorbate (302), Ascorbic acid (vitamin C), Selenium, Vitamin A, Beta carotene, hydrogen peroxide (H2O2), Hypochlorous acid (HClO).

Immune system
The immune system is a remarkably versatile defense system which has evolved for protection of animals from invading pathogenic microorganisms and cancer. It has ability to generate an enormous variety of cells and molecules which are capable of specifi cally recognizing and eliminating an apparently limitless variety of foreign invaders. A specifi c immune response giving rise to production of antibodies or T cells against a particular pathogen, known as adaptive immunity rep resents an adaptation that occurs during the lifetime of an individual as a result of exposure to that pathogen. Adaptive immune responses takes into account the clonal expansion of T and B lymphocytes bearing a huge repertoire of somatically gener ated receptors that can be selected to recognize virtually any pathogen. The adaptive immune system gets profoundly molded by the immunologic challenges encountered by that individual during the course of a life time. A great property of adaptive immune responses is that they being highly specifi c for the triggering agent and for this they provide the basis for immunologic memory. This unique property of memory endows the adaptive immune response with its "anticipa tory" property, thus increasing resistance against future infection with the same pathogen and also allows vaccination against future infectious threats [15].
Adaptive immunity is important for the survival of all mammals and most other vertebrates, but different types of other mechanisms not involving antigen-specifi c lym phocyte responses are also involved in successful immune protection. These varied mechanisms are collectively known as innate immunity, since they are independent of prior exposure to specifi c pathogens for their amplifi ca tion. These responses are controlled by the products of germ line genes that are inherited and similarly expressed by all normal individuals. Innate immune mechanisms involve both constitutive and inducible components and use a wide variety of recognition and effector mechanisms. It has become clear in recent years that innate immune responses have a profound infl uence on the generation and outcome of adaptive immune responses via secretion of various cytokines. This ability of the innate immune system to instruct the responses of the adaptive immune system suggests many ways in which innate immu nity can infl uence the development of both long-term spe cifi c immunity and autoimmune disease [15].
Recently over the last few years the impact of the gut microbiota on immune homeostasis has gained tremendous research interest. Also the gut harbors 60-80% of the host immune system. Thus the intestinal microbiome functions as a signaling hub that integrates environmental inputs, such as diet, genetic and immune signals to affect the host's metabolism, immunity and response to infection.
Host-microbial homeostasis involves appropriate immune regulation within the gut mucosa to maintain a healthy gut, while preventing uncontrolled immune responses against the benefi cial commensal microbiota potentially leading to various infl ammatory conditions such as chron's disease, infl ammatory bowel diseases (IBD) etc. This complex, bilateral interaction between the host and its microbiota has a crucial role in human health. Many 'multifactorial' disorders, formerly con sidered to be idiopathic, might therefore be infl uenced or even driven by alteration of the intimate crosstalk that occurs between the host immune system and the gut microbiota during homeostasis [16].  Table 2) and tumour necrosis factor alpha (TNF) [18]. Th1 cells are responsible for cellmediated immune responses and an excessive Th1 response will result in tissue damage [19]. Th1 cells are most often defi ned by their production of IL-2 and IFN- but have been reported to produce a number of cytokines including: TNF, lymphotoxin, and granulocyte-macro-phage-colony-stimulating factor (GM-CSF) [18]. The signature cytokine of the Th1 subset, IFN-, has long been associated with pathology of several autoimmune diseases including autoimmune type 1 diabetes (T1D), multiple sclerosis (MS) and rheumatoid arthritis (RA) [20,21] Th1 cells promote immune pathology in MS/EAE, conceivably by secreting IFN-, which plays an essential role in promoting autoimmune pathology [22]. IFN- signalling, but DOI: http://doi.org/10.17352/2455-8591.000015 not Th2 cytokines, was found to be crucial for the generation and production of auto antibodies targeting intracellular molecules, similar to those found in SLE [23,24] and IFN- production was found to be elevated in serum of patients with SLE [25]. These results highlighted the pathogenic role of IFN- in autoimmune diseases, even in a disease like SLE that was initially considered to be a Th2/type-2 mediated autoimmune disease (i.e. humoral-mediated) [18] (Figure 1).

Th2 cells:
Th2 cells secrete IL-4, IL-5 and IL-13 [27]. Th2 are responsible for humoral-mediated immunity and excessive Th2 responses can result in atopy/ hypersensitivity [19]. Th2 cells are recognized for their role in host defense against multi-cellular parasites and their involvement in allergies and atopic illnesses [18]. Th2 differentiation and function are intimately regulated by innate and epithelial cell types that inhabit these tissues [26]. Th2 cells are best known for the production of IL-4, IL-5 and IL-13, as well as IL-9 and IL-10 [27]. IL-4 is a multifunctional, pleiotropic cytokine discovered in the early 1980s', which is mainly produced by activated Th2 cells, but also by mast cells, basophils, eosinophils and T cells [28,29]. In experimental models of helminth infection, Th2 cells are thought to promote tissue repair by promoting the function of M2 macrophages through secretion of IL-4 [30].
In autoimmune diseases, Th2 cells were initially described as anti-infl ammatory based on their ability to suppress cellmediated or Th1 models of disease [18,19]. Th2 cells are best known for the production of IL-4, IL-5 and IL-13, as well as IL-9 and IL-10 [21].

Th17 cells: Th17 cells differentiate from naive T cells in the
presence of TGF- plus infl ammatory stimuli such as, IL-1,  IL-6, IL-21, and IL-23. IL-23 is dispensable for the lineage commitment of Th17 cells but is required for the growth, survival, and functions of Th17 cells [31,32]. During infection, IFN- regulates the induction and expansion of pathogenic Th17 cells [33]. These properties of IFN- seem to be pivotal in down regulating the infl ammatory responses mediated by other Th cells and pathology promoted by these cells, in particularly Th2 and Th17 cells [34]. TGF- is essential for the generation of both induced regulatory T cells (iTregs) and Th17 cells via the induction of FoxP3 and RORt. However, in the absence of infl ammation, FoxP3 represses RORt and promotes iTregs. Signaling via infl ammatory cytokines, such as IL-6, IL-21, and IL-23, results in STAT3 phosphorylation, relieves RORt from the suppression of FoxP3, and initiates Th17 programming. STAT3 in combination with IFN regulatory factor 4 (IRF4) further induces ROR expression. The transcription factors STAT3, RORt, and Runx1 bind to the promoter regions of the IL-17, IL-21, IL-22, and CCL20 genes and induce IL-17, IL-21, IL-22, and CCL20. Th17 programming can be antagonized by cytokines, such as IFN-, IL-2, and IL-27. IL-2-mediated and IL-27-mediated activation of STAT5 and STAT1 inhibit STAT3, whereas T-bet induced by IFN- can block RORt [35]. Compared with Th1, Th2, and natural Tregs, Th17 cells display instability. In mice and humans, Th17 cells co-expressing IL-17/IFN-y, RORyt/T-bet, or FoxP3/IL-17/RORyt have been observed during infl ammatory responses [36]. IFN- can up-regulate IL-12/Roryt on Th17 cells and enhance their sensitivity to IL-12, resulting in a Th17/Th1 phenotype that stably co expresses RORt and T-bet [37]. Th17 cells secrete several effector molecules, including IL-21, IL-22, IL-17A/F, and CCL20. These soluble factors act on both immune and non-immune cells and mediate several functions, such as differentiation of cells; release of antimicrobial molecules, cytokines, and chemokines; and recruitment of cells to sites of infl ammation [37]. The prevalence of IL-17 and IL-22 CD4 + T cells is increased in the circulation of patients with RA and ankylosing spondylitis; these cells produce higher quantities of IL-17 after stimulation [38]. IL-17 is also present at the sites of infl ammatory arthritis and amplifi es the infl ammation

Treg cells: Treg cells can be subdivided into naturally
arising cells (nTreg) that are generated in the thymus, and inducible Treg (iTreg) that are converted into Treg upon activation in the periphery [40]. Natural Tregs are a population of CD4 + T lymphocytes residing in the thymus and constitute 5-10% of the peripheral naive CD4 + T lymphocyte pool in normal mice and humans [41]. Induced Tregs are found in peripheral lymphoid tissues from naive T cells [42]. These for autoimmune diseases [45]. Tissue homing is modulated prominently by lymphocytes, including regulatory T cells (Tregs) [46]. Tregs play a pivotal role in the maintenance of homeostasis between immune response and immune tolerance [47]. Although the majority of Treg appears within the CD4 + T cell set, suppressor activity was also reported among CD8 + T cells [48]. Over the last few years, however, most attention was focused on CD4 + regulatory cells and particularly the nTreg, which are characterized by constitutive expression of the -chain of the IL-2 receptor (CD25) and the transcription factor Foxp3 [49]. Foxp3 is essential in the development and function of nTreg which is Foxp3 inhibits IL-2 transcription and induces up-regulation of Treg-associated molecules, such as CD25, CTLA-4 and GITR [50], that can down-regulate the immune response of adjacent cells. IL-10 can suppress differentiation of Th1 and Th2 cells directly by reducing IL-2, TNF- and IL-5 production, and also indirectly by downregulating MHC and co-stimulatory molecules on APC, thereby reducing T cell activation [48]. The failure of only one tolerance checkpoint rarely leads to autoimmune disease [51]; it may, however, increase the level of circulating auto antibodies, without clinical disease. is not limited to bacterial killing because MMPs are also important for extravasations and diapedesis [56]. Neutrophil life spans may be modulated by soluble signals: when exposed to stimuli such as TNF and Fas (CD95) ligand, neutrophils undergo apoptosis or programmed cell death [57,58].

Mast cell
Mast cells are "master regulators" of the immune system. They are also found in the peritoneal cavity, spleen, liver, lung, lymph nodes, thymus, and in uterus during gestation [62].

Effec t of food additives on Immune system
Sodium benzoate (NaB): Sodium benzoate, a metabolite of cinnamon and a FDA-approved drug against urea cycle disorders in children, is a widely used food additive, which is long known for its microbicidal effect [65] (Figure 2). Recent discoveries suggest that NaB is an important modulator of adaptive and innate immune responses of experimental allergic encephalomyelitis (EAE) leading to attenuation of infl ammation and demyelination in EAE [66]. Sodium benzoate counteracts autoimmune diseases by decreasing infl ammation via inhibition of T cell proliferation, the mevalonate pathway, iNOS, NF-B, TNF-, IL-1, Th-1, and adhesion molecules and by increasing Tregs [66]. The release of the T cell-derived lymphokine leucocyte inhibitory factor (LIF), in response to incubation with sodium benzoate or other food additives and with acetylsalicylic acid (ASA), was measured in vitro [67]. Sodium benzoate has ability to deprive cells of oxygen, break down the immune system and cause cancer. Sodium Sodium benzoate (E211), the salt of benzoic acid, is a well characterised food preservative contained in food as well in cosmetic. Benzoic acid is also found naturally in apricots and other foods [70]. NaB on the other hand can also be used as a potential drug candidate for therapy of MS. [73]. Propionic acid (E280), sodium benzoate and colorant curcumin, all three tested compounds suppressed pathways linked with Th1-type immune activation, which indicates an anti-infl ammatory property [70]. NaB inhibited the production of TNF- and IL-1 protein in dose-dependent manner and the expression of TNF- and IL-1 mRNA [71].

Aspartame
Aspartame, a "fi rst generation sweetener", is widely used in a variety of foods, beverages, and medicines. The FDA has determined the acceptable daily intake (ADI) value of aspartame to be 50 mg/kg per day, while the JECFA (Joint FAO/WHO Expert Committee on Food Additives) has set this value at 40 mg/kg of body weight/day. The immune system is now recognized as a target organ for many xenobiotics, such as drugs and chemicals, which are able to trigger unwanted apoptosis or to alter the regulation of apoptosis. It has been observed that oral administration of aspartame for 90 days did not cause any apparent DNA fragmentation in immune organs of aspartame treated animals; however, there was a signifi cant increase in hsp70 expression, apart from signifi cant alteration in bcl-2 and bax at both mRNA transcript and protein expression level in the immune organs of aspartame treated animals compared to controls. Hence, these results indicated that hsp70 levels increased in response to oxidative injury induced by aspartame metabolites; however, these metabolites did not induce apoptosis in the immune organs [72].

Cinnamaldehyde
Low concentrations (up to 1 mg/ml) of CA results in a slight increase in nuclear factor-B activation, whereas higher concentrations led to a dose-dependent decrease of nuclear factor-B activation (up to 50%) in lipopolysachharidestimulated THP1 cells and PBMCs. Accordingly, nitric oxide, IL-10 secretions as well as cell proliferation were reduced in lipopolysachharide-stimulated RAW264.7 cells, PBMCs and THP1, Raji and Jurkat-E6 immune cells in the presence of CA in a concentration-dependent manner. Flow cytometric analysis of PBMCs revealed that CD3 + was more affected than CD20 + , having the ability to block nuclear factor-kB activation in immune cells [82]. Treatment with CA led to inhibition of cell viability, proliferation and induced apoptosis in a dosedependent manner in primary and immortalized immune cells. Its described anti-carcinogenic property in cancer patients might be contraindicated due to its ability to inhibit immune cell activation [73]. Cytokines (pro-or anti-infl ammatory, TNF- or IL10), of signaling molecules (NO) as well as pathways (NF-kB/AP-1) investigated, a decrease in activation and production was observed when using higher concentration of CA than 1 mg/ml ( = 8 mM) [82].

Propionic acid
Propionic acid (PA) suppresses IFN--mediated neopterin production and Trp degradation in PBMCs in a dose-dependent manner. This suppressive effect on Th1-type immunity may be helpful in infl ammatory conditions. It may also be harmful by diminishing the effi cacy of the immune system to respond against pathogens and tumors and may even promote allergic diseases [70]. PA could inhibit the production of infl ammatory Trp degradation in PBMC in a dose-dependent manner [70].
Curcumin decreased LPS-stimulated secretion of IL-6, and also affect the leptin release after co-incubation with LPS from cultured adipocytes in a dose-and time-dependent manner [81]. Curcumin supplementation also resulted in inhibition of LPS-induced IL-10 and IFN- and in stimulation of IL-4 secretion [73]. Long term effects of curcumin shows downregulation of IL-6 and TNF- production [73].

Sodium Nitrite
There are no signifi cant differences in the WBC count of incubation with LPS from cultured adipocytes in a dose-and time-dependent manner. There is no direct effect on leptin secretion after incubation with antioxidants in the absence of LPS, at low levels of IL-6. However, at high levels of IL-6 due to LPS co-incubation, leptin secretion was signifi cantly less than in the absence of antioxidants [71].

Nitric Oxide (NO)
The suppression of Foxp3 in MBP-primed T cells is due to the direct effect of NO signaling, whereas the suppression of CD25 is a secondary consequence of NO, which was evident from the inability of donor NO to decrease the population of

Tartrazine
It is also known as FD&C Yellow # 5. It provides yellow colour and can be found in green and blue candies. There is currently a petition to the FDA to ban tartrazine from food.
Some schools have banned products containing tartrazine and subsequently noticed a big difference in the overall behaviour of their students. Tartrazine is a coal tar derivative, like most artifi cial colourings, and is one of the most controversial of the azo dies used in food. Norway has banned tartrazine because this chemical has been linked to severe allergic reactions, especially in asthmatics and is one of the food additives thought to be a cause of hyperactivity in children [79].

Monosodium Glutamate (E621)
It is a fl avour enhancer additive which is used to bring out the fl avour without adding a fl avour of their Natural source. It can destroy nerve cells and linked with aggravating or accelerating Huntington's, Alzheimer's and Parkinson's diseases. It may cause cancer, DNA damage and fetal abnormalities in animals and is also linked with increased hyperactivity [80]. MSG is a known Excitoxins (glutamate, aspartate, and cysteine) which kills brain cells through a mechanism which causes the cells to fi re repeatedly until they self-destruct. MSG and aspartame, an artifi cial sweetener, are the most common excitotoxins which may causes headache, nausea, weakness, and burning sensation in the back of neck and forearms [79]. MSG has a direct toxic effect on the neutrophils in the blood or it has a deleterious effect on blood production in the bone marrow, especially on the progenitor cells (aplasia) and that it is timedependent [81]. This might be indicative of the deterioration of immune status to the toxic effect of MSG. These results suggest that non-cytotoxic dose of SY may have immunomodulatory effects [82].

Emulsifi ers
The last half-century has witnessed enormous increase in the consumption of various food additives. Emulsifi ers disturb the host-microbiota homeostasis resulting in enhanced mucolytic and pro-infl ammatory activity thereby promoting intestinal infl ammation such as colitis [83]. It is now well established that probiotics (a class of symbiotic bacteria whose administration in adequate amount provides health benefi ts to the host by altering the composition of gut microbiota) can enhance the gut microbiota and can help to overcome several health issues caused due by dysbiosis in the gut [84].
Carboxymethylcellulose (CMC), P80 and other emulsifi ers currently used in food products impact human health in several ways. Studies by various groups in mice suggest the possibility that dietary emulsifi ers contributed to the postmid-twentieth-century increase in incidence of infl ammatory bowel disease, metabolic syndrome, and perhaps other chronic infl ammatory diseases [13].

Conclusion
The use of food additives has increased to a great extent in the last few decades. At present, it has been estimated that about 85% of the Western diet is made up of various processed foods.
Presently on an average each person is consuming 8-10 lbs of food additives per year, with some possibly eating even more. ever increasing use of copious amount of food additives in our daily life is posing a huge risk to our immune system leading to various disorders and diseases. Thus future research on this very intricate and important aspect of the link between nutrition and immune system would not only reveal the molecular mechanisms associated with this but would also lead to discovery of various therapeutics to revert these ill effects along with paving the path for various healthy options as food additives.