Dietary phytochemicals modulate intestinal epithelial barrier dysfunction and autoimmune diseases

The intestinal epithelium acts as a key defensive barrier that protects internal organs from the detrimental gut environment. The homeostasis of the gut epithelium may be altered by environmental conditions and exogenous pathogens that can impair the integrity of the gut barrier, leading to immune response associated with low-grade systemic inflammation, a known contributor to metabolic and inflammatory diseases. Autoimmune diseases (ADs) are a collection of abnormalities of the immune system, in which the immune system of an individual acts against healthy organs or systems, due to a failure in antigenic recognition. Hence, this review aims to focus on modulators of intestinal epithelial barrier dysfunction with effects on autoimmune disorders. All data on dietary phytochemicals and their impact on the modulation of the intestinal epithelium barrier and various ADs were collected from electronic searches of library databases (PubMed, Science Direct, and Google Scholar). An electronic search was conducted using PubMed, Science Direct, and Google Scholar by finding the keywords “phytochemicals” AND “bioactive compounds” AND “flavonoids” AND “polyphenols” OR “intestinal epithelium barrier” OR “autoimmune diseases” OR “inflammatory diseases” in “Title/Abstract/Keywords,” with the date from January 2011 to December 2020, to identify all published studies (in vitro, in vivo, clinical, and case-control) that have investigated the connection between dietary phytochemicals and their various beneficial effects. Dietary phytochemicals are promising key modulators, stabilizing the integrity of the intestinal barrier and attenuating the progression of ADs. Health-modulatory information was gathered and orchestrated in a suitable place in this review.


INTRODUCTION
Over the last decades, numerous studies have been conducted to investigate the crucial functions of the gut and its contents in human health and the progression of various diseases. The gut is a complex anatomical organ, consisting of mucosae involved in the digestion and absorption of major nutrients with water, representing the main interface between the human body and the outside environment . It includes a huge number of specialized immune cells that are involved in the defensive responses, where the epithelial surface of the gut is repetitively exposed to dietary antigens . Similarly, the mucosa of the intestinal tract also participates in the defense mechanism to prevent the entry of microorganisms and dietary antigens .
This permeability of this gut barrier is often controlled by dynamic functions for the concurrent fulfilment of the nutrient absorption and defense mechanisms. The small number of nutritional antigens and microorganisms do frequently enter the gut without any pathogenic stimuli. This event habitually produces a homeostatic immune response considered to be an immune tolerance to exogenous antigens (Kumar Singh et al., 2019). Furthermore, increased gut paracellular permeability facilitates an increased pervasion of luminal antigens, which will eventually cause damage to the intestinal barrier. These processes in turn activate the mucosal immune system, ultimately leading to sustained inflammation and gut damage (Karl et al., 2017).
This failure or damage to the functions of the mucosal barrier is generally referred to as "Leaky gut syndrome." Therefore, the gut luminal mucosal epithelium acts as a structural and immunological barrier against the broad spectrum of noxious substances and exogenous antigens. The regulation of function of the gut mucosal barrier is significant in sustaining gastrointestinal mucosal homeostasis.

ORGANIZATION OF INTESTINAL EPITHELIAL BARRIER
The gut mucosa is composed of heterogeneous compounds, which greatly contribute to its function as a physical and immunological defense mechanism. The outer mucus layer is composed of trillions of commensal bacteria, antimicrobial proteins, defensins, and secretory immunoglobulin A; the central single cell layer houses specific epithelial cells being composed of enterocytes, goblet cells, and endocrine cells; and the inner layer is lamina propria that lodges the adaptive and innate immune cells, which includes, macrophages, dendritic cells, intraepithelial dendritic cells, plasma cells, cluster of differentiation 4+ (CD4 + ) T helper (Th) cells lymphocytes, T regulatory cells, and bone marrow cells (B cells) (De Santis et al., 2015;Vancamelbeke & Vermeire, 2017).
The mucus layer is generally considered to be the first line of physical defense against infection where the invaders are trapped when making direct contact with the epithelial cells (Rinninella et al., 2019).
The mucus layer is made up of glycosylated mucin proteins, which form a gel-like consistency covering the gut epithelium (Vancamelbeke & Vermeire, 2017). The glycosylated mucin (mucin 2 [MUC2]) is the most abundant mucus protein synthesized by goblet cells present throughout the small and large intestine. An increased level of MUC2 secretion is the first line of physical defense against colitis and other gut-associated diseases (Van der Sluis et al., 2006). The colon has two mucus layers, with the thin outer layers generally permitting long-term colonization by commensal bacteria, whereas the thick inner layer is devoid of said commensal bacteria (Vancamelbeke & Vermeire, 2017). Antimicrobial proteins, defensins, and secretory immunoglobulin A are often released into the mucus layer to support the physical separation of the microbiota between the epithelium and the lumen. The composition of the mucus layer can affect the functional activities of gut microbiota, whereas the microbiota can also regulate the properties of the mucus layer (Johansson et al., 2015).
Epithelial cells are positioned beneath the mucus layer, also acting as another durable determinant of the physical intestinal barrier. These epithelial cells often regulate the transport of all lipophilic and larger molecules through the three junctional complexes, adherens junctions (AJs), tight junctions (TJs), and desmosomes (Vancamelbeke & Vermeire, 2017). TJ and AJ together form the apical junction complex (AJC), which provides selective barrier permeability and cell polarity ( Figure 1).
TJ is the adhesive mixture that mostly covers the intercellular space, containing membrane proteins (zonula occludens [ZO]-1, 2, 3), transmembrane proteins (occludin, claudins, MARVEL domain-containing 3 protein, junctional adhesion molecule 1 [JAM-A], tricellulin, and lipolysis-stimulated lipoprotein receptor), and several regulatory proteins such as symplekin, 7H6, cingulin, etc. (Guzman et al., 2013). AJ is located underneath TJs and is mainly involved in the assembly. AJ regulates the integrity of the epithelium through strong ties with desmosomes. AJC is eventually connected to actin and myosin, which allows the maintenance of the junctions, barrier homeostasis, and intracellular signaling pathways (Turner, 2009;Vancamelbeke & Vermeire, 2017). In addition to orchestrated arrangements, the commensal gut bacteria also play a dynamic function in regulating host barrier homeostasis by maintaining cell renewal, stimulating wound healing repair, and restructuring the TJ (Guzman et al., 2013). TJ stability is essential for the regulation of barrier integrity, and the gut epithelial cells in the F I G U R E 1 Organization of the intestinal epithelial barrier integrity TJ formation are thus renewed at every 4-5 days' intervals (Vereecke et al., 2011).

GUT MICROBIOTA AND THE INTESTINAL EPITHELIAL BARRIER
The gut is the vast reservoir of multifaceted microorganisms, collectively known as gut microbiota, which includes about 10 12 bacteria in the distal portion of the gut (Martins dos Santos et al., 2010).
These bacteria are diverse, comprising approximately 1150 species, with around 160 species shared between individuals, with Firmicutes (60%) and Bacteroidetes (10%) as the dominant two phyla (Alneberg et al., 2014;Qin et al., 2010). Actinobacteria, Proteobacteria, Cyanobacteria, Fusobacteria, and Verrucomicrobia are phyla with lower levels of abundance in the healthy gut. These bacterial communities often facilitate food digestion and regulate the immune system and a healthy gut environment . The composition of gut microbiota varies according to the diet and environment (Table 1).
Mucus seals the gut epithelium, acting as a diffusion barrier and preventing a high volume of antibacterial products from approaching the cell surface, ultimately protecting the intestinal tract (Johansson et al., 2013;Vaishnava et al., 2011). The mucus in the small intestine helps prevent microbial entry as well as assisting the development of immunity in the host Shan et al., 2013).
The thicker inner mucus layer can be detected in the gut region of the mouse and human, with this layer of the protection system separating the bacteria from the tissue (Shan et al., 2013).
Elements of the microbiota, such as Bacteroides, Bifidobacteria, and Akkermansia muciniphila, often exist in nonattached forms in the outer mucus of the gut, where they can break down and use mucin glycans as a primary energy source. The degradation of mucin glycans provides the intestinal tract with a stable resource that may provide up to 50% of the carbon flux . The secretion of exoglycosidases regularly takes place in specific genetic loci for definite kinds of substrates, namely, starch, cellulose, and xylose-containing polysaccharides (Johansson et al., 2010;Larsbrink et al., 2014). These mucin glycans normally shield the mucin polymer from redundant degradation. However, the inner mucus layer is more susceptible to gutassociated pathologies and may be rapidly degraded allowing bacteria to reach the epithelium and elicit inflammation (Fu et al., 2011;Johansson et al., 2015). The germ-free mucus is found in both the small and large intestines, and in recent times this colon mucus has been identified as being reliant on the composition of the microbiota. Evidence has shown that although microbiota and hosts have a limited connection, there are massive interactions and communications between them (Jakobsson et al., 2014;Johansson et al., 2015).
The composition of the gut microbiota varies greatly according to diet, lifestyle, age, gender, ethnicity, body mass index, and dietary behaviors. This variation is usually noticed in the form of physiological implications in the healthy gut setting, as well as in intestinal and extra-intestinal disorders. The gut microbiome usually acts as a metabolic organ, producing various bioactive metabolites, including trimethylamine-N-oxide (TMAO), short-chain fatty acid, and bile acids that can disturb the normal physiological functions of the host. Several animal and clinical studies have shown that numerous families of bacteria, namely, Deferribacteraceae, Anaeroplasmataceae, Prevotellaceae, and Enterobacteriaceae, are involved in the production of TMAO (Craciun & Balskus, 2012;Koeth et al., 2013;Zhu et al., 2014) and Escherichia fergusonii, also provide significant production of TMAO (Craciun & Balskus, 2012;Romano et al., 2015). Dysbiosis is certainly recognized as changes in the composition of this gut microbiota and a cause or a consequence of various metabolic and inflammatory disorders.

INTESTINAL EPITHELIAL BARRIER DYSFUNCTION
The importance of the gut epithelial barrier in disease pathogenesis has recently become a fascinating theme. Alterations in the integrity of the intestinal barrier can be detected in both intestinal and systemic diseases, such as metabolic disorders, inflammatory diseases, and systemic/extra-intestinal disorders (Chelakkot et al., 2018;Mu et al., 2019;Oshima & Miwa, 2016). Nevertheless, researchers have not reached a consensus over whether the loss in barrier integrity is the reason or result of these diseases. A low-fiber diet, exogenous pathogens, environmental stress, and certain medications may be critical factors leading to physiological abnormalities and the loss of barrier integrity ( Figure 2). An imbalance in gut microbiota and intestinal dysfunction is greatly associated with several chronic diseases, such as irritable bowel syndrome, IFD, celiac disease, nonalcoholic fatty liver disease, diabetes, obesity, hypertension, cardiac failure, atherosclerosis, renal diseases, colorectal cancers, autism spec-trum diseases, Alzheimer's and Parkinson's diseases, multiple sclerosis, and hepatic encephalopathy Ganesan & Xu, 2018aRinninella et al., 2019;Zhang et al., 2018).

Dietary phytochemicals modulate gut microbiota and intestinal epithelial barrier
The gut microbiota can be recognized as a critical regulator of the IP. Several animal studies have demonstrated that the gut microbiota directly affects intestinal permeability by affecting TJ properties that subsequently promote epithelial barrier dysfunction and modulate low-grade inflammation Mu et al., 2019;Shi et al., 2019). It has been confirmed that microbial dysbiosis can often elevate the production of bacterial lipopolysaccharide (LPS) and enhance intestinal permeability with an increased risk of inflammation and systemic endotoxemia. In immune cells, these LPS have been proved to stimulate nuclear factor-kappa B (NF-κB) and mitogenactivated protein kinase (MAPK) production by activating the Toll-like receptor 4 inflammatory cascade (Chelakkot et al., 2018). Hence, the prevention of microbial dysbiosis and the management of the complex gut microbial ecosystem have been projected as a novel approach to renovating the intestinal epithelial barrier (Damiano et al., 2018).
Dietary phytochemicals are bioactive substances that are extensively present in vegetables, fruits, and spinach. They are rapidly absorbed in the gut and extensively metabolized by gut microbiota.
Based on the poor bioavailability of the compounds, their detoxification process quickly occurs in the liver and kidneys via methylation, glucuronidation, and sulfation (Damiano et al., 2018). Hence, the blood availability of the native compounds is reasonably low, compared to their metabolites. These metabolites have been extensively investigated for their copious biological activities, including antidiabetic, antiobesity, antimicrobial, antioxidant, anticancer, and antiinflammatory functions (Ganesan & Xu, 2017a, 2017b, 2017c, 2017d, 2017e, 2018bMickymaray, 2019;Xu et al., 2020). These effects are often exerted at the intestinal and systemic levels.

Dietary phytochemicals attenuate the complications of T1DM
T1DM arises due to the obliteration of β-cells in the pancreatic islets of Langerhans, by macrophages, natural killer thymus cells (T cells), den-dritic cells, and autoantigen-specific CD4 + and CD8 + T lymphocytes (You & Chatenoud, 2016), often generating inflammation in the tissue (Vives-Pi et al., 2015). This β-cells' obliteration eventually leads to a deficiency in insulin and hyperglycemia (Skyler et al., 2016). Consequently, the development and outcomes of T1DM lead to ketoacidosis, renal failure, cardiovascular diseases, neuropathy, and retinopathy Kumar et al., 2009;. The mechanism involved in the immunological aspect of the disease arises due to the inflammatory response. Hence, the production of TNF-α, IFN-γ, and nitric oxide (NO) by leucocytes inhibits the apoptosis of β-cells and the subsequent recruitment of APCs (Vives-Pi et al., 2015;Wållberg & Cooke, 2013;Zhang et al., 2020). APCs stimulate CD4 + T cells that trigger macrophages to discharge various cytokines and reactive oxygen species (ROS). These cascade mechanisms eventually bring about a pro-inflammatory environment that increases the cytotoxic effects on the islet cells (Vives-Pi et al., 2015;Wållberg & Cooke, 2013).
Therefore, the administration of dietary phytochemicals is auspicious as drugs for T1DM.

Dietary phytochemicals attenuate IBD
IBD is a set of immune disorders categorized by chronic inflammation in the intestine, with general forms of Crohn's disease and ulcerative colitis (UC) (Chen et al., 2019). The disease can be distinguished by the locality, occurrence, deepness of the inflammation, and disease complications. Clinically, both CD and UC have the same symptoms, comprising diarrhea, hematochezia, and abdominal pain (Kim & Cheon, 2017). The etiology of IBD is not well-defined; however, it is recognized as having multifactorial pathogenesis. Various factors are thought to build toward the clinical signs of the diseases, including environmental, genetic, bacterial infection, disruption of the immune system, and chronic intestinal inflammation (Fakhoury et al., 2014). The evidence further recognized that oxidative stress also plays a pathogenic function in chronic inflammatory diseases (Chen et al., 2018;Guan & Lan, 2018). Macrophages and neutrophils generate higher amounts of ROS and reactive nitrogen species that can change the protein function, augment inflammation and cell death, and increase alteration in the gut mucosa environment (Tian et al., 2017).
The intestinal epithelial barrier plays a vital role in regulating human intestinal homeostasis. When it is altered, the products of the commensal gut microbiota translocate from the intestinal lumen to the wall, resulting in the stimulation of immune cells (Neurath, 2014). In IBD, deregulation of effector T cells arises in CD (Th1 and Th17) and in UC (Th2 and Th217), along with increased IL-17 providing an augmented inflammatory process in the lamina propria (Boirivant & Cossu, 2011).
In CD, Th1 lymphocyte stimulation contributes to a release of IL-12, TNF-α, IFN-γ, and IL-23, whereas in UC, Th2 triggers the generation of IL-4, IL-5, IL-6, and IL-10 (Singh et al., 2012). Both in CD and UC, TNF-α is often found at higher levels that stimulate cell proliferation, differentiation, and apoptosis in intestinal endothelial cells via the recruit-ment and autoproteolytic stimulation of caspases (Fakhoury et al., 2014).
Besides, these compounds modulate the gut microbiota and maintain the mechanisms of intestinal homeostasis (Galvez et al., 2014;Larrosa et al., 2010). Hence, the supplementation of dietary phytochemicals is promising as drugs for IBD.

Dietary phytochemicals attenuate psoriasis
Psoriasis is an immune-mediated, chronic, inflammatory disease that is stimulated by various factors including microbial infections and manifests in the skin, joints, tendons, ligaments, nails, and mucosal membranes (Di Nardo et al., 2018). It is mainly characterized by the appearance of red patches in the squamous layers. These cutaneous lesions are characterized by the hyperproliferation of epidermal cells and keratinocytes of the elbows, knees, scalp, and lumbar-sacral region that form along with inflammatory infiltrate (Dimitris et al., 2020).
Psoriasis is generally activated by DNA fragments of keratinocytes conjugated with cathelicidin peptide LL-37, leading to immune complex development by recruitment of dendritic cells and T lymphocytes (Campbell et al., 2018). During the chronic phase, these triggered native dendritic cells generate cytokines (IL-12 and IL-23) related to psoriasis (Zorko et al., 2018). Furthermore, these cytokines support the production of Th1 and Th17, which elevate the expression of IL-12, IL-17, and IFN, the main cytokines in the progression of inflammatory diseases (Campbell et al., 2018;Dimitris et al., 2020). These elevated cytokines often cause the stimulation of keratinocytes that eventually promote cell proliferation and differentiation (Lowes et al., 2014). Although several topical and systemic clinical treatment choices exist for psoriasis (Di Nardo et al., 2018;Farahnik et al., 2016;Fioranelli et al., 2017), none provide excellent clinical outcomes without side effects.
Dietary phytochemicals are compounds that exhibit potential antiinflammatory effects by reducing the generation of pro-inflammatory cytokines and promoting keratinocyte apoptosis. Administration of curcumin, EGCG, and resveratrol showed a reduction in proinflammatory markers such as TNF-α, IFN-γ, IL-2, IL-12, IL-17A, IL-17F, IL-22, and IL-23 in the plasma and tissues (Kang et al., 2016;Lee et al., 2015;Zhang et al., 2016). Treatment with these dietary phytochemicals attenuates skin inflammation, reduces infiltration of T cells, leads to recruitment of reduced populations of dendritic cells, reduces malondialdehyde in plasma, increases populations of CD4(+) T cells of spleens, and increases the bioactivities of plasma SOD and CAT (Kang et al., 2016;Lee et al., 2015;Zhang et al., 2016). In vitro studies have also shown that resveratrol stimulates apoptosis in the HaCaT keratinocyte cell line. Hence, the intake of dietary phytochemicals is a promising candidature for the treatment of psoriasis.

Dietary phytochemicals attenuate RA
RA is a systemic, chronic autoimmune joint disease that affects 1% of the general population, primarily women rather than men (Skoczyńska & Świerkot, 2018;Sung et al., 2019). This disease generally affects the quality of life with increased morbidity and decreased life expectancy.
Numerous factors, including genetic, hormonal, environmental, and immunological factors, may contribute to the pathogenesis of the disease (Smolen et al., 2016). The pathology of the disease is characterized by synovial inflammation of multiple joints, swelling, and the production of autoantibodies that lead to the destruction of cartilage and bone. During the course of inflammation, there is a discharge in inflammatory mediators and proteolytic enzymes and a generation of ROS that contribute to the deterioration of clinical symptoms. These worsening signs in the organs lead to systemic features such as cardiovascular, pulmonary, and skeletal disorders, with augmentation of morbidity and mortality (Mellado, 2015). The cascade mechanisms of the immune response contribute to the decreasing immunological tolerance of B and T cells against autoantigens, with an ensuing autoimmune response in the joints (Scott et al., 2010). T cells activation generally triggers macrophages in the joints that stimulate angiogenesis, secretion of protease, the proliferation of fibroblasts, recruitment of leukocytes and lymphocytes, and specific expression of cell-adhesive molecules such as E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion protein 1 that contribute to the inflammatory destruction of cartilage and bone (Mellado, 2015;Navegantes et al., 2017). Many cytokines such as IL-1, IL-6, IL-12, IL-21, IL-23, and IFN-γ and elevated levels of cyclooxygenase-2, NO synthase, metalloproteinase, and other proteinases promote synovial inflammation and cartilage and bone destruction (Brzustewicz & Bryl, 2015;Makol & Krause, 2016;Tanaka et al., 2014). Another noteworthy mechanism of the inflammatory process in RA is the elevation of ROS production, acting as immunological mediators.

Dietary phytochemicals attenuate ALS
ALS is a serious neurodegenerative disease that causes selective dysfunction of motor neurons of the spinal cord and brain stem (Figueira et al., 2017 (Spaggiari et al., 2019).
Dietary phytochemicals such as morroniside, EGCG, madecassoside, and allicin elevate cellular glutathione, activate phase II detoxifying HO-1 enzyme, and eventually reduce the release of ROS formation (Calo et al., 2010;Guo et al., 2011;Koh et al., 2006;Kou et al., 2011;Wang et al., 2007Wang et al., , 2009). In addition, these natural antioxidant phytochemicals decrease lactate dehydrogenase and inhibit SOD activity that would usually maintain the stability of the cell and the mitochondrial membrane potential (Calo et al., 2010;Guo et al., 2011;Kou et al., 2011). These active compounds also downregulate Bax and caspase-3 expression and upregulate the expression of HO-1 and Bcl-2 through activation of extracellular signal-regulated kinase 1/2 and Akt-dependent signaling pathways (Kou et al., 2011). Finally, these natural dietary compounds protect motor neurons from degeneration and improve the life span.

Dietary phytochemicals attenuate SLE
SLE is a chronic, multiorgan-associated AD, described by the generation of self-reacting antibodies and immune complexes that cause primarily organ and tissue damage (Constantin et al., 2018;Lever et al., 2020). SLE has a range of multifaceted features that vary among individuals, stimulated by various factors including environmental factors (smoking, exposure to chemicals, drugs, diet, stress, and viral infections) and an inherited predisposition (Mok, 2003). Experimental studies show that susceptibility to the disease is 10 times higher in monozygotic twins than in dizygotic twins, which indicates a vital epigenetic role in the onset of the pathogenesis (Moulton, 2018). Its high severity is due to an unpredictable prognosis, including the potential for swift organ damage. Studies show that patients with deficits in primary complement components, particularly C1q, C2, and C4, are at the highest risk for the development of SLE (Looney et al., 2006;Rahman & Isenberg, 2008). Studies have revealed that the autoimmune response could be triggered by an augmented, abnormal apoptosis and decreased apoptotic cell clearance by macrophages elevating intracellular antigens, including anti-double-stranded DNA, in the cell.
The occurrence of this anti-double-stranded DNA is common in SLE patients (Looney et al., 2006;Oliveira et al., 2017;Rahman & Isenberg, 2008). Overall, this process leads to an elevated immune response, with activation of T and B cells, and increased expression of IL-10 following the production of self-reacting antibodies. These high quantities of self-reacting antibodies provide the generation of an immune complex, which can eventually cause impairment in the cardiovascular system and renal system leading to death (Kahlenberg & Kaplan, 2013).
Naturally occurring dietary phytochemicals such as coumestrol, curcumin, resveratrol, and indole-3-carbinol have been described as improving the development of several diseases with their manifold bioactivities, including decreases in oxidative stress, inflammatory response, and apoptosis (Handono et al., 2015;Kurien et al., 2015;Schoenroth et al., 2004;Wang et al., 2014;Yan et al., 2009). These compounds have also been reported to ameliorate immune cell infiltration and to improve organ injury, reduce anti-autoimmune antibodies and pro-inflammatory cytokines release, and normalize Th17-cell differentiation (Kurien et al., 2015;Yan et al., 2009). Hence, these dietary phytochemicals may serve as auspicious candidates to attenuate SLE.

PHENOLIC COMPOUNDS TARGETING INTESTINAL EPITHELIAL BARRIER DYSFUNCTION AND VARIOUS TYPES OF AD
In the present study, most of the phytochemicals are belonging to the classes of phenolic compounds, have the antioxidant capacity that affect Toll-like receptors and proteins of the nucleotide-binding oligomerization domain. This impact generally prevents epithelial cell binding and intestinal inflammation. Moreover, the antioxidant potential of phenolic compounds permits them to decrease the negative impacts of the ROS produced by the overstimulation of the immune system during AD. Polyphenols are pharmacologically dynamic with well-recognized immunomodulatory activity (Ganesan & Xu, 2017b;2017d, 2017e, 2018a, 2018bXu et al., 2020). Nevertheless, the challenging key issues in evaluating their pharmacological activity are the structural diversity of the compounds and their bioavailability that are greatly varied among the classes of the compounds. Additionally, each type of phenolic compound targets different immune cells and, thus, activates a plethora of different intracellular signaling pathways that eventually maintain the host's immune response. The modulation of numerous signaling pathways leads to changes in the expression of proinflammatory genes, cytokines, cyclooxygenase, lipoxygenase, phospholipase A 2 , and inducible NO synthetase, which combine with their capacity to moderate the population and differentiation of specific immune cells. Hence, phenolic compounds have antioxidant and antiinflammatory activities and regulate the inflammatory mechanism. To date, mainstream mechanistic studies have established in vitro cell cul-tures given their greater simplicity and reproducibility; however, they fail to recapitulate several glitches that are inherent to oral administration, bioavailability, and the intense secondary metabolism to which phenolic compounds are subjected. should also be systematically validated.