Anthocyanins as Immunomodulatory Dietary Supplements: History
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Contributor:
Thadiyan Parambil Ijinu
,
Lorenza Francesca De Lellis
,
Santny Shanmugarama
,
Rosa Pérez-Gregorio
,
Parameswaran Sasikumar
,
Hammad Ullah
,
Daniele Giuseppe Buccato
,
Alessandro Di Minno
,
Alessandra Baldi
,
Maria Daglia

Anthocyanins (ACNs) have attracted considerable attention for their potential to modulate the immune system. Research has revealed their antioxidant and anti-inflammatory properties, which play a crucial role in immune regulation by influencing key immune cells, such as lymphocytes, macrophages, and dendritic cells. Moreover, ACNs contribute towards maintaining a balance between proinflammatory and anti-inflammatory cytokines, thus promoting immune health. Beyond their direct effects on immune cells, ACNs significantly impact gut health and the microbiota, essential factors in immune regulation. Emerging evidence suggests that they positively influence the composition of the gut microbiome, enhancing their immunomodulatory effects. Furthermore, these compounds synergize with other bioactive substances, such as vitamins and minerals, further enhancing their potential as immune-supporting dietary supplements.

  • immune cells
  • gut microbiota
  • anthocyanins

1. Introduction

The immune system is vital in safeguarding the body against disease and maintaining its physiological functions. Any disturbance in the immune system can result in various health problems, such as autoimmune diseases, inflammatory disorders, cancer, etc. A debilitated immune system can lead to infections and tumors [1] while an overactive one may cause autoimmune conditions, such as type I diabetes, systemic lupus erythematosus, and rheumatoid arthritis [2][3]. Immune responses can be categorized into two types: innate and adaptive. Innate immunity comprises pre-existing responses triggered without prior exposure to an antigen and is inherent in individuals from birth [4]. Conversely, adaptive immunity includes humoral and cell-mediated immunity, activated only after exposure to a specific antigen [5]. Immune cells, such as lymphocytes, dendritic cells, monocytes/macrophages, natural killer cells, CD4+ and CD8+ T-cells, and myeloid-derived suppressor cells, play crucial roles in regulating innate and adaptive immunity through their distinct structures and functions [6]. In addition to these immune cells, various inflammatory cytokines and chemokines, including interleukins (ILs), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta (TGF-β), and interferon-gamma (IFN-γ), are triggered and regulated [7][8][9]. 
Amidst the global COVID-19 or coronavirus pandemic, it is evident that markets worldwide have become inundated with a plethora of products claiming to be “immunity boosters”. These offerings emerge alongside various speculative cures, treatments, and preventive strategies. However, it is crucial to recognize that the notion of an “immunity booster” is scientifically misleading and frequently exploited to promote unverified products and therapies [10][11]. The “immunity booster” market comprises vitamins, minerals, antioxidants, probiotics, functional foods, nutraceuticals, and other complementary and alternative medicines. In a study conducted using data from a US National Health and Nutrition Examination Survey, more than 50% of the US population acknowledged their use of supplements [12]. This widespread usage has significant economic implications, with the global dietary supplement market estimated to be approximately USD 133.1 billion, projected to accelerate at a CAGR of 9.6% from 2016 to 2024 [13]. It is crucial to underscore that promoting “immunity boosters” can mislead consumers and give rise to false hopes. The scientific community consistently emphasizes the importance of evidence-based practices and rigorous research to substantiate the claims of any product or therapy. Unfortunately, many of the offerings currently flooding the market lack the necessary scientific backing to validate their effectiveness.
Natural products have been extensively studied for their potential immunomodulatory properties [14]. These natural products can modulate the immune system by enhancing or suppressing the immune response. They can also promote the production of cytokines and other immune system molecules, leading to an overall improvement in immune function. One of their key functions is to stimulate non-specific innate immune responses, which involve the use of immune system mediators, such as innate leukocytes (natural killer cells, eosinophils, basophils, and mast cells) and phagocytic cells (neutrophils, macrophages, and dendritic cells), to defend against pathogens [15]. By enhancing innate immunity, these products facilitate effector innate immune responses, such as immune cell infiltration, phagocytosis, and cytotoxic mechanisms, such as natural-killer-cell-mediated cytotoxicity, ultimately destroying tumor cells [16]. Certain natural compounds also act as immunomodulatory agents, activating the adaptive immune system. In adaptive immunity, T- and B-lymphocytes recognize tumor antigens through cell-surface antigen-specific receptors, leading to an augmented humoral response and the elimination of tumor cells through various mechanisms, including T-cell mediated cancer cell death [17].
Insufficient nutrition, malnutrition, or deficiencies in specific nutrients can disrupt the functioning of the immune system, leaving the body vulnerable to disease. To maintain a robust immune system, it is necessary to consume a well-balanced diet that provides all of the necessary nutrients in appropriate quantities [18]. Functional foods and nutraceuticals offer an alternative approach to boosting immune function and support the management of diverse diseases. Several studies have explored the potential of plant-based nutraceuticals as immunomodulating agents, owing to their wide range of effects that can positively impact the immune system [19][20][21]. These substances are often better tolerated than conventional pharmaceutical treatments, making them an attractive supplement for enhancing immune system function [18]. Among them, ACNs, naturally occurring water-soluble flavonoids, have been shown to stimulate immunomodulatory and antioxidant effects. This, in turn, helps to reduce the harmful cooperative and synergistic effects of oxidative stress and proinflammatory cytokines. Consequently, ACN may protect against chronic diseases [22][23]. 

2. Chemistry and Natural Sources of Anthocyanins

ACNs are the glucosides of anthocyanidins and are predominantly found as 3-glucosides or acylglycosides. The primary configuration of their parent nucleus consists of a strongly conjugated 2-phenyl-benzopyran cation. Three carbon atoms connect the benzene rings to form a C6–C3–C6 skeleton, the common motif of ACNs [24][25]. These ACNs can be classified into sugar-free anthocyanidin aglycones and glycosides. ACNs include over 700 different derivatives of 27 aglycons [26]. These compounds are formed, via the phenylpropanoid pathway (Figure 1), from anthocyanidins, which serve as their precursors [27].
Figure 1. Overview of the phenylpropanoid pathway. PAL, phenylalanine ammonia-lyase; C4H, cinnamic acid 4-hydroxylase; 4CL, 4-coumarate:CoA ligase; CHS, chalcone synthase; CHI, chalcone isomerase; F3H, flavanone3-hydroxylase; F3′H, flavonoid 3′-hydroxylase; F3′5′H, flavonoid 3′5′-hydroxylase; DFR, dihydroflavonol 4-reductase; ANS, anthocyanidin synthase; OMT, ortho-methyltransferase; UFGT, UDP flavonoid glycosyltransferase.
The chemical structures of the flavylium cation and ACNs are given in Figure 2. The aglycone forms of anthocyanidins are rarely observed due to their inherent instability and reactivity, primarily caused by the electron-deficient flavylium cation. ACNs are more commonly observed in a glycosylated state as this modification enhances their stability and solubility [28]. They are typically composed of one of six anthocyanidin bases, which differ in their molecular structure at the B-ring and are attached to a sugar moiety at the third position of the C-ring. Approximately 90% of all known anthocyanidins found in plants consist of six bases, namely, pelargonidin, cyanidin, peonidin, delphinidin, petunidin, and malvidin [29][30], with the glycosides of the nonmethylated anthocyanidins (cyanidin, delphinidin, and pelargonidin) being the most abundant natural ACNs, accounting for up to 60% of the total content [31].
Figure 2. Chemical skeleton of anthocyanin; (a) flavylium cation, (b) most common anthocyanidins, (c) basic structure of anthocyanin.
The color of the ACNs becomes bluer as the number of hydroxyl groups in the B-ring increases—conversely, methylation results in a red shift in the color of the ACNs. Moreover, the color is also pH dependent, i.e., blue in basic conditions and red in acidic conditions (where ACNs are positively charged). Methylation of the B-ring offers improved resistance to oxidation and helps stabilize the ACNs. Methyl-modified flavonoids are commonly present on the surfaces of leaves and flowers [32]. On the other hand, the glycosylation of ACNs causes a hypsochromic shift in the absorption maxima of the spectra and enhances their stability during their storage in vacuoles [33][34]. Sugar molecules, such as glucose, galactose, rhamnose, or arabinose, are primarily attached to the aglycone to form derivatives of 3-glycosides or 3,5-diglycosides [22]. The sugar moieties of acylated ACNs, usually attached to the hydroxyl group in C-3 and C-5 of the aglycone, have a covalent ester linkage to one or more of the aliphatic (acetic, malonic, oxalic, and succinic) or aromatic (caffeic, coumaric, ferulic, hydroxybenzoic, and sinapic) acids [35][36]. The acylation of glycosyl moieties in ACNs alters their chemical properties, enhancing stability. Aliphatic acylation does not affect color while aromatic acylation causes a blue shift. As a result, acylated ACNs are more suitable for use as natural colorants and bioactive components in innovative functional foods and nutraceuticals. This modification improves stability and expands their potential applications [34][36][37][38].
Many fruits are rich in ACNs, which serve as the pigments responsible for their vibrant colors. Berries, like blackcurrants, blackberries, blueberries, and cranberries, and vegetables, like black carrots, red cabbage, and purple potato, are well-known sources of ACNs [39][40]. For instance, pistachios contain significant amounts of cyanidin 3-O-galactoside while blackcurrants contain delphinidin 3-O-rutinoside and cyanidin 3-O-rutinoside. Red wine, elderberries, and pomegranate juice are known to contain malvidin 3-O-glucoside, cyanidin 3-O-glucoside, and cyanidin 3,5-O-diglucoside, respectively [41][42]. These compounds exhibit strong antioxidant properties and have the potential to function as preventive bioactive molecules against various illnesses. Additionally, various flowers, particularly those with red, purple, and blue shades, are used in traditional medicine or are consumed as food. These flowers, such as red clover, red rose, red hibiscus, red pineapple sage, pink blossom, blue rosemary, blue chicory, cornflower, purple passion flower, purple mint, common violet, purple sage, and lavender, are also rich in ACNs [31]. Acylated ACNs with varying structures are also present in fruits, berries, vegetables, and tubers. Some rich sources of these compounds include purple sweet potato, red radish, purple carrot, and red cabbage [43]. Within the pigmented members of the Solanaceae family, such as potatoes, peppers, tomatoes, and eggplants, acylated ACNs are identified by the structure of anthocyanidin-3-hydroxycinnamoyl-rutinoside-5-glucoside, with delphinidin being the primary anthocyanidin, excluding pigmented potatoes [36][44].

3. Immunomodulatory Potential of Anthocyanins

Over the years, researchers have explored various avenues to improve immune function and address immune-related disorders. Recently, there has been growing interest in the potential of natural compounds to influence the immune response. ACNs, documented in both in vitro and in vivo studies, have been found to possess diverse health-promoting properties. In addition to their notable antioxidant property, ACNs play a crucial role in modulating the immune system. They protect the immune system through the following cellular processes:
  • ACNs exhibit strong antioxidant characteristics, effectively neutralizing free radicals and diminishing oxidative stress. By safeguarding immune cells against oxidative damage, these compounds preserve the integrity and functionality of the immune system [18][30][45][46];
  • Inflammation disrupts immune homeostasis, leading to diverse diseases or disease conditions. However, ACNs have been proven to play a crucial role in regulating inflammatory pathways by inhibiting the production of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and proinflammatory mediators (COX, LOX, MPO, and PGE2), thereby offering protection against the development of various inflammatory conditions [26][29][47];
  • ACNs influence immune cell activation and proliferation by modulating various pathways. Moreover, they have a significant impact on gene expression within immune cells, leading to the heightened expression of genes responsible for antioxidant defense, anti-inflammatory pathways, and immune cell activation [26][48][49];
  • Recent research indicates that ACNs can influence gut microbiota composition and functionality. Given the pivotal role of the gut microbiota in regulating the immune system, this interaction has the potential to contribute significantly to the immunomodulatory effects exhibited by ACNs [50][51][52][53][54].
ACNs, along with other polyphenols, such as flavones, flavone-3-ols, and flavanones, have shown potential in promoting a balanced T helper cell type 1 (Th1)/Th2 response and reducing the production of allergen-specific immunoglobulin (Ig) E antibodies [55]. Additionally, ACNs can activate gamma-delta (γδ) T cells, a type of immune cell involved in both acquired and innate immunity, by mimicking pathogen-associated molecular patterns [56]. This interaction with γδ T cells enhances the activity of essential immune components, such as natural killer cells, cytokines, and lymphocytes, which are crucial in defending against pathogens that can enter the body through the digestive and respiratory systems.
The immunomodulatory activities of ACNs (reported in vitro, in vivo, and in human studies) have been summarized in Table 1.
Table 1. Immunomodulatory potential of anthocyanins, their aglycons, and metabolites.
Anthocyanin and Its Aglycons Dose Methodology Major Findings Reference
Cyanidin-3-glucoside 100 μM In Vitro
Osteoclasts from C57BL/6J mice cultured with M-CSF (30 ng/mL) and the receptor activator of a nuclear factor kappa B ligand (RANKL) (100 ng/mL) and supplemented with the test sample.		 Inhibited osteoclast differentiation and formation induced by RANKL. [57]
Protocatechuic acid
(anthocyanin metabolite)		 0–25 μM In Vitro
Osteoclasts from ICR mice were cultured in the presence of M-CSF (30 ng/mL) and RANKL (50 ng/mL) and treated with the test sample.		 Inhibited RANKL-induced osteoclast differentiation and suppressed the bone-resorbing activity of mature osteoclasts. [58]
25 mg/kg/d In Vivo
Nine days of administration in LPS (5 mg/kg)-induced bone destruction in male ICR mice.		 Recovered the bone volume per tissue volume, trabecular separation, and trabecular number.
Delphinidin 50 μM In Vitro
Jurkat E6-1 cells were preincubated with gadolinium and N-(4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide for 15 min.		 Induced Ca2+ and Sr2+ influx through the CRAC channel and induced NFAT pathway activation; thereby, the production of IL-2 occurs. [59]
Anthocyanidins 5–20 μM In Vitro
TPA (20 ng/mL)-induced cell transformation was investigated in the parental JB6 Cl41 cells or AP-1-luciferase stable transfectant JB6 cells.		 Ortho-dihydroxyphenyl structure (delphinidin) on the B-ring of aglycon inhibited cell transformation and activator protein-1 transactivation. [60]
Delphinidin 25–100 μM In Vitro
RAW264 cells were treated with LPS (40 ng/mL) for 6 h.		 Inhibited MAPK-mediated COX-2 expression. [61]
Cyanidin-3-O-galactoside and cyaniding-3-sambubioside rich extract of Sambucus ebulus 200 mL infusion Interventional study
Fifty-three volunteers enrolled in a 4-week intervention involving the consumption of infusion.		 Decreased pro-inflammatory status and complemented activity markers in healthy volunteers. [62]
Cyanidin-3-O-glucoside and peonidin-3-O-glucoside rich fraction of black rice germ and bran. 0–200 μg/mL In Vitro
A549 cells and THP-1 macrophages exposed to SARS-CoV-2 spike glycoprotein S1 (100 ng/mL).		 Inhibited NF-κB activity and the NLRP3 inflammasome pathway, leading to the inhibition of inflammatory genes and cytokine secretions. [63]
Cyanidin-3-O-glucoside 0–20 μg/mL
Peonidin-3-O-glucoside 0–20 μg/mL
Cyanidin-3-O-glucoside delivered by enteric sodium alginate 25 mg/kg/d In Vivo
Male BALB/c mice received two sensitization doses of 100 µg ovalbumin and 2.0 mg alum, administered in 200 µL of phosphate-buffered saline via intraperitoneal injection on day 0 and day 14.		 Enhanced the intestinal epithelial barrier by up-regulating the tight junction protein expression and promoting secretory IgA and β-defensin secretion and regulated Th1/Th2 immune balance in the intestinal mucosa. [64]
Anthocyanin-rich roselle extract 0–400 mg/kg In Vivo
1-day-old Ross 308 broiler chicks were fed on basal diets supplemented with extract for 35 days.		 Improved metabolic functions, blood biochemistry, intestinal morphology, antioxidant activity, immune status, and higher ω-3 content in the breast muscle. [65]
Cyanidin-3-glucoside-enriched diet. 26 mg/kg/d Ex Vivo
Myocardial ischemia/reperfusion (I/R) injury in mice. Pretreated with the sample for a month.		 Diet changed the microbiome and the transplantation of the fecal microbiota transferred the cardioprotection. [66]
Total anthocyanin from boysenberry and apple juice concentrate 2.5 mg/kg In Vivo
Ovalbumin-induced airway inflammation in male C57BL/6J mice.		 Reduced immune cell infiltration and tissue damage. [67]
Cyanidin 3-O-glucoside 10 mg/kg In Vivo
Five-week-old male spontaneously hypertensive and Wistar-Kyoto rats were treated daily for a period of 15 weeks.		 Treatment normalized the splenic production of TNFα and IFNγ and the proportion of CD62Llo and CD62L− helper T-cells. [68]
Cyanidin-3-O-glucoside 25 mg/kg In Vivo
Treated twice per week for six consecutive administrations in Sprague Dawley with bovine type II collagen-induced arthritis.		 The study suggests that CD38+ NK cells inhibiting Treg cell differentiation may contribute to the immune imbalance seen in both rheumatoid arthritis and collagen-induced arthritis. [69]
25–100 μM In Vitro
RA synovial fibroblasts collected from arthritic patients.
50 μM In Vitro
Mononuclear cells were collected from arthritic patients.
50 μM In Vitro
Mononuclear cells were cocultured with CD38+ NK cells.
Delphinidin-3-O-glucoside and cyanidin-3-O-glucoside 50–600 µg/mL In Vitro
Both the compounds alone or in combinations were added and incubated with HCT-116 and HT-29 human colorectal cancer cells for 24 h.		 Both showed potential for binding with and inhibiting immune checkpoints, PD-1 and PD-L1, which can activate the immune response in the tumor microenvironment and induce cancer cell death. [70]
Anthocyanin-rich mix 40 mg/kg BW In Vivo
High-fat-diet-induced obesity, dyslipidemia, insulin resistance, and steatosis in C57BL/6J mice.		 Increased glucagon-like peptide-2 levels, the intestinal hormone that upregulates tight junction protein expression. [71]
Anthocyanin-rich mix (AC mix) 5 μg/mL In Vitro
Caco-2 cell monolayers were pre-incubated for 24 h with IFNγ (10 ng/mL) to upregulate the TNFα receptor.		 PCA, C3G, and the AC mix, fully prevented p65, ERK1/2, and MLC phosphorylation. D3G inhibited TNFα-triggered p65 phosphorylation; Peo3G had no effect.
Protocatechuic acid (PCA) 0.5 μM
Delphinidin-3-O-glucoside (D3G) 0.5 μM
Cyanidin-3-O-glucoside (C3G) 1 μM
Peonidin-3-O-glucoside (Peo3G) 0.1 μM
Cyanidin-3-glucoside-rich anthocyanin extract of Lonicera caerulea fruit 0–0.8 mg/mL In Vitro
Human hepatoma cell line SMMC-7721.		 Inhibits proliferation of the tumor cells. [72]
50, 100 and 200 mg/kg BW In Vivo
Tumor-bearing male Kunming strain mice model was established using the murine H22 hepatoma cells line. Treated with sample for 15 days.		 Extract effectively combats tumours by dynamically adjusting the redox balance and enhancing immunoregulatory activity.
Cyanidin-3-O-glucoside 20 and 40 μM In Vitro
TNF-α-stimulated intestinal cells tested on endothelial cell activation by using cocultures (Caco-2, HUVEC, and mononuclear cells)		 Inhibited NF-κB pathway in epithelial cells. [73]
Cyanidin chloride and cyanidin 3-O-glucoside 0–25 μM In Vitro
LPS- (100 ng/mL) or IFNγ- (10 ng/mL) induction in immortalized mouse microglial (bv-2) cells pretreated with samples.		 Both compounds reduced ROS production in a dose-dependent manner. Cyanidin chloride showed a maximum decrease in NO production. [74]
Cyanidin-3-glucoside chloride 1.25–5.0 μg/mL In Vitro
EL-4 T cells were pretreated with various concentrations of the sample for 1 h and stimulated with PMA/ionomycin for 16 h.		 Suppressed Th2 activation through the downregulation of Th2 cytokines and the GATA3 transcription factor. [75]
Black raspberry Ethanol extract 0–200 μg/mL In Vitro
Normal donor peripheral blood mononuclear cells were induced with IL-6 and GM-CSF (10 ng/mL) and were pretreated with samples for 7 days.		 Limited expansion of myeloid-derived suppressor cells (MDSC). Attenuated IL-6-mediated phosphorylation of STAT3 and IL-2-induced STAT5 phosphorylation.
Pretreatment of immune cells inhibited MDSC
expansion and IL-6-mediated STAT3 signalling.		 [76]
Cyanidin-3-rutinoside 0–200 μM
Delphinidin-3-glucoside 0–100 μM In Vitro
BM185 cells were incubated with test samples for 48 h.		 Inhibited cell proliferation dose-dependently. [77]
Cyanidin-3-rutinoside 0–100 μM
Anthocyanin-rich berry extract 10–100 μg/mL
Cyanidin-3-rutinoside 50 mg/kg/d In Vivo
Eight-week-old female Balb/c mice challenged with BM185 cells treated with samples for 21 days.		 Moderate induction of caspases. [77]
Anthocyanin-rich berry extract 500 mg/kg/d
Cyanidin glycosides-rich juice (total polyphenol = 236 mg) 330 mL/d Clinical trial
Randomized, crossover study divided into five periods each lasting two weeks.		 Enhanced antioxidant status, reduced
oxidative DNA damage, and stimulated immune cell functions (IL-2 production).		 [78]
Proanthocyanidins 30 µM In Vitro
LPS (10 ng/mL) or IL-4 (1 ng/mL) activated murine J774 macrophages.
LPS (10 ng/mL) or IL-4 (1 ng/mL) activated human U-937 monocytes.		 Enhanced the expression of Arg-1 and MRC-1 in a dose-dependent manner. Enhanced the phosphorylation of STAT6.
Increased CCL-17 expression.		 [79]
Delphinidin 3-O-β-d-glycoside 50 µM In Vitro
LPS-induced mesenchymal stem cells.		 Modified the immunomodulatory properties and increased the IL-10 production. [80]
Black lentil water extract 600 mg/kg BW In Vivo
Azoxymethane/dextran sodium sulphate-induced C57BL/6 mice model.		 Modulated cytokines are involved in mediating communication between immune cells and anti-inflammatory action.
Reduced colon mucosa of markers like IL-1β and IL-6 and gene expression, such as CXCR2 and CSF3.		 [81]
Delphinidin 3-O-(2-O-β-D-glucopyranosyl-α-L-arabinopyranoside rich lentil extract 41 mg/kg BW
Delphinidin chloride 20 and 40 µM In Vitro
CD4+ T cells were purified from the spleen of C57BL/6 mice and were activated with 1 µg/mL of plate-bound anti-CD3 and plate-bound anti-CD28 antibodies in the presence samples for 3 days.		 Promoted the differentiation of Tregs and enhanced immune response control. [82]
1.5 and 3 mg/kg In Vivo allograft model
Five-week-old male C57BL/6 mice were subcutaneously injected with a fixed number of P815 cells		 Reduced activated T cells by promoting Treg differentiation.
Delphinidin 10−2 g/L In Vitro
T-lymphocytes from non-metabolic-syndrome and metabolic syndrome patients were stimulated for 24 h with the sample and 5 µg/mL of PHA.		 Inhibited Ca2+ signalling via reduced store-operated Ca2+ entry and release and the subsequent decrease of HDAC and NFAT activations. Also inhibited ERK1/2 activation and suppressed differentiation of T cells toward Th1, Th17, and Treg without affecting Th2 subsets.
Prevented the PHA-induced proliferation in cells isolated from WT.
Inhibited HDAC activity by a mechanism downstream of its effect on Ca2+ signaling.		 [83]
Peripheral blood mononuclear cells isolated either from 57BL/6 females ERα Wild-Type or Knock-Out mice stimulated for 48 h with 5 µg/mL of PHA.
T-lymphocytes stimulated with thapsigargin (1 µM).
Delphinidin 0–20 µM In Vitro
Normal Human epidermal keratinocytes treated with rhIL-22 and TPA.		 Suppressed key kinases involved in psoriasis pathogenesis and alleviated IMQ-induced murine psoriasis-like disease, suggesting a novel PI3K/AKT/mTOR pathway modulator for psoriasis. [84]
Delphinidin 0–50 µM In Vitro
Caspase activation in human prostate LNCaP and Du145 cells treated with sample for 12 h.		 Sensitized prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, causing caspase-mediated HDAC3 cleavage. [85]
Delphinidin 0–50 µM In Vitro
MH7A and Jurkat cells were treated with the sample and cultured for 2 h with TNFα or LPS.		 Inhibited NF-ĸB expression, thereby decreasing cytokine expression. [86]
Resveratrol and peonidin 3-O-glucoside rich red grape vine leaf extract 100 μg/mL In Vitro
THP-1 cells were stimulated with 2 μg/mL Cy3-labeled DNA for 4 h.		 Restricted the AIM2 inflammasome activation by preventing DNA entry. [87]
140 mg/kg In Vivo
Treated in IMQ-induced BALB/c mice (6–9 weeks old) model for 5 days.		 Inhibited proinflammatory caspase-1 activation, IL-1β maturation, and IL-17 production.
Malvidin-3-O-glucoside 10 µM In Vitro
Murine microglia primary cultures primed and activated with LPS.		 Targets NLRP3, NLRC4, and AIM2 inflammasomes, subsequently reducing caspase-1 and IL-1β protein levels.
Stopped the release of IL-1β in the hippocampus.		 [88]
12.5 mg/kg/d In Vivo
Chronic unpredictable stress was subjected to the mice for 28 days, consisting of different stressors. A 2-week pretreatment was followed.
Malvidin-3-O-glucoside 0.5 µg/kg/d In Vivo
C57BL/6 male mice were treated with the sample for 2 weeks before and throughout repeated social defeat stress and then performed social avoidance/interaction testing.		 Modulated synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. [89]

4. Gut Microbiota in the Immunity and Metabolism of Anthocyanins

Gut health has become a global concern due to its significant impact on human well-being; it is often called “the second brain” [90]. The human body houses a substantial number of bacteria, estimated to be 3.9 × 1013 in the entire body of a 70 kg “reference man” [91]. The gut microbiota includes Bacteroides, Clostridium, Prevotella, Eubacterium, Ruminococcus, Fusobacterium, Peptococcus, and Bifidobacterium, with a smaller presence of Escherichia and Lactobacillus [92][93]. This microbiota plays a vital role in the innate and adaptive immune system, which ensures a symbiotic relationship with the microbiota [94]. The gut microbiota plays a significant role in metabolizing ACNs into phenolic acids and aldehyde metabolites, primarily through specific bacteria in the large intestine. These metabolites can influence various physiological processes [95][96][97]. Conversely, ACNs contribute to the enhancement of gut health by modulating the function of the gut barrier and promoting the colonization of beneficial bacterial species. This dynamic interplay leads to heightened protection against pathogens, optimized nutrient metabolism, and an overall reinforcement of the immune response [54].
A significant portion of dietary ACNs remains unabsorbed, arriving at the colon without absorption during digestion, then, interacting with gut microbiota and undergoing degradation, potentially increasing their bioavailability through bacterial or chemical processes. Notably, certain bacteria in the colon, such as Bacteroides spp., Enterococcus casseliflavus, Eubacterium spp., and Clostridium spp., play a key role in this process by producing enzymes, such as β-glucosidase, α-galactosidase, and α-mannosidase, that break down ACNs [98][99]. In the colon, unabsorbed ACNs are hydrolyzed by microbial enzymes capable of cleaving sugar linkages and releasing ACN aglycones [100][101], which are then further metabolized into phloroglucinol aldehyde (e.g., 2,4,6-trohydroxybenzaldehyde, 3,4-dihydroxy benzaldehyde) and phenolic acids (PAs) derived from phloroglucinol (A ring) and benzoic acids (B ring) [100]. Research findings have identified distinct metabolic pathways associated with the fermentation of various anthocyanidins (aglycones), leading to diverse phenolic compounds. For example, the fermentation of cyanidin-3-O-rutinoside and C3G yields PCA, p-coumaric acid, and phloroglucinol aldehyde [102]. Similarly, delphinidin-3-O-rutinoside undergoes elaboration, resulting in gallic acid, syringic acid, and phloroglucinol aldehyde [102]. M3G is converted to syringic acid [103] while pelargonidin-3-O-glucoside (Pel3G) is metabolized into 4-hydroxybenzoic acid [104]. The initial conversion of petunidin yields 3-O-methyl gallic acid; subsequent O-demethylation leads to the production of gallic acid [104]. Furthermore, peonidin undergoes sequential transformations, first into vanillic acid (3-methoxy-4-hydroxybenzoic acid) and then into PCA [103]. In red radish, acylated ACNs, such as pelargonidin-3-sophorosid-5-glucoside acylated with ferulic acid and malonic acid, undergo degradation, resulting in the formation of 4-hydroxybenzoic acid, p-coumaric acid, ferulic acid, and caffeic acid [105].
A high-fat, high-sucrose diet induced metabolic and inflammatory changes in mice, resulting in decreased levels of beneficial gut bacteria (Bacteroidetes and Muribaculaceae) and propionate. However, supplementation with Saskatoon berry powder, C3G, or PCA mitigated these effects and increased fecal Muribaculaceae and propionate [106]. Another study using an ApcMin/+ mouse model compared the effectiveness of the dietary administration of PCA and black raspberries (BRB) in preventing colorectal cancer. Both 5% BRBs and 500 ppm PCA-supplemented diets significantly reduced the development of adenoma in the small intestine and colon. They promoted a shift to anti-inflammatory bacterial profiles, suggesting potential benefits for colorectal cancer patients. Interestingly, 500 ppm PCA increased IFN-γ and SMAD4 (mothers against decapentaplegic homolog 4) in primary cultured human natural killer cells. In comparison, 1000 ppm PCA did not show the same effects [107]. Furthermore, a study investigated the long-lasting cardioprotective effect of dietary ACNs by examining gene expression, histology, and resistance to ischemia/reperfusion in mice hearts after a month following the cessation of a C3G-enriched diet. The results indicate that the cardioprotective benefits persisted, independent of immune responses, and were attributed to changes in the gut microbiota induced by the C3G-enriched diet [66].
C3G also alleviated polystyrene (PS)-induced toxicities in Caco-2 cells and Caenorhabditis elegans by promoting autophagy and discharge. In C57BL/6 mice, C3G supplementation reduced tissue accumulation, promoted fecal PS discharge, alleviated oxidative stress and inflammation caused by PS, and modulated PS-associated gut microbiome perturbations, indicating its potential protective role against PS-induced toxicity and gut dysbiosis [108]. In a study investigating the potential of purple sweet potato ACN extract in modulating the gut microbiota in a dextran sulfate sodium (DSS)-induced chronic colitis mouse model, treatment with the extract prevented the loss of beneficial bacteria (Bifidobacterium and Lactobacillus), inhibited increases in harmful bacteria (Gammaproteobacteria and Helicobacter), and maintained colonic tight junction protein expression and architecture, resulting in attenuated intestinal inflammation. These findings suggest that the extract could be an effective and safe treatment for chronic colitis [109]. Combining bilberry ACN with chitosan and low molecular citrus pectin was proposed to enhance digestive stability and modulate the microbiome for programmed cell death-ligand 1 (PD-L1) blockade treatment. This combo enriches subdominant species, increases butyrate concentration, enhances intra-tumoral CD8+ T cell infiltration, and restores gut microbiome diversity, improving control over tumor growth. These findings indicate potential opportunities for probiotic combos to enhance the therapeutic efficiency of immune checkpoint inhibitors through gut microbiome manipulation [110].
Bilberry ACN supplementation attenuated western diet-induced serum aspartate aminotransferase, alanine transaminase, low-density lipoprotein cholesterol levels, liver fat content, thiobarbituric acid reactive substances, and alpha-smooth muscle actin. Additionally, it modified the gut microbiota by reducing the Firmicutes/Bacteroidetes ratio and increasing the relative abundance of Akkermansia spp. and Parabacteroides spp., which suggests it may have the potential to ameliorate nonalcoholic fatty liver disease by addressing dyslipidemia and gut microbiome dysbiosis [111]. M3G ingestion improved histopathological scores, enhanced IL-10 expression, promoted beneficial microbial interactions, and reduced the abundance of pathogenic bacteria and inflammatory mediators, demonstrating its unique mechanism of action on the gut microbiome compared to a whole blueberry in the DSS-induced colitis mouse model [112]. C3G has shown the potential to support gut integrity and overall health by producing phenolic compounds that combat gut inflammation and oxidative stress. These metabolites activate nuclear factor erythroid 2-related factor 2 (Nrf2) and influence TGFβ-activated kinase 1 (TAK1)-mediated mitogen-activated protein kinase (MAKP) and sphingosine kinase (SphK)/sphingosine-1-phosphate(S1P)-mediated NF-κB pathways, collectively reducing inflammation and creating an optimal environment for gut metabolism [113].

5. Nutraceutical Potential of Anthocyanins

ACNs have gained considerable attention in the nutraceutical industry, primarily for their role as natural colorants and antioxidants (Figure 3). ACN chalcones and quinoidal bases have been reported to be efficient antioxidants, with the glycosylated B-ring structure of ACNs enhancing their antioxidant activity, especially in terms of ortho-hydroxylation and methoxylation [30][45][114]. However, anthocyanidin, the aglycone form of ACNs, exhibits higher ORAC values due to its greater stability and reactivity [115]. The acylation of ACNs with phenolic acids significantly increases their antioxidant activity; diacylation enhances their activity further while 5-glycosylation reduces said activity [115][116]. Studies have shown that various ACNs extracted from plants possess antioxidative properties. C3G, D3G, and Peo3G from black bean seed coats exhibit strong antioxidative activity and reduce malondialdehyde formation by ultraviolet B (UV-B) irradiation [117]. Delphinidin and D3G show the highest inhibitory effect on lipid peroxidation and O2•− scavenging activity. On the other hand, cyanidin and C3G demonstrate the highest inhibitory effect on copper (II)-induced low-density lipoprotein (LDL) oxidation, while delphinidin has intermediate efficacy [118]. Moreover, ACNs activate Nrf2 and antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), enhancing their enzymatic activity [119][120]. In addition to their antioxidant effects, ACNs demonstrate potent activity against inflammation and associated disease conditions [47]. The imbalance between proinflammatory molecules and anti-inflammatory mediators leads to chronic inflammation, which is linked to various chronic diseases, such as neurodegenerative disease, arthritis, allergies, liver disease, diabetes, obesity, cardiovascular disease, and cancer [121]. Several studies showed that the ACNs suppress the activation of NF-κB [122] and MAPK signaling cascades [61], inhibiting the production of proinflammatory cytokines and enzymes, such as COX-2 [123]. ACNs directly inhibit COX-1 and COX-2 enzymes, thus reducing the production of prostaglandin E2 (PGE2) [123]. Moreover, ACNs also suppress NLRP3 inflammasomes, a complex involved in inflammatory responses [124][125].
Figure 3. Nutraceutical potential of anthocyanins based on reported studies.
Furthermore, ACNs exhibit promising potential as oral hepatoprotective agents against chemically-induced liver damage. They effectively combat liver lipid accumulation, inhibit lipogenesis, promote lipolysis, and counteract oxidative stress. They decrease liver enzyme levels, enhance antioxidant enzymes, and suppress the expression of COX-2 and iNOS, suggesting their potential therapeutic use in treating oxidative stress in the liver and its associated diseases [126]. C3G–lauric acid ester displayed enhanced antioxidant activity compared to its precursor C3G; safeguarding cells through the regulation of oxidative stress and PI3K/Akt-mediated Nrf2–heme oxygenase 1 (HO-1)/nicotinamide adenine dinucleotide (phosphate) reduced quinone oxidoreductase (NQO1) pathway activation, highlighting the potential of acylation for improved antioxidative effects and stability [127]. Myrciaria jaboticaba (Vell.) O.Berg and Syzygium cumini (L.) Skeels peel powders exhibited protective effects against liver fibrosis and hepatocarcinogenesis while Syzygium malaccense (L.) Merr. and L.M.Perry showed antioxidative benefits, emphasizing the anthocyanin profile effect [128]. Lonicera caerulea L. anthocyanin extract demonstrated hepatoprotective potential against alcoholic steatohepatitis through AMP-activated protein kinase (AMPK)-mediated anti-inflammatory and lipid-reducing pathways [129]. Bilberry fruit anthocyanin extract showed hepatoprotective effects against acute liver failure, reducing damage markers, oxidative stress, inflammation, and necrosis; these effects are attributed to antioxidative and anti-inflammatory properties [130].
Due to a high lipid content and energy demand, the central nervous system (CNS), particularly the brain, is highly vulnerable to excessive ROS [131]. ROS can be generated internally during cellular respiration and externally through environmental factors, such as pollution, smoking, UV-B radiation, and infections [132]. An excessive inflammatory response in the CNS can contribute to neuronal apoptosis and the progression of neurodegenerative diseases [133]. In this context, ACNs found in various fruits and vegetables have shown neuroprotective effects in preclinical models of neurodegenerative diseases and cerebral ischemia [134]. ACNs exert their neuroprotective effects through multiple mechanisms. They act as direct scavengers of ROS [135], enhance antioxidant response pathways [136], and inhibit neuroinflammation by modulating specific signaling pathways [137][138][139]. Studies in animal models have demonstrated that ACNs can prevent cognitive decline, delay the onset of neurodegenerative diseases, such as Alzheimer’s [140] and Parkinson’s [141], and reduce brain damage in cerebral ischemia. In a randomized controlled trial involving twelve participants with mild cognitive impairment, older adults demonstrated enhanced learning and memory capacity after 12 weeks of grape juice supplementation, compared to the placebo group [142]. Similarly, in another study, a 12-week supplementation of blueberry juice in the same group improved memory function [143][144]. These findings suggest that ACNs could be a potential co-adjuvant therapy to pharmacological treatments or a preventive strategy to reduce drug dosage and adverse effects in managing neurodegenerative diseases, cerebral ischemia, and cognition.
Dietary ACNs have demonstrated beneficial effects in protecting against cardiovascular diseases (CVDs) in animal and human studies [144]. Animal studies have shown that ACNs can prevent hypertriglyceridemia, hypercholesterolemia, and platelet hyperactivity induced by high-fat or high-fructose diets, while also protecting cardiac tissue against oxidative stress in ischemia/reperfusion conditions [145]. Human intervention studies have revealed that berry ACN intake can increase high-density lipoprotein (HDL)-cholesterol and reduce LDL-cholesterol, triglycerides, blood pressure, and inflammatory markers [146][147]. Furthermore, higher ACN intake has been associated with a reduced risk of myocardial infarction and decreased incidence of coronary heart disease and CVD-related mortality [148][149]. The cardioprotective mechanisms of ACNs include increasing plasma antioxidant capacity and nitric oxide levels, reducing LDL oxidation and platelet aggregation, and enhancing glutathione and omega-3 fatty acid synthesis. Cardiovascular diseases, including myocardial infarction, ischemic heart disease, and stroke, are major causes of mortality globally. Atherosclerosis, driven by oxidized low-density lipoproteins (ox-LDL), plays a key role in these diseases. ACNs have been found to protect against atherosclerosis in animal models by reducing the formation of atherosclerotic plaques and improving dyslipidemia. ACNs also prevent LDL-cholesterol oxidation [150], reduce inflammation [151], and decrease the expression of adhesion molecules in the aorta [151][152], leading to decreased leukocyte infiltration and proinflammatory cytokines. Additionally, ACNs have shown cardioprotective effects in animal models of myocardial infarction and chemotherapeutic drug-induced cardiotoxicity [153].
Obesity is a significant global health issue associated with numerous metabolic disorders. Studies have shown that dietary ACNs can have beneficial effects in combating obesity. One mechanism through which ACNs act as anti-obesity agents is by increasing energy expenditure [154]. Berries rich in ACNs, such as petunidin and malvidin, were found to effectively reduce the metabolic damage caused by a high-fat diet by boosting energy expenditure and reducing mitochondrial dysfunction in adipose tissue [155]. Moreover, ACNs have been found to modulate AMPK, a key regulator of energy balance [156][157]. By activating AMPK, ACNs can promote mitochondrial biogenesis, reduce lipid metabolism, increase fatty acid oxidation, and improve glucose metabolism. This activation of AMPK has been associated with improved glucose uptake in skeletal muscle, decreased glucose production in the liver, and decreased liver lipid content and serum lipoproteins. Furthermore, dietary ACNs have been shown to affect lipid metabolism by downregulating key molecules, such as fatty acid synthase and sterol-regulatory element-binding proteins. ACNs from different sources were found to reduce hyperglycemia and inhibit hepatic lipogenesis, potentially suppressing inflammation in obese individuals [158][159].
In addition to their effects on energy expenditure and lipid metabolism, ACNs have been linked to the modulation of the gut microbiota [160]. Changes in the gut microbiota in obese individuals can contribute to metabolic disorders and ACNs have been studied for their potential role in regulating the gut microbiota to combat obesity-related conditions. Moreover, ACNs have demonstrated promising results in protecting pancreatic β cells, improving insulin resistance, and reducing cholesterol levels in diabetic subjects [161]. ACN-rich beverages have also positively affected the postprandial glycemic response and insulin excretion [162]. Numerous in vitro and in vivo studies have consistently supported the potential anti-obesity effects of ACNs, demonstrating their ability to inhibit fat accumulation [163], improve lipid profiles [159], and reduce adipocyte hypertrophy [164]. Furthermore, ACNs have shown anti-inflammatory properties by suppressing NF-κB signaling and promoting an anti-inflammatory phenotype in adipose tissue macrophages [165]. Thus, ACNs present a promising natural approach to combat obesity and related metabolic disorders. The mechanisms through which ACNs exert their anti-obesity effects involve increased energy expenditure, modulation of AMPK, lipid metabolism, gut microbiota, and anti-inflammatory properties.
ACNs have emerged as potential antitumoral agents, attracting significant interest in recent decades [166][167]. Cancer is characterized by the uncontrolled cell proliferation, resistance to apoptosis and cell migration, often involving the dysregulation of pathways, such as Notch, Wnt/β-catenin, NF-κB, and MAPK [168]. Dietary ACNs extracted from berries have been found to modulate the levels of proteins involved in these pathways, leading to cell growth inhibition. Notably, ACN mixtures have shown enhanced effects compared to single purified ACNs, indicating overlapping pathways in cell growth inhibition [169]. ACNs exhibit diverse mechanisms for the prevention and inhibition of cancer, targeting pathways related to cell survival, proliferation, apoptosis, inflammation, and angiogenesis. They have been shown to suppress NF-κB [170], PI3K/Akt [171][172], and Akt/mTOR [173] signaling pathways. ACNs can also inhibit tumor growth, promote apoptosis and autophagy in cancer cells, and inhibit angiogenesis and metastatic migration [174]. In vitro and in vivo studies have demonstrated the anticancer potential of ACNs from various sources, including berry extracts [72][175] and pure ACNs, such as delphinidin [176] and cyanidin 3-rutinoside [172]. These findings suggest that ACNs hold promise regarding potential anticancer properties, making them a subject of considerable research and exploration in cancer therapy and prevention.
ACN pigments found in various berries are beneficial for maintaining good vision and have been associated with improved night vision [45][177]. Berries rich in ACNs have long been known for their positive effects on eye health. For instance, administering bilberry extract, containing about 39% ACNs, to mice has been shown to protect photoreceptor cell function during retinal inflammation [178]. In a study with 132 patients suffering from normal-tension glaucoma, daily supplementation with two capsules containing 60.0 mg ACNs from bilberry resulted in improved visual function [179]. Additionally, other berries, like blackcurrant [180] and purple corn seed [181], have shown a protective effect on eyesight, with blackcurrant ACN supplementation increasing ocular blood flow in patients with open-angle glaucoma and purple corn seed extract reducing lens opacity and malonaldehyde levels. Furthermore, ACNs from black soybean seed coats have effectively prevented retinal degeneration and suppressed human lens epithelial cell death under oxidative stress [182].
ACNs exhibit potent antimicrobial properties against a wide range of microorganisms, particularly in inhibiting the growth of food-borne pathogens. Their antimicrobial effects are attributed to various mechanisms, including cell wall, membrane, and intercellular matrix damage [166]. For instance, maqui berry extracts have shown antibacterial activity, being highly effective in working against Aeromonas hydrophilia and Listeria innocua [183], commonly associated with refrigerated foods and used as indicators of pathogenic or spoilage microorganisms [184]. Cranberry extract also demonstrates antibacterial activity against certain resistant strains of Enterococcus faecium, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli, with its effect not solely due to low pH but rather to specific bioactive components, such as ACNs and flavonols [185]. ACN-rich extracts from various fruits, like blueberry, raspberry, blackcurrant, and strawberry, display inhibitory effects on gram-negative bacteria but not on gram-positive bacteria [186], likely due to differences in cell wall structures. These antimicrobial actions are likely a result of synergistic effects from various phytochemicals in the extracts, including ACNs, weak organic acids, phenolic acids, and other chemical forms [187]. Hence, the complex nature of these compounds necessitates further comprehensive analysis of their antimicrobial potential.

This entry is adapted from the peer-reviewed paper 10.3390/nu15194152

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