Cross Talk Between Polyphenols and Gut Microbiota

After oral assumption, dietary polyphenols are recognized by the human body as xenobiotics and only a small amount is hydrolyzed in active compounds and absorbed in the small intestine (48). The remaining polyphenols accumulate in the large intestinal lumen where they might be hydrolyzed by the enzymatic activities of the gut microbial community into various metabolites before absorption. It is becoming clear that the GM, after degradation of food macromolecules (49), plays a crucial role in the maturation, development, and function of the host immune system (18, 50–52). Nevertheless, a continuous dialogue between microbiota and innate and adaptive immunity (53) regulates intestinal tissue homeostasis. When this functional control is lost, dysbiosis occurs leading to inflammatory disorders that might promote tumorigenesis (54–58).

Recently, advances in defining the effects of the microbiota on polyphenol bioavailability and function have been made. Moreover, it has been recognized that polyphenol-rich foods can affect the composition and activity of the microbiota (59, 60). Dietary polyphenols exert a prebiotic-like effect, contribute to maintain the gut health and to reduce levels of inflammation through the stimulation of beneficial bacteria growth and inhibition of pathogenic microbe development (61, 62). The large inter-individual variation of metabolites (30) can be related, at least partly, to differences in the GM composition and therefore in the way the polyphenols are catabolized.

Epidemiological data (33, 63) are concordant in suggesting that the adherence to MD decreases the risk of a variety of cancers. The polyphenol-rich MD modulates multiple processes involved in inflammatory response and carcinogenesis, such as free radical production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and the eicosanoid-derived pathways. Thus, an appropriate diet can maintain the equilibrium between the inflammatory pathway and the anti-inflammatory process induced by many dietary compounds including polyphenols (64). Furthermore, great attention has been addressed to the effect that MD has on maintenance of “good” GM (65) and on control of carcinogenesis through specific epigenetic alterations (66).

Recently, the association between microbiota and different stages of CRC and the role of microbiota in the therapeutic response including that of the immune checkpoint-blocking therapy has shown to be highly relevant (67).

Polyphenols as Immunomodulatory Agents

Growing evidence clearly indicates that diet influences the innate and adaptive arms of the immune system (Figure 1) (68). Innate immune cells, such as macrophages, myeloid-derived suppressor, dendritic and natural killer cells and adaptive immune cells (T and B lymphocytes) may infiltrate the tumor tissues impacting the immune microenvironment and the clinical outcome (49). Several investigations have reported the antitumor effect of polyphenols through the modulation of T lymphocyte functionality to recognize and lyse tumor cells enhancing the immune response and counteracting the immune escape, a cancer progression hallmark (69, 70).

Among polyphenol studies, the dose dependent therapeutic efficacy of resveratrol has been demonstrated in an animal model of ulcerative colitis. Resveratrol, a flavonoid stilbene compound, treatment is associated with the regulation of T regulatory (Treg)/T helper 17 (Th17) balance and the level of plasma and intestinal mucosal cytokines including interleukin 10 (IL-10), transforming growth factor-beta1 (TGF-β1), interleukin 6 (IL-6), and interleukin 17 (IL-17) (71).

Curcumin, a no-flavonoid compound, suppressed the development of Dextran Sulfate Sodium (DSS)-induced colitis in a mouse model through the inhibition of NF-κB activation and the induction of mucosal Treg cells. Treatment with nanoparticles of curcumin induced an alteration of the gut microbial structure and a change in the level of fecal short chain fatty acids, indicating nanoparticles curcumin as a therapeutic option for the treatment of IBD diseases (72).

Trans-Scirpusin A (TSA), a resveratrol oligomer, has been reported to inhibit the growth of colorectal cancer in in vivo model. Among different mechanisms involved in its antitumor efficacy, TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25-FoxP3 regulatory T cells and myeloid-derived suppressor cells (73).

Dietary anti-inflammatory polyphenols, such as chlorogenic acid and resveratrol, significantly suppressed the secretion of several cytokines (interferon gamma IFN-γ, tumor necrosis factor alfa TNF-α), reduced the colonic infiltration of CD3⁺T cells producing these cytokines and neutrophils in colitis and in colitis-associated to CRC experimental model (74, 75). In mouse C57BL/6J-Min/⁺, bearing a germline Apc mutation, a classical model of familial adenomatous polyposis (FAP) and sporadic colorectal cancer, administration of curcumin increases mucosal CD4⁺ T and B cells and contributes to prevent adenoma formation (76). Apple polyphenolic extracts (77), soy and sulforaphane flavonoid compounds (78, 79) reduce pro-inflammatory cytokine expression (IL-1β, TNF-α, IL-6, IL-17, and IFN-γ) in the context of a chemically induced colitis. The immunomodulatory activity of cocoa, a flavonoid compound, has been demonstrated to affect the gut immune responses in young rats by increasing the percentage of γδ T cells and lowering the effect of IgA (80).

It has been demonstrated an important role of chemokine receptor 3 (CXCR3) and its ligands in both inflammation and colorectal cancer (81). Recently it has been shown that resveratrol trihydroxy trans stilbene (TS) is able to hamper the suppressive ability of Treg by increasing CXCR3 in CD8+ Tregs facilitating Teff recruitment with a reduction of number and size of tumors (82). Dendritic cells (DCs) play a relevant role in cancer by exerting both pro-tumorigenic and anti-tumorigenic functions depending on the local environment (83) having an impact upon clinical outcome in CRC patients (84). Furthermore, Kajihara et al. analyzed the potential role of a dendritic-based cancer immunotherapy treatment in patients with recurrent or metastatic CRC (85). The potential effects of polyphenols on the function of DCs, the most effective antigen-presenting cells, with the capacity to shift immune response toward tolerance or immune activation (86, 87) has been highlighted in different studies. In particular protocatechuic acid, an anthocyanin flavonoid metabolite, has been demonstrated to have a main regulatory effect on the functional activation of DCs, suggesting the potential therapeutic application of this dietary compound against inflammatory conditions (88).

Quercetin and piperine, a flavonoid and no-flavonoid compound, when combined represent an effective and potent anti-inflammatory strategy to treat acute colitis in mice. This anti-inflammatory effect was mediated by impaired DC immune responses (89). Moreover, quercetin has been shown to suppress the secretion of TNF-α and interfere with the onset of IBD (90).

Polyphenols and Inflammation

Chronic inflammation characterized by the continuous presence of inflammatory cells and inflammatory mediators is known to play a key role in the development of various cancers. A long-standing chronic inflammation is a key predisposing factor of CRC in IBD since an excessive ROS production present in the inflamed mucosa alters important cellular functions and damages intestinal mucosa (91–93).

For several years, polyphenols have been extensively studied for their ability to scavenge free-radicals endogenously generated (94) or formed by radiation and xenobiotics (95).

Polyphenols have anti-inflammatory effect and their antioxidant properties are mainly mediated by ability to down-regulate the nuclear factor NF-kB, modulating crucial cell signaling pathways involved in inflammation and cancer (96–100).

Evaluating the polyphenolic fraction of olive oil, a principal component of MD, Serra et al. reported the inhibition of some crucial colonic inflammatory processes mediated by NF-kB, inducible nitric oxide synthases (iNOS), IL-8 and IL-6, thus proposing olive oil as a major dietary compound able to prevent and counteract the progression of IBD (101).

Green tea polyphenols ameliorate antioxidant response, decrease inflammatory markers (TNF-α, IL-6, and serum amyloid A), attenuate the pathological lesions and preserve colonic microstructure in a similar manner of sulfasalazine, the standard-of-care agent in IBD as shown in DSS mice (102). Several studies have demonstrated that cocoa exhibits a potential anti-inflammatory effects in in vitro and in vivo CRC models and might be a promising dietary preventive compound. Experiments performed in TNF-α stimulated colon cancer Caco-2 cells demonstrated that cocoa polyphenols down-regulate inflammatory marker expression by suppressing NF-kB nuclear translocation and c-Jun N-terminal kinase (JNK) phosphorylation. A cocoa-rich diet decreased the nuclear level of NF-kB and the expression of cyclooxigenase-2 (COX-2) and nitric oxide (NO) synthase pro-inflammatory enzymes, in a colon carcinogenic rat model (98, 99). Moreover, recent findings demonstrated that cocoa suppresses the development of colitis-associated tumorigenesis by modulating NF-kB/IL-6/Signal transducer and activator of transcription 3 (STAT3) signaling pathways and also induces apoptosis by activating caspase-3 in a mouse model (103).

Evidence has been provided that pomegranate phenolic extract (PE) and/or its microbiota derived metabolite-urolithin-A (UROA), have antioxidant, anti-inflammatory, and anticancer properties as showed by Larrosa et al. (104). They demonstrated that pomegranate could prevent colon inflammation before and during colitis disease in rats. PE and UROA decreased inflammation markers (iNOS, COX-2, prostaglandin E synthase, and prostaglandin E2) in colonic mucosa and could have a beneficial effect on the gut microbiota.

Flavanol extract from Chaenomeles japonica, a Japanese fruit, inhibited COX-2, matrix metalloproteinase-9 (MMP-9), and NF-kB expression indicating a cytotoxic anti-inflammatory and anti-metastatic activities toward the colon cancer SW-480 cells (105).

A recent study has shown that sugarcane extracts, containing a potent reservoir of polyphenols, provide anti-inflammatory activity by decreasing NF-kB phosphorylation and subsequently reduced expression of IL-8 signaling in lipopolysaccharide-stimulated colon cancer cells (106).

Edible mushroom (Pleurotus eryngii), rich in polyphenols, has been shown to inhibit the production of pro-inflammatory molecules, such as ROS and NO in RAW264.7 macrophage cell line and to induce an anti-proliferative effect on HCT116 colon cancer cells (107). All these results indicate the relevance of dietary polyphenol intake derived from food throughout the world.

The consumption of many varieties of plant derivatives is very ancient remedy against all kinds of ailments. Since ancient times folk medicine has made use of plants like Opuntia ficus indica and Ceratonia Siliqua and recently their polyphenolic extracts have received much attention for their antioxidant, anti-inflammatory, immunomodulatory and anticancer properties. Aboura et al. demonstrated the protective effects of polyphenol-rich infusions from C. Siliqua leaves on inflammation either in in vitro and in vivo experimental models, reducing pro-inflammatory cytokine expression (such as TNF-α, IL-1β, and IL-6), and NO production (108). The anti-inflammatory activity of Garcinia Kola (109) and Ocimum Gratissimum (110) polyphenolic extracts is exerted by reducing TNF-α and pro-inflammatory cytokine production in a rat colitis experimental model.

We apologize to those authors whose work could not be cited due to a space limitation.