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Subjects:
Immunology
The intestine is critically crucial for nutrient absorption and host defense against exogenous stimuli. Inflammation-related intestinal diseases, including enteritis, inflammatory bowel disease (IBD), and colorectal cancer (CRC), are heavy burdens for human beings due to their high incidence and devastating clinical symptoms. Studies have confirmed that inflammatory responses, along with oxidative stress and dysbiosis as critical pathogenesis, are involved in most intestinal diseases. Polyphenols are secondary metabolites derived from plants, which possess convincible anti-oxidative and anti-inflammatory properties, as well as regulation of intestinal microbiome, indicating the potential applications in enterocolitis and CRC.
- polyphenols
- biological functions
- colorectal cancer
- enteritis
- inflammatory bowel disease
1. Introduction
The intestine is the main site for digestion and absorption of dietary nutrients and reabsorption of water and ions, whose homeostasis is extremely crucial for maintaining the health of the host [1]. Meanwhile, the intestine is also the largest immune organ within the human body, composed of multiple immune cells resident in the lamina propria and the gut-associated lymphoid tissue [2,3]. The complicated milieu in the intestinal tract is kept in a subtle balance between pro-inflammation and anti-inflammation to guarantee intestinal homeostasis [4]. Nevertheless, dysfunction of the intestinal mucosal immunity characterized by uncontrolled pro-inflammatory responses and oxidative challenges generally leads to inflammatory intestinal diseases, such as enteritis, inflammatory bowel disease (IBD), and colorectal cancer (CRC) [5,6,7].
A series of natural dietary phytochemicals have been found in natural plants, including polyphenols, terpenoids, organo-sulfurs, and phytosterols [8]. Among all these plant-derived biological compounds, polyphenols have been reported to exhibit substantial health-promoting benefits; thus, foods rich in polyphenols are used as functional foods to address cardiovascular and neurodegenerative disease, diabetes mellitus and obesity, as well as osteoporosis through signal cascade regulation properties [9,10]. Likewise, most of the current studies have revealed that the benefits of polyphenols are linked with intestinal health, including anti-oxidative stress, anti-inflammation, and regulation of the intestinal microbiome [11,12]. Thus, functional foods rich in polyphenols are also widely used for the management of inflammation-related intestinal diseases [13,14,15]. There has also been an increasing research interest in the extraction, identification, and purification of natural polyphenols with high bio-efficacy and low side effects for the prevention or treatment of intestinal diseases. Recently, numerous studies focused on the regulation of intestinal health by natural polyphenols have revealed the beneficial effects and relevant mechanisms [11,16,17].
2. Categories and Metabolism of Plant-Derived Polyphenols
2.1. Categories of Polyphenols
According to the different chemical structures characterized by the presence of different numbers of phenolic rings, along with two or more hydroxyl substitutions, these polyphenols customarily can be classified into two major groups, namely flavonoids and non-flavonoids [20]. At least 9000 varieties of flavonoids have been identified [23], all of which share a basic oxygenated heterocycle structure consisting of two aromatic rings bounded by three carbon atoms [9]. In general, flavonoids naturally occur as glycosides, aglycones, or as modified forms, including acetylated, methylated, prenylated, and sulphated derivatives [24,25]. Flavonoids include six subcategories, including anthocyanidin, flavanol, flavanone, flavone, flavanol, and isoflavone [26,27], with cyanidin, epigallocatechin, hesperidin, apigenin, quercetin, and genistein being the most studied represented species, respectively.
Meanwhile, the non-flavonoids are also a large group of polyphenols, which are composed of phenolic acids, stilbenes, tannins, and lignans [26]. Phenolic acids are the main polyphenolic category consisting of benzoic acid, cinnamic acid, and their derivatives [9]. Another important non-flavonoid polyphenol is resveratrol, which belongs to stilbenes and is the research interest due to its novel biological functions [28]. The most common polyphenols with novel biological functions belong to the flavonoids group, such as catechin, epicatechin and derivatives, procyanidins quercetin, kaempferol, as well as genistein. Nevertheless, non-flavonoids polyphenols, such as resveratrol and cinnamic acid, were also reported with functional roles in human health [28,29].
2.2. Bioavailability, Metabolism, and Metabolites of Common Polyphenols
Bioavailability represents the proportion of polyphenols that can be digested, hydrolyzed, and availably absorbed in the gastrointestinal tract [30]. The bioavailability of each polyphenol is different, which is associated with its native chemical structure, extensive modifications, and site of absorption. [31]. Studies carried out in rats and mice showed that anthocyanins and quercetin can be absorbed in the stomach [31,32,33]. Even though the fate of glycosides in the acid milieu is not fully understood yet, one thing that is certain is that most glycosides are probably resistant to acid hydrolysis in the stomach and usually arrive in the intestine [9,34]. In general, aglycones can be absorbed in the small intestine, while most polyphenols exist in the forms of esters, glycosides, or polymers, which cannot be absorbed [31]. Prior to absorption, these polyphenols must undergo transportation by sodium-dependent glucose transporter 1 and hydrolysis by host enzymes in the small intestines [35]. Two host enzymes are required for the hydrolysis of glycosides and release of aglycone, namely the lactase phloridzin hydrolase and cytosolic β-glucosidase, which locates in the brush border of and within the small intestinal epithelial cell, respectively [36].
Even though some polyphenols can be hydrolyzed and absorbed, the bioavailability of polyphenols is quite low in the stomach and small intestines [13,40]. Most of the polyphenols show resistance to acid in the gastrointestinal tract, and very few of them can be hydrolyzed and absorbed in the small intestines [23]. The literature has reported that about 5–10% of polyphenols are absorbed in the small intestine [41], and the remaining polyphenols enter into the colonic lumen and undergo biotransformation by colonic microbiota [42,43]. The intestinal microbiota, equipped with a series of enzymes, can utilize dietary polyphenols in the colon by catalyzing hydrolysis, cleavage, reduction, decarboxylation, demethylation, isomerization, and dihydroxylation reactions [44,45,46]. A fraction of the polyphenols can be degraded into aglycones by the colonic microbiota and is further metabolized into simple aromatic acids, which can be utilized by the host [47,48]. Flavones and flavanones are mainly metabolized into hydroxyphenylpropionic acids, whereas metabolites of flavanols are phenylvalerolactones and hydroxyphenylpropionic acids [48]. Phenylpropionic acids undergo further metabolism to benzoic acids [49].
3. Inflammation-Related Intestinal Diseases and Corresponding Experimental Models
3.1. Clinical Classification of Inflammation-Related Intestinal Diseases
Generally, the most common intestinal disease is IBD, a non-infectious, chronic, and relapsing inflammatory disorder of the gastrointestinal tract with a multifactorial pathophysiology [57]. Two typical phenotypes have been classified regarding the pathogenic sites, namely ulcerative colitis (UC) and Crohn’s disease (CD). Inflammatory responses happen at any segment of the gastrointestinal tract, especially in the terminal ileum and perianal regions of CD patients, while the pathogenic site of UC patients is usually limited in the colon and rectum, with the distal colon and rectum being the most severely affected [58]. Although both innate and adaptive immune systems are involved in CD and UC, the two types of IBD differ in T cell-mediated adaptive immune responses, where T helper 1 (Th1) and Th17 cell responses are active in CD instead of Th1 and Th2 in UC [59]. Nevertheless, CD and UC also share overlapping pathological and clinical symptoms, such as diarrhea, abdominal pain, cramping, rectal bleeding, bloody stool, weight loss, spontaneous remission, and relapsing inflammation [60,61].
Another type of inflammation-related intestinal disease is enteritis, wherein inflammatory responses happen in the small intestines as compared with UC and CRC. Typical symptoms of enteritis include abdominal pain, cramping, fever, and diarrhea. Of note, Clostridium difficile (C. difficile)-induced enteritis is the most commonly observed enteritis with dramatically increasing incidence [63]. Hemorrhagic enterocolitis induced by Escherichia coli (E. coli) can also be considered enteritis, which causes inflammation and bleeding in the small intestine. This kind of inflammatory intestinal disease is less observed and with low preference to develop into cancer.
3.2. Animal Models of Inflammatory Intestinal Diseases
Dextran sodium sulfate (DSS) is a synthetic sulfated polysaccharide with a ranging molecular weight between 5–1400 kDa, which showed high relevance with the severity of colitis along with its duration and dosage [64,65]. DSS-induced colitis is an animal model for human UC, as continuous administration in drinking water induces similar symptoms and Th cell responses [55]. DSS acts as a direct chemical toxin to the colonic epithelial cells, which leads to the breakdown of mucosal integrity, resulting in the exposure of mucosal and submucosal immune cells to luminal antigens and inflammatory responses [66]. Acute, chronic, and relapsing models of UC can be achieved by modifying the concentration and frequency of DSS administration [67]. In addition, DSS-induced colitis spontaneously recovers once termination of administration, which allows for another mouse model for the mechanisms in the recovery phase [58].
Histopathological changes in acetic acid-induced colitis include transmural necrosis, edema, and goblet cell depletion, similar to UC patients [70]. Thus, rectal administration of acetic acid is a well-established animal model as DSS. Physical destruction of colonic mucosal integrity starts within 4 h post acetic acid challenge, and inflammatory responses follow to accelerate mucosal damage via the release of pro-inflammatory cytokines and reactive oxygen species (ROS) [71]. Furthermore, 2,4,6-trinitrobenzenesulfonic acid (TNBS) is a tissue protein-binding hapten in the intestine and can elicit a number of inflammatory responses [55]. Studies have identified that TNBS-type colitis comprises two forms of IBD, as activation of Th1, Th2, and Th17 cell responses were all observed [66]. Even though increased mucosal thickness instead of mucosal damage was observed, which indicated CD-type clinical features of TNBS-induced colitis [66]. Lipopolysaccharide (LPS) is a structural component of the outer membrane of most Gram-negative bacteria.
Lines of evidence indicate that intestinal bacteria, especially pathogens, play crucial roles in the onset and development of IBD. Epidemiological and clinical studies have observed an elevated abundance of E. coli in the intestines of IBD patients and identified enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) as the main inducers of CD [75,76].
4. Therapeutic Applications of Polyphenols in Inflammatory Intestinal Diseases
4.1. Potential of Polyphenols in Intervention of Inflammation-Related Intestinal Diseases
Generally, the widely accepted theory is that genetic factors, intestinal dysbiosis, environmental factors, and aberrant inflammatory responses are the main inducible factors in the initiation and/or progression of inflammation-related intestinal diseases [58]. In consideration that environmental factors interact with the intestinal microbiota whose dysbiosis results in the over-activation of inflammatory responses where almost genetic factors are involved [94,95,96], thus dysfunction of intestinal mucosal immunity represented by uncontrolled inflammatory responses contributes mostly to the onset and development of inflammation-related intestinal diseases. Actually, aberrant innate and adaptive inflammatory responses are common consequences in intestinal diseases, mostly represented by the activation of NF-κB and up-regulated levels of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and interleukins [97].
The conclusive signature of biological functions of polyphenols is anti-oxidative stress, achieved through neutralizing free radicals by donating an electron or hydrogen atom from hydroxyl groups [101], reducing highly reactive hydroxyl radicals-induced oxidation by chelating with Fe2+ [102], regeneration of essential vitamins [103], and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) related antioxidant system [104]. In addition, numerous sources also reported the anti-inflammatory roles of polyphenols. Mechanically, these polyphenols regulate intestinal inflammatory responses by inactivating NF-κB, modulating mitogen-activated protein Kinase (MAPK), and phosphatidylinositide3-kinases/protein kinase B (PI3K/AkT) signaling cascades, thus reducing synthesis and release of pro-inflammatory cytokines [105].
4.2. Interventional Options of Polyphenols in Inflammation-Related Intestinal Diseases
Functional foods and their extracts rich in natural polyphenols, such as fruits, coffee, vegetables, and whole grains, have been wildly applied in clinical trials. Anthocyanidins are a group of flavonoids that exist in berries. Anthocyanin-rich bilberry extract was demonstrated to ameliorate disease activity in UC patients [110]. Further study showed anthocyanin-rich bilberry extracts reduced TNF-α and IFN-γ, as well as phosphorylated NF-κB levels, while enhanced levels of IL-22 and IL-10 in colonic biopsies of UC patients [111]. Another clinical study showed that supplementation with anthocyanin-rich purple corn could improve infliximab-mediated disease remission in IBD [112]. One study confirmed that green tea extract enriched in EGCG was an effective supplement for the chemoprevention of relapse of metachronous colorectal adenomas [113]. Resveratrol is a natural polyphone found in grapes, red wine, and berries. A randomized, double-blind, and placebo-controlled pilot study has confirmed that resveratrol capsules treatment increased anti-oxidative capacity, decreased serum malondialdehyde (MDA) level and disease activity, and increased quality of life in patients with UC [114]. Resveratrol was also reported to potentially improve the therapeutic outcomes in patients suffering from CRC when used either alone or as a combination therapy [115].
More recently, robust experimental studies have been performed to investigate the protective or preventive effects of polyphenols in inflammation-related intestinal diseases based on the persuasive regulatory roles in oxidative stress, inflammation, and dysbiosis.
Cyanidin-3-Glucoside (C3G) is one of the anthocyanins which can be hydrolyzed into cyanidin (Cy), both of which were reported to improve clinical symptoms and reverse the colonic histological changes in TNBS-challenged mice [119]. In addition, C3G improved DSS-induced body weight loss, colon length shortening, and morphology of colonic mucosa [120]. However, intraperitoneal injection with C3G showed no effects against DSS-induced symptoms except for decreases in pro-inflammatory cytokines and an increase in the regulatory T cell (Treg) population in the colon [121]. In vitro analysis revealed that C3G significantly decreased TNF-α and IL-6 mRNA levels by inactivation of NF-κB in THP-1 [122]. Except for C3G, pelargonidin 3-Glucoside (P3G) also showed beneficial roles in inflammatory intestinal diseases. Oral therapy with P3G reversed DSS-induced diarrhea, bloody stools, erosion of mucosal epithelium, crypt atrophy, loss of villi and goblet cells, as well as inflammatory cell infiltration in the colon of rats [123].
Procyanidin, which is formed from catechin and epicatechin, belongs to proanthocyanin. Several studies have shown the protective effects of procyanidins against DSS-induced murine colitis, which were associated with increased goblet cells, enhanced claudin 1, anti-oxidative enzymes, and short chain fatty acid (SCFA) levels, as well as decreased mRNA levels of pro-inflammatory cytokines [127,128]. Meanwhile, procyanidin treatment activated the AMPK/mTOR/p70S6K signal pathway, thus alleviating DSS-induced colitis by promoting cell proliferation [129]. EGCG is a major bioactive polyphenol in green tea. Several studies revealed the critical roles of EGCG in alleviating DSS-induced clinical manifestations, including intestinal permeability, histopathological changes, and inflammatory cells infiltration in the colon [130], decreasing pro-inflammatory cytokine levels, maintaining Th1/Th2 balance, and inactivating TLR4-NF-κB signaling pathway [131]. Another study indicated that increased abundance of SCFAs-producing microbiota, such as Akkermansia, may also be responsible for the beneficial roles [132]. In addition, two studies revealed the therapeutic effects of EGCG in TNBS-induced murine colitis via inhibiting the activation of NF-κB, mast cells and macrophage activation [133,134]. Dietary supplementation with EGCG improved acetic acid-induced colitis, as indicated by colon mucosal damage index and histological scores, and decreased levels of NO, MDA, TNF-α, IFN-γ, p65, as well as increased superoxide dismutase (SOD) activity [135]. EGCG treatment significantly decreased the mean number of aberrant crypt foci and tumor load, as well as increased the abundance of Bifidobacterium and Lactobacillus in AOM/DSS-induced CRC [136].
Oral administration with apigenin alleviated colon length shortening, decreased levels of colonic myeloperoxidase (MPO), alkaline phosphatase (AKP), TNF-α, IL-6, and restored intestinal microbiome in TNBS and DSS colitis models [141,142].
Hesperidin and naringin are natural flavonoid compounds that occur in citrus fruits. Several studies suggested that both hesperidin and naringin could alleviate DSS-induced colitis in mice by improving the integrity of the colon, decreasing the expression of pro-inflammatory cytokines, and elevating the expression of colonic tight junction (TJ) proteins [147,148]. Meanwhile, oral administration of hesperidin and naringin reversed the DSS-disturbed microbial community in the colon and increased the ratio of Firmicutes/Bacteroides [149,150,151,152].
Kaempferol was widely used in DSS-induced colitis due to its anti-inflammatory property. Treatment with kaempferol alleviated DSS-induced body weight loss, bloody stool, shortened colon, colonic morphological damage, and up-regulated pro-inflammatory cytokines. Mechanically, kaempferol decreased serum LPS concentration, inactivated the downstream TLR4-NF-κB signal pathway, and restored microbial community [154]. The same positive outcomes were also observed in the fecal microbiota from kaempferol-treated mice [154]. Compared to the LPS group, kaempferol dramatically restored transepithelial resistance (TEER), evaluated the expression of TJ proteins, and inactivated of NF-κB signal pathway in Caco2 cells [155].
Quercetin is another member of flavanol that exists in vegetables and fruits. Supplementation with dihydroquercetin significantly reversed DSS-induced colitis in mice via down-regulating levels of IL-1β, IL-6, TNF-α, and up-regulating serum IL-10, colonic ZO-1, occludin, and Lactobacillus levels [157]. The literature also reported that quercetin alleviated DSS-induced murine colitis by increasing the expression of the glutamate-cysteine ligase catalytic subunit (GCLC) and serum glutathione level [158]. Supplementation with quercetin attenuated LPS-induced intestinal injury and decreased pro-inflammatory cytokines and oxidative stress indices. Further analysis revealed that quercetin evaluated the expression of intestinal TJ proteins, inhibited apoptosis of intestinal epithelial cells, and increased the abundance of SCFAs-producing bacteria [159,160]. Quercetin dramatically decreased the number and size of colon tumors in AOM/DSS-induced murine CRC [161]. The AOM rat model revealed that quercetin inactivated the PI3K-Akt signal pathway to reduce proliferation, increase cell apoptosis, and suppress the formation of early preneoplastic lesions in colon carcinogenesis [162].
Supplementation with genistein alleviated body weight loss, shortened colon, and inflammation, which skewed M1 macrophages towards M2, and decreased the mRNA levels of pro-inflammatory cytokines, thus attenuating DSS-induced colitis in mice [166]. Another study reported the beneficial effects against DSS-induced colitis were achieved via ubiquitination of NLRP3 inflammasome [167].
Oral administration of resveratrol significantly alleviated DSS-induced laboratory symptoms in mice and reduced mRNA levels of pro-inflammatory cytokines, as well as diminished p38 MAPK activation [171]. Another study showed that resveratrol alleviated DSS-induced colitis by down-regulating protein abundance involved in autophagy and up-regulating levels of phosphorylated mTOR and SIRT1 [172]. Intraperitoneal administration of resveratrol to rats also significantly improved TNBS-induced colon injury, decreased MDA level, and increased glutathione peroxidase (GSH-Px) and catalase (CAT) activity [173]. Resveratrol was also reported to alleviate LPS-induced enteritis in broilers and ducks via regulation of Nrf2 and NF-κB signaling pathways [174,175]. An AOM/DSS-induced CRC model indicated the positive outcomes, which were associated with modulating the balance of the colonic microbial community, inhibiting histone deacetylases, and decreasing the populations of Th1 and Th17 cells [176].
This entry is adapted from the peer-reviewed paper 10.3390/ijms24119581
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