Table 1.
Summary of polyphenols’ effects on intestinal inflammatory diseases along the TLR4/NF-κB-mediated signaling pathway in vitro and in vivo.
| Polyphenol | Cell Type or Animal Model | Induction of Intestinal Inflammation | Anti-Inflammatory Mechanism | References |
|---|---|---|---|---|
| Apigenin | Swiss albino mice | Radiation-induced gastrointestinal damages | It inhibited NF-κB expression | Begum et al. [40] |
| HCT-116 human colonic epithelial cancer cells | 5 μg/mL LPS | It downregulated NF-κB and STAT3 expression, as well as IL-6 and IL-10 secretion in a dose dependent manner | Ai et al. [41] | |
| C57BL/6J mice | Oral administration of 1% DSS for 21 d | It reduced the severity of colitis by decreasing TNF-α, IL-1β, IL-6, and COX-2 levels | Ai et al. [41] | |
| Luteolin | Human Caco-2 cells | 5 μmol/L decabromodiphenyl ether (BDE-209) for 12 h | It inhibited ERK and NF-κB p50 expression and IκBα phosphorylation, as well as secretion of TNF-α, IL-6, IL-1β | Yuan et al. [42] |
| C57BL/6J mice | Drinking water containing 3.0% DSS | It decreased the levels of IL-6, IL-1β, and TNF-α in the serum and colon, and the protein levels of TLR4, MyD88, and NF-κB p65, and phosphorylation of NF-κB p65 | Zuo et al. [43] | |
| Caco-2/RAW264.7 co-culture model | LPS stimulation | It suppressed NF-κB nuclear translocation, and mRNA expression of IL-8 and TNF-α | Nishitani et al. [44] | |
| Baicalein | Female Balb/c mice | 2 mg of TNBS | It reduced TNF-α and IL-1β, and phosphorylation of NF-κB p65 and IκBα, and protein expression of TLR4 and MyD88 | Luo et al. [45] |
| Sprague-Dawley rats | Ulcerative colitis | It inhibited NF-κB and MAPK expression, as well as IL-1β, IL-6, and IL-17 | Liang et al. [46] | |
| Quercetin | IEC-6 cells | 300 μmol/L indomethacin for 24 h | It suppressed calcium-mediated JNK and Src activation | Fan et al. [47] |
| Human intestinal epithelial cell line Int407 | Vibrio cholerae | Pretreatment with it reduced the IL-8 secretion and NF-κB translocation into the nucleus | Das et al. [48] | |
| Male Sprague-Dawley rats | Acute necrotizing pancreatitis induced by 3.5% sodium taurocholate solution | It downregulated intestinal protein expression of TLR4 and MyD88, and phosphorylation of p38 MAPK | Zheng et al. [49] | |
| Sprague-Dawley rats | Indomethacin dissolved in 5% NaHCO3, at 40 mg/kg body weight | Its oxidation metabolite prevented NF-κB activation and IL-8 secretion | Fuentes et al. [50] | |
| Kaempferol | Rat intestinal microvascular endothelial cells | 10 µg/mL LPS for 12 h | It inhibited LPS-induced NF-κB, I-κB and STAT phosphorylation, decreased TLR4 overexpression, and LPS-induced IL-1β, IL-6 and TNF-α upregulation | Bian et al. [51] |
| C57BL/6J male mice | High fat diet | It reduced the protein expression of TLR4, MyD88 and NF-κB, and mRNA expression of TNF-α in the colon | Bian et al. [52] | |
| Rutin | Rag1 −/− mice | CD4+ CD62L+ T cells transfer model of colitis | It inhibited STAT4 and IκBαphosphorylation, as well as IL-1β and IFN-γ expression in CD4+ spleen cells of the mice | Mascaraque et al. [1] |
| Female Wistar rats | 10 mg of TNBS induced ileitis and colitis | Intragastric rutin resulted in reduced IL-1β and IL-17 mRNA expression in the treatment of ileitis rats, while just tended to decrease levels of IL-17 and IFN-γ in the colitis rats | Mascaraque et al. [53] | |
| Myricetin | IEC-6 cells | 300 μmol/L indomethacin for 24 h | It increased the expression of tight junction proteins, and reduced JNK/Src phosphorylation | Fan et al. [47] |
| Male Kunming mice | Oral administration of 3% DSS solution for 2 weeks | It suppressed TNF-α, NF-κB and COX-2 expression, and increased tight junction proteins expression | Li et al. [54] | |
| Myricetin-3-O-b-D-lactose sodium salt | Male C57BL/6 mice | Oral water containing 1.0% DSS | It reduced the protein expression of IL-6, and the phosphorylation of JAK2, STAT3 and NF-κB, as well as TNF-α pathway, increased IL-4 and IL-10 secretion | Zhou et al. [55] |
| Hesperidin | Wistar albino male rats | TNBS-induced colitis | It reduced the colonic levels of NF-κB, TNF-α and IL-6 | Polat et al. [56] |
| Hesperidin methyl chalcone | Male Swiss mice | Acetic acid-induced colitis | It reduced acetic acid-induced TNF-α, IL-6, IL-1β, and IL-33 production and inhibited NF-κB activation by blocking Ser276 | Guazelli et al. [57] |
| Naringin | Mice | Cecal ligation and puncture-induced intestinal sepsis | It inhibited the release of TNF-α and IL-6, increased IL-10, inhibited NF-κB expression | Li et al. [58] |
| RAW 264.7 macrophages | LPS (1 μg/mL /mL) stimulation for 24 h | It reduced NF-κB translocation and phosphorylation of p38, ERK, and JNK, as well as the expressions of COX-2, IL-1β and TNF-α | Ha et al. [59] | |
| EGCG | Male C57BL/6J mice | High fat diet | It protected against gut barrier dysfunction, and decreased ileal and colonic mRNA expression of TNF-α | Dey et al. [60] |
| Rat intestinal epithelial cells | LPS (1 μg/mL) stimulation for 24 h | It blocked NF-κB signaling via degradation of IκBα and inhibition of NF-κB nuclear translocation, thereby suppressed the expression of adhesion molecules ICAM-1 and VCAM-1 | Myung et al. [61] | |
| Bone marrow-derived macrophages | LPS (1 μg/mL) incubation for 0–1 h | It prevented LPS-induced inflammation through inhibiting IκBα phosphorylation/degradation, NF-κB RelA nuclear translocation, and phosphorylation of ERK1/2, JNK and p38 expression | Joo et al. [62] | |
| Genistein | Male Arbor Acre broilers | Escherichia coli O78 | It improves intestinal mucosa barrier function by modulating apoptosis and secretion of TNF-α and IL-6 | Zhang et al. [63] |
| Caco-2 cells | 3% DSS for 7 d | It reduced nuclear NF-κB p65 and upstream TLR4 expression | Zhang et al. [64] | |
| RAW 264.7 macrophage cells | LPS stimulation | It down-regulated TLR4 and NF-κB expression, IκBα degradation and phosphorylation of ERK1/2 and p38, as well as COX-2, TNF-α, IL-6 and IL-1β expression | Byun et al. [65] | |
| Cyanidin-3-glucoside | Caco-2 cells | Exposed for 3 h to 50 ng/mL TNF-α | It inhibited NF-κB translocation into the nucleus, and IκBα degradation, as well as IL-6 and COX-2 expression | Ferrari et al. [66] |
| Caco-2-HUVECs coculture model | Exposed for 1 h to 50 ng/mL TNF-α | It prevented translocation of NF-κB into the nucleus and inhibited leukocyte adhesion in a dose dependent manner | Ferrari et al. [67] | |
| Balbc mice | Drinking water containing 2.5% DSS | It suppressed NF-κB phosphorylation, thereby inhibited IL-1β, IL-6, IL-8, COX-2 and TNF-α mRNA expression | Tan et al. [68] | |
| Malvidin 3-glucoside | HUVECs | TNF-α (10 μg/L) stimulation for 6 h | It suppressed IκBα degradation and blocked the nuclear translocation of NF-κB p65 | Huang et al. [69] |
| Male Wistar rats | TNBS-induced colitis | It reduced leukocyte infiltration, downregulated iNOS and COX-2 expression | Pereira et al. [70] | |
| Caco-2-HUVECs coculture model | TNF-α (1 ng/mL) stimulation for 3h | It reduced NF-κB mRNA expression, and IL-8 and IL-6 secretion | Kuntz et al. [71] | |
| Pelargonidin | Balb/c mice | TNBS-induced colitis | It decreased the colonic expression of IL-6, TNF-α, IL-1β, and IFN-γ, and increased IL-10 expression | Biagioli et al. [72] |
| Female C57BL/6 mice | Drinking water containing 2.5% DSS for 8 d | It inhibited the activation of NF-κB p65 and IκBα degradation, as well as reduced the serum level of IL-6, IFN-γ and TNF-α | Zhang et al. [73] | |
| Myofibroblasts-like cell line | 1 ng/mL IL-1β stimulation for 24 h | It reduced the IL-8 and COX-2 expression | Zielińska et al. [74] | |
| Pelargonidin-3-O-glucoside | RAW 264.7 Macrophages | 1 μg/mL LPS stimulation for 24 h | It inhibited nuclear translocation of NF-κB p65, phosphorylation and degradation of IκBα, as well as phosphorylation of JNK, thereby reduced the expression of pro-inflammatory cytokines, including IL-1α, TNF-α, IL-27, and IL-6, and enzymes related to inflammation, such as COX-2 and iNOS | Zhang et al. [75] |
| RAW 264.7 Macrophages | 1 μg/mL LPS stimulation for 24 h | It suppressed phosphorylation of JNK, p38 MAPK, IκBα and NF-κB p65, and reduced TNF-α and IL-6 production | Duarte et al. [76] | |
| Caffeic acid phenethyl ester | Male Sprague-Dawley rats | X-ray irradiation (9 Gy) | It reduced the plasma level of TNF-α, and phosphorylation of p38MAPK | Jin et al. [77] |
| Male Balb/c mice | Drinking water containing 3.5% DSS for 7 d | It reduced the production of key cytokines and expression of NF-κB p65 | Pandurangan et al. [78] | |
| Chlorogenic acid | IPEC-J2 cells | 50 ng/mL TNF- α for 3 h | It inhibited the phosphorylation of NF-κB p65 and IκBα | Chen et al. [79] |
| Caco-2 cells | LPS (0.1 mg/mL) stimulation for 24 h | It blocked nuclear translocation of NF-κB p65, and suppressed TNF-α, IL-1β and IL-6 production | Yu et al. [80] | |
| Ellagic acid | C57BL/6 mice | Drinking water containing 5% DSS for 7 d | It reduced the protein expression and phosphorylation of ERK1/2, p38, and JNK | Gao et al. [81] |
| Wistar Albino rats | 3% acetic acid (2 mLintrarectal) induced colitis | It decreased the protein levels of TNF-α, COX-2, and NF-κB | Yipel et al. [82] | |
| Female Balb/C mice | Drinking water containing 5% DSS for 7 d | It reduced the production of IL-6, TNF-α, and IFN-γ | Marín et al. [83] | |
| Female C57BL/6 mice | Four week-long cycles of DSS (1% and 2%) | It inhibited p38 MAPK and STAT3 phosphorylation, IκBα degradation, NF-κB p65 activation, as well as IL-6, COX-2 and iNOS expression | Marín et al. [83] | |
| Four-week-old male Wistar rats | TNBS-induced colitis | It decreased the expression of TNF-α, COX-2, and iNOS, and p38 MAPK, p-JNK and p-ERK1/2, as well as the nuclear translocation of NF-κB p65 | Rosillo et al. [84] | |
| Resveratrol | Black-boned chickens | Circular heat stress | It reduced the jejunal protein expression of NF-κB | Liu et al. [85] |
| Weaned piglets | Weaning stress | It downregulated MAPK pathway and reduced the levels of intestinal pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α | Meng et al. [86] | |
| 50 eligible patients | Ulcerative colitis | It reduced plasma levels of TNF-α and activity of NF-κB in peripheral blood mononuclear cells (PBMC) | Samsami-kor et al. [87] | |
| Curcumin | Male Sprague-Dawley rats | Diarrhea and constipation induced by intracolonic acetic acid instillation or cold water gavage | It inhibited IκBα degradation and NF-κB phosphorylation, as well as IL-1β and TNF-α | Yao et al. [88] |
| Male Sprague-Dawley rats | Experimental colitis induced by intra-rectal administration of TNBS | It Inhibited TLR4, MyD88 and NF-κB protein expression | Lubbad et al. [89] | |
| Emodin | IEC-6 cells | TNF-α (50 ng/mL) stimulation | It inhibited the expression of TLR4, NF-κB and NLRP3, also the production of IL-1β and IL-6 | Zhuang et al. [90] |
| HT-29 cells | Flagellin (500 mg/L) stimulation for 24 h | It increased the expression of IκB, but inhibited the expression of TLR5 and MyD88, nuclear translocation of NF-κB p65, as well as the IL-8 production in flagellin-stimulated HT-29 cells | Luo et al. [91] | |
| Male Wistar rats | Cecal ligation and puncture induced jejunal sepsis | It decreased the levels of IL-6 and TNF-α, and increased the phosphorylated levels of JAK1 and STAT3 | Chen et al. [92] |