Table 1.

Flavonoids explored in the context of inflammatory bowel diseases (IBDs)

Subgroups	Compounds	Dietary/Exogenous sources	Mechanisms of action (Preclinical models)	Studies in humans (including observational and intervention studies	References
Flavones	Apigenin	Parsley, chamomile, celery, vine spinach, artichokes and oregano	Shows anti-inflammatory and antioxidant properties by inhibiting TNF-α transactivation and blocking inflammasome pathways. It alleviates intestinal injury in animal models, promotes anti-inflammatory cytokine expression, and maintains the intestinal epithelial barrier. Also, it inhibits inflammation related to carcinogenesis by repressing STA3-NF-κB signaling and regulating gut microbiota and SCFA production	-	63,65,66,333
	Baicalein	Oroxylum indicum	Reduces IBD impact by inhibiting COX-2 activity, modulating AhR/IL-22 pathways, and inactivating the NLRP3 inflammasome, among other mechanisms	-	70-75
	Baicalin	Scutellaria baicalensis	Act as an anti-inflammatory, anticarcinogenic, and immunomodulatory agent, improving intestinal health by regulating pathways such as TLR4/NF-κB, AhR/IL-22 and autophagic flux. And also, it is efficacy in human UC cells, reducing pro-inflammatory markers	-	76,78-80,82,84,88,90,92
	Luteolin	Carrots, parsley, broccoli, peppers, celery, olive oil, onion leaves, cabbages, apple skins, chrysanthemum flowers, peppermint, thyme, rosemary, and oregano	Inhibits pro-inflammatory mediators such as COX-2, TNF-α, and IL_6, and regulates pathways like NF-κB, JAK/STAT, and MAPKs, reducing inflammation in ulcerative colitis	-	93,95-97,100,102,103
	Wogonoside	Schulletaria	Alleviate colitis by protecting against intestinal barrier dysfunction through the reinforcement of tight junctions via the MLCK/pMLC2 signaling pathway in Caco2 cells. It also leads to the dual inhibition of NF-κB and the NLPR3 inflammasome in DSS-induced UC mice	-	105,106
	Wogonin	Schulletaria	Prevents colonic ulceration, neutrophil infiltration, oxidative stress, proinflammatory cytokines, and histological changes in DSS-induced colitis models. It promotes apoptosis by inhibiting Bcl-2 and iNOS to suppress NF-κB. Also, it regulates the Nrf2 and TLR-4/ NF-κB pathways and modulates ILC3/ILC1 plasticity	-	107,108
	Tangeretin	Citrus spp pericarp	Improves colonic tissue damage reduction and enhances gut microbiota activity in DSS-induced colitis mice. Oral administration inhibits UL-12 ND TNF-α expression through interaction with the NF-κB pathway	-	109,110
	Nobiletin	Citrus peels	Exhibits anti-inflammatory effects in TNBS-induced colitis by downregulating iNOS and COX-2 expression. It restores barrier functions by inhibiting the Akt/ NF-κB MLCK pathway	-	111
	Chrysin	Honey, propolis, and various plants, fruits, and fungi	Downregulates the PXR/ NF-κB pathway in induced colitis in vivo	-	112-114
Flavonols	Quercetin	Citrus, and green leafy vegetables like broccoli, flowers, and nuts	Enhances intestinal integrity, modulates microbiota, and reduces inflammation in IBD. It acts through pathways including inhibition of NF-κB, modulation of PI3K/AKT signaling, activation of AhR for TJ enhancement and suppression of NLPR3 inflammasome	Two observational studies linked higher quercetin intake to lower IBD risk and improved outcomes in UK biobank participants. An intervention study found higher patient satisfaction with quercetin containing flavonoid mixtures for hemorrhoidal disease in IBD patients. A pilot study showed potential benefits of quercetin-rich beverages on blood nutrient parameters in IBD patients, indicating the need for further research	119,120,122,124,126,128-130
	Kaempferol	Edible plants such as tea, broccoli, cabbage, kale, beans, endive, leek, tomato, strawberries and grapes, and herbal medical plants	It is protective against DSS-induced UC by enhancing colonic mucosal integrity and regulating gut microbiota. It reduces inflammatory markers like IL-1β, IL-6, and TNF-α, while increasing IL-10 expression through pathways involving TLR4, NF-κB, and STAT	-	131,132,134,135
	Galangin	Ginger, gangal, honey, and propolis	Inhibits HSP90β, elevated in UC mucosal biopsies and colitis, correlating with disease severity. It alleviates colitis by blocking HSP90β and suppressing NLRP3 inflammasome activation, reducing inflammatory markers in vitro and in vivo. Also downregulates TLR4, inhibits NF-κB p65, and promotes autophagy proteins	-	136-139
	Myricetin	Cranberry, dock, sweet potato leaves, chard, broad beans, and immature seeds	Reduces inflammation in acute UC by increasing IL-10 and TGFβ levels, enhancing Treg cell proportions	-	140-144,334
	Fisetin	Strawberries, apples, mangoes, persimmons, kiwis, grapes, tomatoes, onions, cucumbers, nuts and wine	Inhibits senescence markers and upregulates miRNAs and Akkermansia muciniphila in DSS-induced UC mice, correlating with reduced senescence and inflammation. It also exerts anti-inflammatory effects by inhibiting akt, p38, MAPK, and NF-κB signaling in colonic tissues, fomenting GSH levels, and reducing MDA	-	145-147
	Isorhamnetin	Opuntia ficus-indica, Hippophae rhamnoides, and Ginkgo biloba	It can alleviate IBD through PXR-mediated up-regulation of xenobiotic metabolism and down-regulation of NF-κB signaling. Also, it can inhibits ferroptosis	-	148,149
Flavanones	Naringin	Lemon, orange, mandarin, and grapefruit	Reduces inflammation, oxidative stress, and improves intestinal microbiota in UC models. It enhances antioxidant enzymes, decreases inflammatory cytokines, and modulates PPARγ, NF-κB, and NLPR3 inflammasome pathways. Also exhibits potential in preventing intestinal fibrosis, colorectal carcinogenesis, bone loss in IBD, and alleviating depressive behaviour in colitis models	-	152-156,158,160
	Naringingenin	Lemon, orange, mandarin, and grapefruit	Act as an important immunomodulator against T cell-dilated autoimmune diseases like IBDs	-	162,163
	Hesperidin	Lemon, sweet oranges, bitter oranges, citron, clementines, and mandarins, as well as in Menthae piperitae, Hypericum perforatum, and Salvie officinalis	Reduces neutrophil infiltration, colon damage, and inflammation by inhibiting pro-inflammatory cytokines (TNF-α, IL-6, IL-1β and IL-33, and NF-κB activation	-	128,165-168
	Hesperetin	Lemon, sweet oranges, bitter oranges, citron, clementines, and mandarins, as well as in Menthae piperitae, Hypericum perforatum, and Salvie officinalis	Amilorates DSS-induced colitis by maintaining an epithelial barrier through blocking the intestinal epithelial necroptosis. Also, alleviates TNBS-induced ulcerative colitis through antioxidant, anti-inflammatory properties, and by modulating JAK2/STAT3/SOCS3	-	169,170
	Eriodictyol	Citrus fruits, vegetables, and most medical plants	Decreases MPO expression and modulates cytokines and oxidative stress in TNBS-induced colitis in rats, inhibiting the TLR4/NF-κB pathway. It also upregulates the Hh pathway, reducing DAI, colon shortening, histological scores, and apoptosis while increasing tight junction proteins ZO-1 and occluding	-
	Eriocitrin	Lemons	Significantly alleviated DSS-stimulated severe colitis in experimental animals, reducing body-weight loss, colon shortening, histopathological injury, inflammatory cell infiltration, and inflammatory cyrokine secretion	-	173,177
	Poncirin	Hardy oranges and mandarins. Poncirus trifoliata	Seems to extert antidepressant effects in mice by restoring vascular endothelial cell integrity in the hippocampus and controlling the neuroinflammatory responses of CA1 and DG regions of the hippocampus	-	178
Isoflavones	Daidzein	Soy, legumes, currants and raisins	In vitro studies show daidzein upregulates metallothionein gene expression, induces CAT activity, and improves tight junction integrity in Caco-2 cells. Also, attenuates LPS-induced inflammatory responses via NF-κB dependent mechanism and reduces DSS-induced UC inflammation by modulating p38, JNK, and NF-κB pathways	Observational studies suggest daidzein may reduce mucus in UC patients' feces but increase fecal pus with high intake, while isoflavone consumption may raise UC risk, especially in females. European studies linked higher daidzein intake to reduced gastrointestinal plain in UC patients. These findings highlight the importance of dosage in the impact of daidzein and polyphenols on IBD	182-186,189-191,193
	Genistein	Soy, legumes, currants and raisins	It has reduced DSS-induced colitis by shifting macrophages to an M2 phenotype, inhibiting the NLPR3 inflammasome, and modulating gut microbiota and inflammatory pathways. It enhances the expression of protective proteins and reduces pro-inflammatory markers.	-	194-202
	Glycitein	Soybeans	Is identified as a critical modulator in UC treatments like Fuzi-Lizhong Pill and Huangquin Decotion, alleviates UC by inhibiting the PI3K7Akt signaling pathway. Also, UC patients in remission reported less constipation and lower glycitein intake	-	193,209,210
	Formononetin	Soybeans	Bioactive compound that explains the success of UC therapy of FLP and HQT, and others.	-	212-215,217,218
	Biochanin A	Soybeans	Inhibits the elevation of ROS, IL-1β, IL-18, and TNF-α release, nitrite production, and the expression of iNOS and COX-2 in RAW 264.7 cells under LPS stimulation. Also promotes the restore of the intestinal barrier and promotes autophagy.	-	219,220
	Equol	Soybeans	A bacterial metabolite of isoflavones, has controversial roles I IBD. One study shows that equol promotes DSS-induced UC by downregulating IL-10 production, while in other study observed that equol production alleviated colitis by promoting beneficial gut microbiota	-	222,223
Flavanols	Catechins (Focus on EC and EGCG)	Epicatechin (EC), epicatheni gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG)	Catechins exter anti-inflammatory effects in IBD by modulating immune cell infiltration, oxidative stress pathways (MAPK, NF-κB , Nrf2, STAT 1/3)m and gut microbiota. EC specially reduces inflammation markers and increases antioxidant enzymes in UC models, while EGCG improves colitis symptoms by lowering pro-inflammatory cytokines and enhancing intestinal health	-	224-237
	Proanthocyanidins (condensed tanins)	Fruits, nuts, bark, chocolate, wine, and some plant seeds and flowers	GSPE benefits animal models of UC by reducing inflammation markers and oxidative stress while increasing antioxidant proteins like SOD and Nrf2. Also improves gut health by rebalancing microbiota, promoting beneficial bacteria, and enhancing tight junction protein expression	-	242,244-246
	Procyanidins	Catechin and epicatechin molecules	Show promise in treating UC by preventing M1 macrophage polarization and downregulating pro-inflammatory factors via STAT3 and NF-κB pathways. They also enhance ROS clearance, suppress MMP9 and NLPR3 inflammasome expression, and modulate gut microbiota and SCFA production	-	247-257
Anthocyanins	Anthocyanidins (Cyanidin, delphidin, malvidin, peonidin, pelargodin, petudin) + 1-3 sugar molecules (arabinose, galactose, glucose, rhamnose, and xylose)	Barberry, bilberry, blueberry, cranberry, currants, grapes, mulberry black/red raspberry, grapes, strawberry, purple (sweet) potatoes, dark/purple rice and red cabbage.	Barberry anthocyanins reduce inflammation and ulcer induces UC models. Bilberry, blueberry, and cranberry anthocyanins mitigate colitis symptoms, enhance antioxidant capacity, and regulate gut microbiota, with cranberries showing superior efficacy in reducing colitis severity. Mulberry, raspberry, strawberry, and anthocyanins from purple potato, rice, and red cabbage also demonstrate significant anti-inflammatory and gut microbiota modulation effects, suggesting their potential in managing IBDs	In a pilot study, 63.4% of UC patients achieved remission and 90.9% showed a response to a daily anthocyanin-rich bilberry preparation, with decreased total Mayo scores and fecal calprotectin levels during the treatment phase. Molecular analysis revealed reduced pro-inflammatory cytokines and increased immunoregulatory cytokines in responsive patients, with no serious adverse effects reported. However, calprotectin levels and DAI increased after stopping bilberry intake	261-300
Chalcones	Xanthohumol	Humulus lupulus L.	Demonstrates anti-inflammatory and anti-fibrotic effects in colitis by inhibiting pathways such as TLR4/MD-2, NF-κB, and TGF-β/Smad, ad reducing oxidative stress and pro-inflammatory cytokines. Studies show XN alleviates colitis symptoms, prevents colonic lesions, and modulates gut microbiota, increasing anti-inflammatory microorganism	No studies have specially evaluated xanthohumol (XN) in humans with IBD, but a phase II clinical trial is testing its safety and tolerability in adults with active Chron´s disease. A pilot study with a micronutrient and phytonutrient-rich formula, including XN, showed significant increases in serum folate and changes in leukocyte subtypes in IBD patients. Although preliminary evidence is promising, further studies are needed to confirm XN´s potential in IBD treatment	101,301-307,309,310
	Isoliquiritigenin	Glycyrrhiza uralensis, Mongolian glycyrrhiza, and Glycyrrhiza glabra	Exhibits anti-inflammatory and antioxidants effects by inhibiting NF-κB, NLRP3, and MAPK pathways, and activating Nrf2. In DSS-induced UC mice, ISL improved symptoms and colon integrity by suppressing ERK1/2 and p38 phosphorylation, and reducing inflammation markers. Preclinical studies suggest ISL and licorice extract as potential IBD treatments	-	311-316
	Cardamonin	Various plants	Exhibits anti-inflammatory properties by reducing NO production and downregulating iNOS, TNF-α, and IL-6 expression, while inhibiting NF-κB signaling. In DSS-induced colitis mice, it mitigates symptoms, reduces inflammatory markers, and blocks NF-κB and MAPK pathways	-	317-322
	Phloretin	Apples, pears, and strawberries	Acts as a potent antioxidant and anti-inflammatory agent by modulating signaling pathways and maintaining epithelial integrity. It reduces inflammation markers, oxidative stress, and mitochondrial membrane depolarization in vitro and in a rat and mouse colitis models, while also preserving gut microbiota balance	-	323-327
	Liochalcone A	Glycyrrhiza inflata	Significantly protected mice against DSS-induced colitis, reducing weight loss, disease activity index, histological damage, and inflammation while preserving intestinal barrier integrity and modulating gut microbiota	-	328,329
	Butein	Toxicodendron verniciflumm	Significantly ameliorated colitis in Il-10 (-/-) mice by reducing the colonic inflammatory score by over 50%. It lowered the expression of Il-6, IL-1β, IFN-γ, pSTAT3, and MMP-9, and inhibiting IL-6 induced STAT3 activation in colon 205 cells	-	330
	Flavokawain B	Zingiberaceae and Kawa family	Demonstrated significant therapeutic effects in a DSS-induced IBD mouse models by reducing weight loss, restoring colon length, and mitigating inflammation. It targeted TLR2 to inhibit the TLR2-MyD88 complex formation, suppressing the NF-κB signaling pathway in vivo and in vitro	-	331
	Artipilin C	Brazilian green apples propolis	It ameliorates UC and colts-associated colorectal cancer by targeting p21-activated kinase 1 (PAK1).	-	332