Research progress in the treatment of ulcerative colitis with natural products

Table 1 Summary of sources, intervention mechanisms and experimental models of core active components of natural products in ulcerative colitis[39-87]

Name	Source	Related mechanisms	Experimental models	Ref.
Nicotiflorin	San-Ye-Qing	Inhibiting the NF-κB pathway and activating the NLRP3 inflammasome to exert anti-inflammatory effects	LPS + BMDMs	Ruan et al[39]
Berberine	Coptis chinensis Franch.	Inhibiting the PI3K/AKT/mTOR pathway by targeting IRGM1	2.0% DSS induced UC in C57BL/6 J mice	Meng et al[40]
Epiberberine	Coptidis Rhizoma	Activating intestinal FXR, regulating BAs metabolism/FGF15, and relieving intestinal BAs accumulation/inflammation	3% DSS induced UC in C57BL/6 J mice	Chen et al[41]
Anemoside B4	P. chinensis	Enhancing intestinal epithelial barrier via regulating MLCK-pMLC2 signaling	3% DSS induced UC in C57BL/6 J mice	Feng et al[42]
Paeoniflorin	Paeonia emodi, Paeonia obovata	Targeting CDC42 inhibits the CDC42/JNK signaling pathway	4.0% DSS induced UC in SD rats	Hu et al[43]
Benzoylpaeo-niflorin	Baishao	Suppressing ferroptosis by regulating Nrf2/SLC7A11/GPX4 signaling pathway	3.5% DSS induced UC in C57BL/6 J mice	Tang et al[44]
Formononetin	Astragalus membranaceus	Regulating gut microbiota and M1/M2 macrophage polarization balance	2.5% DSS induced UC in C57BL/6 J mice	Xiao et al[45]
Anemoside B4	P. chinensis	Regulating Lactobacillus abundance, promoting SCFA metabolism/butyrate production, and activating the AhR pathway to inhibit ROS/NLRP3 inflammasome activation	3% DSS induced UC in C57BL/6 J mice	Wu et al[46]
Gastrodin	Gastrodia elata	Promoting gut microbiota-derived tryptophan metabolite production and inhibiting inflammation via the AhR/NLRP3 pathway	2.5% DSS induced UC in C57BL/6 J mice	Zhang et al[47]
Plantamajoside	Plantago	Regulating gut microbiota, enhancing intestinal barrier, increasing cystathionine β-synthase expression, and inhibiting the NF-κB pathway	2.5% DSS induced UC in C57BL/6 J mice	Jia et al[48]
Morin	Moraceae family	Inhibiting MAPK/NF-κB pathways, regulating gut microbiota	2.5% DSS induced UC in C57BL/6 J mice	Qiu et al[49]
Caffeic acid	Coffee, Argan	Alleviating intestinal injury by inhibiting the Toll/Imd signaling pathways and suppressing mitochondria damage-mediated apoptosis	4% DSS induced UC in drosophila	Xiu et al[50]
Curcumin, tryptophan	Turmeric	Restoring intestinal barrier function, reducing oxidative stress and inflammation, and regulating gut microbiota homeostasis	2.5% DSS induced UC in BALB/c mice	Jiang et al[51]
Vanillic acid	Vanilla bean	Inhibiting arachidonic acid metabolic pathway and promoting macrophage polarization from M1 to M2 phenotype	2.5% DSS induced UC in C57BL/6 J mice	Zhao et al[52]
Gastrodin	Gastrodia elata Blume	Enriching the Akkermansia mucinniphila population	2% DSS induced UC in BALB/c mice	Zhang et al[53]
Vanillic acid	Angelica sinensis	Regulating oxidative stress, inflammatory responses, macrophage polarization, and the AMPK signaling pathway	2.5% DSS induced UC in BALB/c mice	Ma et al[54]
Theabrownin	Fu Brick Tea	Enhancing antioxidant and anti-inflammatory capacities, regulating gut microbiota, and participating in the AhR pathway	1.5% DSS induced UC in C57BL/6 J mice	Yang et al[55]
Butylchloro-genate	Chaenomeles speciosa	Inhibiting the activation of the NLRP3 inflammasome	4% DSS induced UC in C57BL/6 J mice	Huang et al[56]
Quercetin	Vegetables and Fruits	Regulating the gut microbiota-isovanillic acid-intestinal barrier axis	3% DSS induced UC in BALB/c mice	Lei et al[57]
Proanthocyanidins	Ephedra sinica Stapf	Regulating gut microbiota and restoring impaired serum tryptophan and glycerophospholipid metabolism	4% DSS induced UC in KM mice	Lv et al[58]
TCP80-1	Tupistra chinensis Baker	Enhancing the intestinal barrier and promoting the proliferation and differentiation of intestinal stem cells into intestinal epithelial cells	4% DSS induced UC in drosophila	Wang et al[59]
Kaji-ichigoside F1	Rosa roxburghii Trat	Regulating gut microbiota and metabolism, and inhibiting the PI3K/AKT pro-inflammatory signaling pathway	3% DSS induced UC in C57BL/6 J mice	Liu et al[60]
Fraxin	Cortex Fraxini	Inhibiting ROS production, reducing pro-inflammatory cytokines, and regulating the TLR4/NF-κB and MAPK signaling pathways	2.5% DSS induced UC in C57BL/6 J mice	Sun et al[61]
Isosinensetin	Pericarpium Citri Reticulatae	Inhibiting the PI3K/AKT signaling pathway, alleviating oxidative stress and inflammatory responses, and enhancing barrier function	3% DSS induced UC in C57BL/6 J mice	Li et al[62]
Homogalacturonan	Passiflora edulis f. flavicarpa	Enhancing MUC-2 expression and promoting epithelial barrier restoration	5% DSS induced UC in Swiss mice	Mazeti et al[63]
Bergenin	Ardisia japonica	Reducing Bacteroides vulgatus abundance to regulate branched-chain amino acid metabolism, thereby inhibiting TLR4 and modulating the phosphorylation of NF-κB and mTOR	2.5% DSS induced UC in C57BL/6 J mice	Huang et al[64]
Theabrownin	Pu-erh tea	Increasing Akkermansia abundance and intestinal epithelial barrier function, regulating CD4+ T cell differentiation and Treg/Th17 balance, and inhibiting TLR2/4-mediated MyD88-dependent NF-κB, MAPK, and AKT signaling pathways	5% DSS induced UC in Swiss mice	Zhao et al[65]
Gypenosides	Gynostemma pentaphyllum	Regulating the tricarboxylic acid cycle and glutamine metabolism, modulating stem cell bioactivity, and promoting the repair of damaged mucosa	3% DSS induced UC in C57BL/6 J mice	Yang et al[66]
Glycyrrhizic acid, patchouli alcohol	Huoxiang Zhengqi	Modulating 11β-HSD1-mediated endogenous corticosterone metabolism to exert anti-inflammatory effects	2% DSS induced UC in C57BL/6 J mice	Wang et al[67]
Neohesperidin	Brassicaceae family plants	Inhibiting the MAPK/NF-κB inflammatory signaling pathway, maintaining intestinal barrier integrity, and regulating gut microbiota	2.5% DSS induced UC in C57BL/6 J mice	Ju et al[68]
Linderanine C	Lindera aggregate	Inhibiting the MAPK signaling pathway and macrophage M1 polarization	2.5% DSS induced UC in C57BL/6 J mice	Lan et al[69]
Loganic acid	Swertia cincta	Inhibiting TLR4/NF-κB-mediated inflammation and activating the SIRT1/Nrf2 antioxidant response	2.5% DSS induced UC in BALB/c mice	Prakash et al[70]
Pulchinenoside B4	Bai-Tou-weng-Tang	Targeting the CD1d-mediated AKT-STAT1-PRDX1-NF-κB signaling pathway and inhibiting NLRP3 inflammasome activation	3% DSS induced UC in C57BL/6 J mice	Li et al[71]
Rhoifolin	Citrus grandis	Activating CEMIP/SLC7A11-mediated cystine uptake and inhibiting epithelial ferroptosis	2.5% DSS induced UC in C57BL/6 J mice	Liu et al[72]
Berberine	Coptis chinensis Franch.	Modulating the bile acid/S1PR2/RhoA/ROCK pathway to restore intestinal epithelial barrier function	2.5% DSS induced UC in C57BL/6 J mice	Yu et al[73]
Gypenoside LXXV	Gynostemma pentaphyllum	Targeting the glucocorticoid receptor to inhibit NF-κB-COX2 signaling and promote M1-to-M2 macrophage polarization	2.5% DSS induced UC in C57BL/6 J mice	Wu et al[74]
Mangiferin	Pueraria tuberosa	Restoring colon length and body weight, and reducing inflammatory responses	Inducing colitis via rectal administration of 2 mL of 4% acetic acid in BALB/c mice	Dharmapuri et al[75]
Didymin	Citrus grandis	Regulating gut microbiota and altering metabolites, thereby modulating the STAT3 and NF-κB pathways	2% DSS induced UC in ICR mice	Chu et al[76]
JNUTS013	Marine fungi	Inhibiting inflammation through inducing NLRP3 protein degradation	3% DSS induced UC in C57BL/6 J mice	Wang et al[77]
Isolinderalactone	Lindera aggregata	Binding to LXRα and upregulating the expression of LXRα target genes such as ABCA1, thereby activating the LXRα pathway and inhibiting macrophage M1 polarization	2.5% DSS induced UC in C57BL/6 J mice	Huang et al[78]
Linderane	Lindera aggregata	Suppressing IL-6/STAT3-mediated Th17 differentiation and apoptosis resistance	2.5% DSS induced UC in C57BL/6 J mice	Lai et al[79]
(-)-Fenchone	Foeniculum vulgare Mill	Enhancing intestinal barrier function, exerting anti-inflammatory and antioxidant effects, and regulating immune function	Inducing colitis via rectal administration of trinitrobenzene sulfonic acid in Wistar rats	Araruna et al[80]
Ganoderic acid A	Ganoderma lucidum	Regulating gut microbiota-related tryptophan metabolism (especially 3-IAld), activating the aryl hydrocarbon receptor, and inducing IL-22 production	2.5% DSS induced UC in C57BL/6 J mice	Kou et al[81]
Oxymatrine	Sophora flavescens	Regulating ferroptosis and alleviating intestinal inflammation	4% DSS induced UC in ICR mice	Gao et al[82]
Diosmin	Citrus grandis	Inhibiting PANoptosis, regulating gut microbiota and metabolites	3% DSS induced UC in C57BL/6 J mice	Tan et al[83]
Naringenin	Citrus grandis	Activating the Nrf2 signaling pathway to exert antioxidant effects	3.5% DSS induced UC in BALB/c mice	Li et al[84]
Dihydromyricetin	Ampelopsis grossedentata	Inhibiting the formation of neutrophil extracellular traps and regulating the HIF-1α/VEGFA signaling pathway	3.5% DSS induced UC in C57BL/6 J mice	Ma et al[85]
Homoplantaginin	Salvia plebeia R. Brown	Regulating the MMP9-RLN2 signaling axis	2.5% DSS induced UC in C57BL/6 J mice	Tao et al[86]
Apigenin	Citrus grandis	Regulating mast cell degranulation via the PAMP-MRGPRX2 feedback loop	5% DSS induced UC in C57BL/6 J mice	Huang et al[87]

P. chinensis: Pistacia chinensis; NF-κB: Nuclear factor kappa-B; NLRP3: NOD-like receptor thermal protein domain associated protein 3; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; FXR: Farnesoid X receptor; BA: Bile acid; FGF: Fibroblast growth factor; MLCK: Myosin light-chain kinase; pMLC2: Phospho-myosin light chain 2; JNK: C-Jun N-terminal kinase; Nrf2: Nuclear factor-erythroid 2 related factor 2; GPX4: Glutathione peroxidase 4; SCFAs: Short-chain fatty acids; AhR: Aryl hydrocarbon receptor; IL: Interleukin; ROS: Reactive oxygen species; MAPK: Mitogen-activated protein kinase; AMPK: Adenosine 5’-monophosphate-activated protein kinase; TLR: Toll like receptor; Treg: Regulatory T cells; Th: T helper; CD: Cluster of differentiation; 11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1; SIRT1: Silent information regulator 1; STAT: Signal transducer and activator of transcription; PRDX1: Peroxiredoxin 1; COX2: Cyclooxygenase-2; LXRα: Liver X receptor α; HIF-1α: Hypoxia inducible factor 1 alpha; VEGFA: Vascular endothelial growth factor A; PAMP: Pathogen-associated molecular patterns; LPS: Lipopolysaccharides; BMDMs: Bone marrow-derived macrophages; DSS: Dextran sulfate sodium; UC: Ulcerative colitis.

Table 2 Summary of clinical trials of natural products for ulcerative colitis[134-142]

Natural product/active component	Trial design	Sample size	Ref.
Anthocyanin-rich extract	Multicenter, randomized, placebo-controlled, double-blind study	48	Biedermann et al[134]
Hudi enteric-coated capsule, modified Wumei pill, and Qingchang Wenzhong decoction	Multicenter, randomized, double-blind study	143	Li et al[135]
Zataria multiflora	Multicenter, randomized, placebo-controlled, triple-blind trial	92	Morvaridi et al[136]
Curcumin, resveratrol	Prospective multicenter three-arm RCT	48	Erol Doğan et al[137]
Zuoqing San	Single-center, double-blind study	126	Li et al[138]
1-kestose	Randomized, double-blind, placebo-controlled pilot trial	40	Ikegami et al[139]
Curcumin-QingDai	A retrospective multicenter adult cohort study	88	Yanai et al[140]
Icanbelimod	Single-center, double-blind study	28	Lickliter et al[141]
Pegmispotide	Double-blind study	29	Allegretti et al[142]

RCT: Randomized controlled trial.