Beneficial effects of nutritional supplements on intestinal epithelial barrier functions in experimental colitis models in vivo

Table 1 Nutritional supplements tested in dextran sulphate sodium-induced colitis (all studies refer to mice unless otherwise stated)

Product	Active compound	Effects on barrier function and mechanism	Ref.
Long chain fatty acid	10-hydroxy-cis-12-octadecenoic acid (HYA)	Preserves stability and expression of occludin and ZO-1 Decreases acute inflammation induced by TNF-α and increases expression of GPR40 HYA decreases expression of TNFR2 by GPR40-MEK-ERK signaling pathway	[40]
Short chain fatty acid	Propionate	Stabilizes intercellular junctions and avoid down-regulation of ZO-1, occludin and E-cadherin Reduces acute inflammation Inhibits production of IL-1β, IL-6 and TNF-α Reduces neutrophil recruitment Inhibits STAT3 phosphorylation	[41]
Terpenoid	Oleanolic acid	Stabilizes intercellular junctions and avoid down-regulation of ZO-1, occludin and E-cadherin Modulates inflammatory response suppressing Th17 cell differentiation Promotes expression of anti-inflammatory cytokine IL-10 Inhibits activation of NF-κB and IL-17 expression	[42]
Scavenger enzymes	NAC/L-NAME	Protects against disruption of intercellular junctions Decreases oxidative stress mediated by intracellular calcium. Decreases activation of JNK and c-Src preventing ZO-1 phosphorylation	[19,20]
Peptides	Chromofungin	Prevents down-regulation of claudin-1, ZO-1 and Ecadherin Decreases acute inflammation Decreases expression of IL-18 Increases expression of IL-10 Promotes IL-10, Arg1, Fizz1, and Ym1 expression, and the release of IL-10 Promotes arginase activity probably through p38 MAP kinase or STAT1	[43]
	Catestin	Maintains expression of claudin-1, ZO-1 and occludin Protects against inflammation induced by DSS Decreases expression of IL-8 and IL-18 Decreases activation of STAT-3 signaling pathway	[45]
	Substance P	Maintains expression of ZO-1 and E-cadherin Reduces inflammation and damage induces by DSS Decreased apoptosis and inflammation via Neurokinin-1 receptor	[46]
	Porcine β-defensin 2	Decreases paracellular flux Preserves expression of ZO-1, ZO-2 and claudin-1. Decreases production of NO synthetase and COX-2 Decreases expression of TNF-α, IL-6 and IL-8 Reduces apoptosis and neutrophil infiltration Inhibits the activation of NF-κB	[47]
	8-kDa antrum mucosal protein	Strengthens the formation of intercellular barrier by promoting the assembly of ZO-1, ZO-2 and JAM-A Ameliorates UC symptoms Promotes the phosphorylation PKCζ and recruitment of the Par6/Cdc42∙GTP/ECT2/Par3 complex	[48,49]
Vitamin D	1,25-dihydroxy-vitamin D3 [1,25(OH)2D3]	Restores epithelial barrier function and expression of ZO-1, occludin and claudin-1 Modulates inflammation turning M1 into M2 macrophage responses Reduces the expression of TNF-α, IL-12 and IL-1β	[34,37,38]
Corabion	Vitamin C, vitamin E, L-arginine	Preserves ZO-1 and E-cadherin expression Decreases inflammation Reduces production of IL-1, IL-6, INF-γ and KC	[39]
Compatible solutes	Ectoine, Homoectoine	Decreases Evans blue permeability Increases expression of ZO-1 and occludin Prevents claudin-1 to claudin-2 switch Decreases ROS production	[50]
Exopolysaccharides	Streptococcus thermophilus MN-BM-A01	Increases expression of claudin-1 and occludin	[51]
	Synechococcus sp. PCC 7002	Increases expression of ZO-1, occludin, claudin-4 and Hsp27	[52]
Lucilia sericata larvae	Maggot protein	Upregulation of MUC2 gene Increases expression of ZO-1 and occludin	[53]
Periplaneta americana	Ethanol extract	Increases expression of ZO-1, occludin and claudin-1	[54]
Donkey milk	Lysozyme	Increases expression of ZO-1 and occludin Decreases expression of claudin-2	[55]
Naringenin	Polyphenol	Decreases FITC-Dextran permeability Decreases LPS-binding protein levels in plasma Increases expression of occludin, JAM-A and claudin-3 Normalizes the colonic localization of occludin and claudin-3 proteins	[56]
Naringin	Flavonoid	Increases expression of ZO-1 Decreases NF-ĸB signaling pathway Regulation of PPARγ activation Inhibition of the MAPK activation Suppression of NLRP3 inflammasome activity	[57]
Red raspberries	Polyphenol	Increases mRNA expression of MUC2 Reduces pore forming TJ protein claudin-2 Increases ZO-1 and claudin-3 proteins Decreases NF-ĸB p65 phosphorylation Activates AMPK	[58]
Phlorentin	Flavonoid	Increases the expression of ZO-1 and occludin Inhibition of serum LPS levels Inhibits oxidative stress Decreases TLR4 expression Increases PPARγ expression Decreases NLRP3 inflammasome pathway (NLRP3, ASC, Caspase-1 and IL-1β protein expression) Suppression of NF-ĸB activation	[59]
Formomentin	Isoflavone	Increases ZO-1, claudin-1 and occludin protein expression Inhibition of NLRP3 inflammasome pathway (NLRP3, IL-1β and ASC protein expression)	[60]
Phellinus igniarius fruiting body	Polyphenols and polysaccharides	Increases mRNA levels of ZO-1 protein Decreases LPS plasma levels Inhibition of NF-ĸB pathway Decreases the transcription of ASC3 and caspase-1 pathway	[63]
Barley and soybean mixture	Isoflavone β-glucan	Increases ZO-1, claudin-1 and occludin protein expression and improves their localization Reduces FITC-Dextran serum levels Prevents bacterial translocation into the MLNs Anti-inflammatory activity	[64]
Evodia rutaecarpa	Alkaloid extract (Evodiamine)	Increases ZO-1, occludin and MUC2 expression Decreases plasmatic levels of LPS Decreases NF-ĸB signaling pathway Down-regulation of NRLP3, ASC, caspase-1 and IL-1β protein expression	[65]
Salvia miltorrhiza Bunge	Water-soluble-phenolic acid	Increases ZO-1 and occludin expression in rat colons	[66]
Magnolia officianalis	Magnolol	Increases ZO-1 and occludin protein expression Decreases NF-ĸB signaling pathway and regulation of PPAR-γ expression	[67]
Artemisia argy and Artemisia asiatica	Ethanol extract. Flavonoid (Eupatilin)	Increases occludin and ZO-1 protein expression Decreases NOX4 protein expression Down-regulation of NF-ĸB/MAPK signaling pathway Increases AMPK activation	[68]
QingBai Decoction		Decreases FITC-Dextran permeability Increases MUC2, ZO-1, claudin-1 and occludin protein expression Increases the number of Ki67 positive cells Decreases active caspase-3 expression Inhibits Notch and NF-ĸB signaling pathway	[70]
Zanthoxylum bungeanum	Essencial oil (Terpinen-4-ol)	Increases ZO-1 and occludin protein expression Decreases NF-ĸB pathway and NLRP3 inflammasome activation	[71]
Alnus japonica Steud	Ethanol extract.	Increases of ZO-1 and occludin expression Increases HO-1 expression	[75]
Pogostemon cablin Benth	Aqueous extract: Patchouli alcohol	Increases expression of MUC1, MUC2, claudin-1, occludin, ZO-1 and ZO-2 Down-regulation of apoptosis Suppresses tryptophan catabolism	[76]
Rhizoma Coptidis	Berberine Berberrubine	Upregulates gene expression of MUC1 and MUC2 Increases ZO-1, ZO-2, claudin-1 and occludin protein expression Decreases the Bax/Bcl-2 ratio	[77]
Moringa oleifera	Flavonoids, phenolic acids and glucosinolates	Increases expression of ZO-1 and claudin-1 Upregulates GSTP1 and Nrf2-mediated phase II detoxifying enzyme	[78]
Wasabia japonica	Glucosinolates, isothiocyanate.	Increases MUC2 and ZO-1 expression Regulation of ERK pathway	[79]
Acer palmatum Thumb	Ethanol extract (KIOM-2015E)	Increases ZO-1 and occludin expression	[80]
Guar gum	Galactomannan	Upregulates ZO-1, occludin, JAM-A, claudin-3, -4 and -7 protein expression Decreases plasmatic levels of LBP	[83]

LPS: Lipopolysaccharide; LBP: Lipopolysaccharide-binding protein; JAM-A: Junctional adhesion molecule-A; ZO-1/2: Zonula occludens-1/2; HO-1: Heme-oxygenase 1; NF-κB: Nuclear factor-ĸB; AMPK: adenosine monophosphate-activated protein kinase; MAPK: Mitogen-activated protein kinase; PPARγ: Peroxisome proliferator-activated receptor γ; IL: Interleukin; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α; COX-2: Cyclo-oxygenase-2; UC: Ulcerative colitis.

Table 2 Nutritional supplements tested in 2,4,6-trinitrobenzene sulfonic acid-induced colitis

Product	Active compound	Animals	Effects on barrier function	Ref.
Citrus fruit peels	Nobiletin	Rats	Decreases FITC-dextran permeability Reduces MLCK and NF-κB and PI3K expression Decreases Akt phospho-rylation	[94]
Rhododendron	Farrerol	Mice	Upregulates ZO-1, claudin-1 and occludin genes	[95]
Garnedia jasminoides	Geniposide	Rats	Increases expression of ZO-1 and occludin Decreases FITC-Dextran permeability Decreases MLCK activity and increases AMPK phosphorylation	[96]
Anemarrhena asphodeloides, Mangifera indica L	Neomangiferin	Mice	Increases expression of ZO/1, claudin-1 and occludin	[97]
Ziziphus jujuba	Sarcocarp polysaccharides	Rats	Decreases Evans blue permeability Increases expression of ZO-1, occludin, claudin-1 and claudin-4 Decreases AMPK activity	[98]
Dietary fiber	Sodium butyrate	Mice	Decreases FITC-Dextran permeability Upregulation of ZO-1, claudin-1 and occludin genes	[100]
Schistosoma japonicum	Ova	Mice	Increases expression of ZO-1 and occludin Upregulation of ZO-1 and occludin genes	[101]

ZO-1: Zonula occludens-1; AMPK: adenosine monophosphate-activated protein kinase; NF-κB: Nuclear factor-ĸB