Potential of the ellagic acid-derived gut microbiota metabolite – Urolithin A in gastrointestinal protection

Table 2 Anti-inflammatory activity of urolithin A relevant to the intestine

Cell line/model	Mechanism	Ref.
CCD18-Co/cytokine-induced inflammation IL-1β or TNF-α	↓IL-1β-induced PGE2 level	Giménez-Bastida et al[41]
	↓IL-1β or TNF-α -stimulated migration
	↓non-stimulated migration
	↓IL-1β-stimulated adhesion
	↑TNF-α -decreased cell viability
	↓IL-1β or TNF-α -induced expression of members of the EGF, PGF, PDGF, VEGF, M-CSF, and IGF families
	↓IL-1β -induced PAI-1 and TNF-α -induced IL-8 levels
Fischer rats/DSS-induced colitis	↑HCT, RBCs	Larrosa et al[42]
	↓Loss of epithelium, total histological scores
	↑Bifidobacteria
	↓E. coli, enterobacteria, and total aerobic bacteria CAT activity
	↓NO, iNOS
	↓PGE2, COX-2, PTGES
	↑Rb1, p53 ↓CD40, IL-1β and IL-4
C57BL/6 x FVB F1/BRB intervention	↑Shannon diversity index	Gu et al[44]
	↑Bacteroidetes, Barnesiella
	↓Firmicutes, Clostridium, Turicibacter, Lactobacillus
BMDMs/LPS	↓IL-6, TNF-α level	Singh et al[45]
C57BL/6 mice	↓LPS-induced serum level of IL-6, TNF-α	Singh et al[45]
	↑Colonic and hepatic Cyp1A1 activity in WT not in AhR−/− mice
	↑Colonic Cldn4, Nrf2, and NQO1 in WT not in AhR−/− and Nrf2−/− mice
	↑Colonic Cldn4, Nrf2, and NQO1 in WT not in AhR−/− and Nrf2−/− mice
HT-29, Caco-2	↑Cldn4, Ocln, and ZO1	Singh et al[45]
	↑Cldn4, Ocln, and ZO1
	↓LPS-induced leakage of FITC-dextran
	↑Cyp1A1, Cyp1A1 protein expression, and activity
	↑AhR-reporter, nuclear translocation of AhR
	Cldn4 expression not affected in Ahr SiRNA and CYP1A1 SiRNA cells
	↑Nrf2 levels, nuclear translocation of Nrf2
C57BL/6 mice/TNBS	↓Weight loss, diseases activity index, intestinal permeability	Singh et al[45]
	↓Colonic MPO level
	↓Serum IL-6, TNF-α, CXCL1, and IL-1β levels
	↑Colon length, Cldn4
	↓Tissue damage and inflammation scores
AhR-knockdown caco-2 cells/TCDD/IL-1β /TMF	↓IL-6, CYP1A1, PTGS2 in siControl	Muku et al[47]
	NS IL-6, CYP1A1, PTGS2 in siAhR

AhR: Aryl hydrocarbon receptor; BMDMs: Mouse bone marrow derived macrophages, BRB: Black raspberries; CAT: Catalase; Cldn4: Claudin 4; COX-2: Cyclooxygenase 2; CXCL1: Chemokine (C-X-C motif) ligand 1; CYP: Cytochrome; EGF: Epidermal growth factor; HCT: Haematocrit; IGF: Insulin-like growth factor; IL: Interleukin; iNOS: Inducible nitric oxide synthase; LPS: Lipopolysaccharide; M-CSF: Macrophage colony-stimulating factor; MPO: Myeloperoxidase; ns: non significant change; NO: Nitric oxide; Nrf2: Nuclear factor erythroid 2-related factor 2 ; NQO1: NAD(P)H dehydrogenase [quinone] 1; Ocln: Occludin; siAhR: AhR knockdown by siRNA Caco-2 cells; siControl: Caco-2 cells transfected with siControl; PAI-1: Plasminogen activator inhibitor-1; PDGF: Platelet-derived growth factor; PGE2: Prostaglandin E2; PTGES: Prostaglandin E synthase; PGF: Placental growth factor; PTGS2: Prostaglandin-endoperoxide synthase; RBCs: Red blood cells; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin (agonist of AhR); TMF: 6,2',4'-trimethoxyflavone (AhR antagonist); TNBS: 2,4,6-Trinitrobenzenesulfonic acid; TNF-α: Tumor necrosis factor α; WT: Wild type; VEGF: Vascular endothelial growth factor; ZO-1: Zonula occludens-1.