Flavonoids are biologically-active polyphenolic compounds with antioxidative, antineoplasic, cardiovascular protective and anti-inflammatory properties. Pharmacological therapy is essential in inflammatory bowel disease but has many adverse effects and does not cure the disease. Flavonoids are excellent candidates because of their anti-inflammatory properties and their low toxicity. Several flavonoids have been shown to exert intestinal anti-inflammatory activity in vivo, including (mg/kg) quercitrin 1–5(Reference Sanchez de Medina, Galvez, Romero and Zarzuelo1), rutin 10–25(Reference Galvez, Cruz and Crespo2), morin 25(Reference Galvez, Coelho and Crespo3, Reference Ocete, Galvez and Crespo4), hesperidin and diosmin 10–25(Reference Crespo, Galvez, Cruz, Ocete and Zarzuelo5). However, the mechanism of action is unclear. Since inflammation is associated by significant oxidative stress, this mechanism may be relevant. Indeed, flavonoid treatment counters colitis-induced glutathione depletion. On the other hand, quercitrin treatment reduces macrophage infiltration in the dextran sulfate sodium colitis model(Reference Camuesco, Comalada and Rodriguez-Cabezas6). The effects of flavonoids on primary macrophages have been studied and their structure–activity relationship characterized(Reference Comalada, Ballester and Bailon7). A number of flavonoids inhibit macrophage proliferation (but not cell viability) and some additionally reduce TNF and inducible NO synthase (iNOS) expression, probably interfering with the NF-κB pathway. The structural determinants of activity include the C-2=C-3 double bond, the catechol group in the B ring and the 2-position of the B ring.
Most of these flavonoids are glycosides, which are known to be hydrolysed by bacterial enzymes in the gut. Since luteolin and quercetin are not active in vivo and aglycone flavonoids are absorbed in the small intestine it is likely that glycosides act as prodrugs, releasing the biologically-active aglycone in the lumen and preventing their premature absorption, which has been proven in the case of quercitrin(Reference Comalada, Camuesco and Sierra8). In particular, a faecal homogenate was shown to mediate quercetin release from quercitrin in vitro, and the resulting aglycone retained TNF, iNOS and IL-1β inhibitory activity in murine bone marrow-derived macrophages. This principle probably applies to the other heterosides with known intestinal anti-inflammatory activity.
In conclusion, flavonoids have intestinal anti-inflammatory activity that is associated with macrophage inhibition and antioxidative effects. Further investigation of the mechanistic aspects of flavonoid pharmacological action is underway.
