The effect of citrus fruits in human health has been an active field of research particularly during the lasttwenty years. This activity has been associated with benefits for cardiovascular and bone health, and withthe decrease of cancer risk. Many of these studies have used in vitro models that do not reflect the complexsituation in vivo. Clinical studies, however, have shown large inter-individual variability, leading to nonsignificanteffects in many cases. The recent advances in the knowledge of citrus bioactives metabolism andbioavailability, and in human nutrigenetics, and gut microbiome open great expectations to understand theeffects of citrus phytochemicals on health. In this workshop the research strategies, trends and perspectives,to support the role of citrus fruits in human health will be discussed. Are the in vitro studies valid to demonstrate citrus health effects? Many mechanistic studies use human cell cultures to evaluate the biological effect of citrus extracts, orisolated bioactives from citrus, and these studies are often extrapolated to the potential effects in vivo. Mostof these studies, however, have some mayor flaws, although they can be published in very good scientificjournals, although they usually do not correlate with the effects observed in vivo. The main problems foundare associated with the dose, the chemical nature of the citrus bioactive tested and the human tissue usedin the assay. The dose used is often much higher than the amounts found in vivo, and these high doses arenecessary to see a relevant effect. The long term approach, using low metabolite concentration or mixturesof them, which is the situation found in vivo, is difficult to evaluate with the classical models. The type ofmetabolite used in the assays is often that found in the food products, although these compounds aremetabolized but the gut microbiota and the human Phase II enzymes to produce metabolites that differfrom those found in citrus fruits.

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