This Research Topic is part of a series: Therapeutic Index for Nutraceuticals in Inflammation-Related Diseases: Efficacy, Bioavailability, Metabolism and Interactions with Drugs

Many studies suggest that some plant-derived phytochemicals from food or medicinal herbs could be therapeutically effective agents in the prevention and/or management of cancer and noncommunicable diseases associated with dysbiosis, oxidative stress, and chronic low-grade inflammation. Although the definition of nutraceutical develops as the hybrid of ‘nutrient’ and ‘pharmaceutical’, the term of “phytonutrients” for food phytochemicals can increase the attitude to use nutraceuticals and herbal remedies (included in some supplements), due to the conviction that they are safe and natural. Contrarily to vitamins, there are no symptoms of deficiency for natural occurring bioactive compounds and our body would treat them like any other xenobiotics. These xenobiotics can affect the intestinal microbiota composition and modulate the transcription of genes that are involved in drug metabolism/transport and in inflammatory, immune and redox status. It is well known that inflammation and oxidative stress regulate the expression of drug transporters and drug metabolizing enzymes, as well as interactions that occur in the gut between xenobiotics, microbiota and host immunity. Hydrolysis of natural glycosides by gut bacteria, with further metabolism of released aglycones by the host, could partly account of the phenotypic heterogeneity in metabolism. This interindividual variability can be explained by both genetically determined polymorphisms of xenobiotic-metabolizing enzymes, transport proteins and by microbiota diversity.

Case reports of food-drug and nutraceutical-drug interactions suggest that metabolomics of food-bioactive phytochemicals, in association with dietary intake assessment, could have great potential for predictive drug efficacy or toxicity in advance, giving further insights on the host/gut microbiota co-metabolism.

On the other hand, overlaps in molecular targets have been reported between drugs and naturally occurring bioactive phytochemicals. However, more studies are needed in order to establish the efficacy and pharmacological targets of both phytochemicals and their metabolites. Moreover, both on-target toxicity (exaggerated pharmacological effects) and off-target toxicity, often occurring in tissues (i.e. liver) other than those targeted to achieve drug efficacy, could occur after high intake of nutraceuticals, in particular when the consumption is associated to drug treatment. Therefore, a therapeutic index (the quantitative relationship between the efficacy and safety) and upper levels of dietary intake should be determined for natural occurring phytochemicals when used as complementary (potential food-drug interactions) or alternative (efficacy versus conventional drugs) medicines.

Thus, the aim of this Frontiers Research Topic is to collect preclinical (in vitro and in vivo) and human studies to evaluate therapeutic index for natural occurring phytochemicals based on their molecular targets, metabolism, pharmacokinetic and potential interactions with drugs on the light of the interindividual variations (redox, inflammatory, immune and healthy/disease status, genetic polymorphisms, microbiota diversity).

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