Future prospects for dissecting inter-individual variability in the absorption, distribution and elimination of plant bioactives of relevance for cardiometabolic endpoints

Review article, 2019

Key messages Human intervention studies are typically too small and do not report data from individuals to allow investigations of relevant determinants of inter-individual variability in ADME and bioefficacy. For some plant food bioactive compounds (isoflavones and ellagitannins), particular metabolites are produced only in a subset of the population, i.e., among individuals with a specific metabotype. Microbiota is an important determinant of the ADME of many bioactive compounds but microbial gene annotation is often lacking and interference with background diet and temporal variability is high: microbial metabolism capacity is, therefore, difficult to predict. Genetic variability is considered an important determinant of the ADME of some bioactive compounds, but there is a large gap in knowledge for many families of plant bioactive compounds regarding biotransformation enzymes and transport proteins. Information on other determinants such as age, sex, and diet is too incomplete to make firm conclusions about their impact on the inter-individual variability for most compounds investigated Metabotyping individuals appears as essential to increase our understanding and improve prediction of ADME and health effects of plant bioactive compounds. Yet successful stratification examples are scarce and if available (e.g., urolithins), validation studies in larger cohorts are still required. Purpose The health-promoting potential of food-derived plant bioactive compounds is evident but not always consistent across studies. Large inter-individual variability may originate from differences in digestion, absorption, distribution, metabolism and excretion (ADME). ADME can be modulated by age, sex, dietary habits, microbiome composition, genetic variation, drug exposure and many other factors. Within the recent COST Action POSITIVe, large-scale literature surveys were undertaken to identify the reasons and extent of inter-individual variability in ADME of selected plant bioactive compounds of importance to cardiometabolic health. The aim of the present review is to summarize the findings and suggest a framework for future studies designed to investigate the etiology of inter-individual variability in plant bioactive ADME and bioefficacy.
Results Few studies have reported individual data on the ADME of bioactive compounds and on determinants such as age, diet, lifestyle, health status and medication, thereby limiting a mechanistic understanding of the main drivers of variation in ADME processes observed across individuals. Metabolomics represent crucial techniques to decipher inter-individual variability and to stratify individuals according to metabotypes reflecting the intrinsic capacity to absorb and metabolize bioactive compounds.
Conclusion A methodological framework was developed to decipher how the contribution from genetic variants or microbiome variants to ADME of bioactive compounds can be predicted. Future study design should include (1) a larger number of study participants, (2) individual and full profiling of all possible determinants of internal exposure, (3) the presentation of individual ADME data and (4) incorporation of omics platforms, such as genomics, microbiomics and metabolomics in ADME and efficacy studies.