Insights on the human microbiome and its xenobiotic metabolism: what is known about its effects on human physiology?

Abstract

The influence of our microbiota reaches from primary metabolites to secondary effects such as substrate competition or the activation of eukaryotic Phase I and Phase II enzymes. Further on it plays a hitherto underestimated role in drug metabolism, toxicity and pathogenesis. These effects are partly caused by entero-endocrine crosstalk and interference with eukaryotic regulatory networks. On first sight, the resulting concept of a metabolically competent microbiome adds enormous complexity to human physiology. Yet, the potential specificity of microbial targets harbours therapeutic promise for diseases such as diabetes, cancer and psychiatric disorders. A better physiological and biochemical understanding of the microbiome is thus of high priority for academia and biomedical research.

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…In carrier-mediated events the drug molecule represents a substrate for (a) specific transporter(s) which localize(s) within the biological membrane (Kapitza et al, 2007). Carrier-driven translocation of transand behavior (Arpaia et al, 2013;Foster and McVey Neufeld, 2013;Hsiao et al, 2013;Possemiers et al, 2009;Tralau et al, 2014). Yet, the microbial side of xenobiotic skin metabolism has so far not been addressed, and none of the aforementioned systems is fit to include the metabolic competence of the microbiome.…”

The human microbiome, from Achilles armour to Nessus’ shirt

“…Genomics and transcriptomics allow access to microbial communities and their transcriptomic profiles, while highresolution mass spectrometry and metabolomics can provide insight into the underlying biochemistry and metabolic processes. At the same time a variety of model systems and culturing techniques are available for the analysis of selected communities or isolated members, and soon probably also co-culture systems (Donia and Fischbach 2015;Spanogiannopoulos et al 2016;Tralau et al 2015). Challenging as it still might be analysis of microbiome's toxicology has thus become feasible.…”

“…Given the sheer size of this commensalic cell pool and the mostly symbiotic impact on its host the microbiome is thus often considered an "organ." However, the growth dynamics and flexibility of microbial communities together with gene transfer rates 25-fold in excess of what is typically observed in soil communities equip this organ with a versatility and adaptability far beyond other organs (Smillie et al 2011;Tralau et al 2015). What is more, unlike eukaryotic organs the microbiome is not primarily subjected to the pressure of host well-being but strives for nutritional gain.…”

“…Unsurprisingly, a lot of the microbiome's xenobiotic capability serves the primary purpose of gaining carbon, sulphur and micronutrients, respectively (i.e. Sowada et al 2014;Tralau et al 2015).…”

“…Similarly to eukaryotic phase I and phase II metabolism prokaryotic interference with drugs can lead to substance inactivation, activation or toxicity. At least 37 established drugs are known targets of microbial metabolism as are up to 37% of drug candidates (Sousa et al 2008;Tralau et al 2015). However, although some prodrugs exploit canonical microbial transformations for their activation targeted screening for microbial metabolism and microbiome-mediated effects are not part of routine testing but depend on structural alerts (i.e.…”