Pharmacomicrobiomics

Pharmacomicrobiomics, proposed by Prof. Marco Candela for the ERC-2009-StG project call (proposal n. 242860, titled "PharmacoMICROBIOMICS, study of the microbiome determinants of the different drug responses between individuals"), and publicly coined for the first time in 2010 by Rizkallah et al. (from Ramy K. Aziz research group), is defined as the effect of microbiome variations on drug disposition, action, and toxicity. Pharmacomicrobiomics is concerned with the interaction between xenobiotics, or foreign compounds, and the gut microbiome. It is estimated that over 100 trillion prokaryotes representing more than 1000 species reside in the gut. Within the gut, microbes help modulate developmental, immunological and nutrition host functions. The aggregate genome of microbes extends the metabolic capabilities of humans, allowing them to capture nutrients from diverse sources. Namely, through the secretion of enzymes that assist in the metabolism of chemicals foreign to the body, modification of liver and intestinal enzymes, and modulation of the expression of human metabolic genes, microbes can significantly impact the ingestion of xenobiotics. Efforts to understand the interaction between specific xenobiotics and the microbiome have traditionally involved the use of in vivo as well as in vitro models. Recently, next generation sequencing of genomic DNA obtained from a community of microbes has been used to identify organisms within microbial communities, allowing for accurate profiles of the composition of microbes within an environment. Initiatives such as the Human Microbiome Project (HMP) have aimed to characterize the microbial composition of the oral, gut, vaginal, skin and nasal environments. This and other microbiome characterization projects have accelerated the study of pharmacomicrobiomics. An extensive understanding of the microbiome in the human body can lead to the development of novel therapeutics and personalized drug treatments that are not potentiated or activated by processes carried out by the microbiome.

History In a 1973 paper, Ronald Scheline stated that the gastrointestinal microbiome has the ability to act as an organ with metabolic potential at least equal to the liver. Since then, the importance of the human microbiome in mediating health and disease has been acknowledged, and specific interactions between xenobiotics and microbes have been characterized using in vitro or in vivo methods. However, few studies have taken into account the complete metabolic profile, leading some to say that the microbiome's cumulative role in xenobiotic metabolism and toxicology has largely remained unexplored. It is reported that 84% of the top-selling pharmaceuticals in the US and Europe are administered orally, making it the most common mode of drug administration. The implication of this is that a large proportion of drugs, especially those that are lowly soluble and permeable ones, encounter the microbiome and are subject to reductive and hydrolytic reactions. The view of the human microbiome as an organ is quite common in scientific literature; however, it is more biologically correct to view it as a cloud, since a 'microbiome cloud model' better reflects the uncertainty associated with the dynamic composition of the microbiome. Understanding the microbiome variability is key to understanding and modulating pharmacomicrobiomic interactions. The same patient can respond properly to a drug on a given day, then—as the patient's microbiome dramatically varies after an infection, antimicrobial therapy, or radiation therapy (for example), the drug response can surprisingly be much different. Sequencing technologies such as 16S rRNA shotgun metagenomic sequencing have facilitated the rapid expansion of the pharmacomicrobiomics field by capturing organismal diversity in microbial communities. The Human Microbiome Project and METAgenomics of the Human Intestinal Tract (MetaHIT), established in 2007 and 2008, respectively, aimed to characterize the variation in human microbiomes. These large scale projects are foundational to pharmacomicrobiomic studies, as they allow for the generation of statistic models that can take into account variation in microbial composition across individuals.

History of the term The term 'pharmacomicrobiomics' was first proposed in literature in 2010 and subsequently, in 2011, the domains 'pharmacomicrobiomics.org' and 'pharmacomicrobiomics.com' were released. A team of freshly graduated pharmacy students (Mariam Rizkallah and Rama Saad) built and published the first public database with that name "PharmacoMicrobiomics" (with a capital M for branding). Since then, the term started appearing in PubMed year after year, and crossed the 50 publications landmark 11 years later (PubMed search).

Methods to elucidate microbiome composition

Animal models Interactions between xenobiotics and the host microbiome have primarily been assessed through the use of in vivo animal models, as it is difficult to model the natural human gut. In general, the pattern of bacterial colonization is the same in different animals, with both pH and the number of microorganisms gradually increasing from the small intestine towards the ileo-caecal junction of the large intestine. Germ-free rats colonized with human faecal matter are generally regarded as the gold standard in animal modeling of gut microbial environment. However, enzyme activity can vary greatly between organisms.

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