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. Sequencing technologies such asMethods 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.''In vitro'' models
Microbes found in human fecal samples are fairly representative of the gut microbiome, and are used frequently in ''in vitro'' cultures. A variety of ''in vitro'' microbial modelling techniques have also been developed. Static batch culturing consists of plating bacteria without replenishing the media at regular intervals. Semi-continuous culture systems allow for the addition of medium without disrupting bacterial growth, and include pH control capabilities. The continuous culture system more closely resembles that of the gut, as it continuously replenishes and removes culture medium. The simulator of the human intestinal microbial system (SHIME) models the small and large intestine through the use of a five-stage reactor, and includes numerous ports for continuous monitoring of pH and volume. Most recently, researchers improved on SHIME by including a computer controlled peristaltic wave to circulate chyme throughout the apparatus. These technologies have given researchers close control over the culturing environment, facilitating the discovery of interactions between xenobiotics and microbes.Next generation sequencing
16S rRNA Sequencing
Shotgun sequencing
Advances in high-throughput sequencing has facilitated shotgun metagenome sequencing (SMS), a technology that provides a broader characterization of microbial samples by sequencing a larger number of genes in each organism. SMS involves collecting microbial samples from the environment, isolating DNA, shearing the DNA into small fragments, and then performing whole genome sequencing (WGS). Reads can be assembled de novo or using reference genomes. However, SMS is not without limitations. Reads may overlap and prevent accurate alignment to reference genomes. In addition, reads may be contaminated by human DNA sequence, confounding results. In reference-based assembly, reads may also be biased towards species which have publicly available reference genomes.Composition of the microbiome
Individual Microbiomes
Gut
Within the intestines, the majority of microbes can be found in the large intestine, where the pH is higher and more conducive to survival. These bacteria are often more efficient than our own digestive enzymes, and function to digest protein and carbohydrates. The results of over 690 human microbiomes have shown that the majority of bacteria of the gut microbiome belongs to four phyla: Bacillota, Bacteroidota, Actinomycetota, and Pseudomonadota.Vagina
The vagina possesses over 200 phylotypes, the most predominant belonging to the phylaPlacenta
The first profile of microbes in healthy term pregnancies identified non-pathogenic commensal microbiota from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla.Oral cavity
Through the HMP, nine intraoral sites were in investigated, and found to be enriched in over 300 genera belonging to more than 20 bacterial phyla.Human Microbiome Project
TheKnown Drug Interactions
Microbiota-mediated interference in xenobiotic activity
The microbiome can significantly affect the potency of a pharmaceutical drug. Even though most drugs are absorbed in the upper part of the large intestine, long-acting drugs that are exposed to the microbe-rich area of the lower intestine can be affected by microbial metabolism. For instance, chloramphenicol may cause bone marrow aplasia following oral administration, due to the presence of coliforms that convert chloramphenicol to its toxic form, known as p-aminophenyl-2-amin-1,2-propanediol. In addition, altered abundances of Eggerthella lenta between populations have been found to affect the metabolism of digoxin, potentiating both its activity and toxicity. A non-exhaustive list of drugs and the microbiota’s role in potentiating/increasing their effect is provided below.Xenobiotic mediated interference in microbiome composition
Even though pharmacomicrobiomics is often interpreted as the impact the microbiome has on xenobiotic metabolism, the term can also encompass the effects of xenobiotics on the microbiome and microbial genes. The impact of antibiotics on the human microbiome has been well studied. It has been shown that antibiotic therapies not only target a specific pathogen, but also the commensal inhabitants of a host. Evidence suggests that commensal bacteria levels in some cases are not normalized after antibiotic treatment, and in fact may be negatively affected for extended periods of time. A study which assessed the oral and gut microbes before, immediately after, and up to 12 months after exposure to antibiotics, found that the microbiome can be altered for over 12 months. Since the microbiome composition can be altered by antibiotics, this implies positive selection for resistant opportunistic pathogens, which can cause acute disease.The PharmacoMicrobiomics Web Portal
The PharmacoMicrobiomics Web Portal is a student-led initiative to explore how microbes modulate drugs that is intended for bioinformaticians, microbial geneticists, and drug developers. The goal of the project is to mine literature data and extract microbe-drug interactions, including information about drug classes, microbial families, and body systems. Furthermore, the portal includes a relational database with information on microbial composition at different body sites and their specific effects on drug pharmacokinetics and pharmacodynamic properties.Personalized Medicine
Personalized medicine in the context of pharmacomicrobiomics refers to the ability to predict an individual’s response to a xenobiotic based on the composition of their gut microbiome. However, current omics approaches investigating microbiome composition using metagenomic sequencing after xenobiotic treatment are sparse. Instead, research efforts have focused predominantly on modeling changes in microbial composition in different disease states. Future research efforts should combine knowledge relating to what microbes preferentially metabolize certain compounds (garnered from ''in vitro'' studies) with the identification of species abundance to predict drug tolerance in patients. However, modeling a microbe’s interaction with a particular xenobiotic may not stably predict interactions, as the genomes of microbes are continually reshuffled throughLimitations
The limitations of pharmacomicrobiomics primarily arise from the uncertainty associated with metagenomic profiling. Namely, short reads obtained by shotgun sequencing can be difficult to align to reference genomes since many organism have homologous sequences. In addition, 16S rRNA sequencing cannot consistently resolve species identity, a finding that casts doubt on species identities in metagenomic samples. Limitations also arise from differing study designs, as unique approaches to identifying the nature of the xenobiotic-microbiome interactions are often taken. For instance, because pharmacomicrobiomics very broadly denotes the association between xenobiotics and the microbiome, the extent to which studies profile the genetics of the microbiome can vary significantly. Studies aiming to characterize organism identity, but not gene identity or copy number may elect to use 16S shotgun sequencing as opposed to SMS. Conversely, studies aiming to identify genes and their products rather than organism identity may elect WMGS coupled with transcriptomic analysis. Initially, these differences may mean that researchers wanting to investigate publicly available data may have to target their research questions to fit the data at hand.References
{{pharmacology, state=collapsed Omics Gut flora