The impact of the gut microbiota on drug metabolism and clinical outcome

The significance of the gut microbiota as a determinant of drug pharmacokinetics and accordingly therapeutic response is of increasing importance with the advent of modern medicines characterised by low solubility and/or permeability, or modified-release. These physicochemical properties and release kinetics prolong drug residence times within the gastrointestinal tract, wherein biotransformation by commensal microbes can occur. As the evidence base in support of this supplementary metabolic “organ” expands, novel opportunities to engineer the microbiota for clinical benefit have emerged. This review provides an overview of microbe-mediated alteration of drug pharmacokinetics, with particular emphasis on studies demonstrating proof of concept in vivo. Additionally, recent advances in modulating the microbiota to improve clinical response to therapeutics are explored

Gut microbiota-mediated bile acid transformations alter the cellular response to multidrug resistant transporter substrates in vitro: focus on P-glycoprotein

Pharmacokinetic research at the host-microbe interface has been primarily directed toward effects on drug metabolism, with fewer investigations considering the absorption process. We previously demonstrated that the transcriptional expression of genes encoding intestinal transporters involved in lipid translocation are altered in germ-free and conventionalized mice possessing distinct bile acid signatures. It was consequently hypothesized that microbial bile acid metabolism, which is the deconjugation and dehydroxylation of the bile acid steroid nucleus by gut bacteria, may impact upon drug transporter expression and/or activity and potentially alter drug disposition. Using a panel of three human intestinal cell lines (Caco-2, T84, and HT-29) that differ in basal transporter expression level, bile acid conjugation-, and hydroxylation-status was shown to influence the transcription of genes encoding several major influx and efflux transporter proteins. We further investigated if these effects on transporter mRNA would translate to altered drug disposition and activity. The results demonstrated that the conjugation and hydroxylation status of the bile acid steroid nucleus can influence the cellular response to multidrug resistance (MDR) substrates, a finding that did not directly correlate with directionality of gene or protein expression. In particular, we noted that the cytotoxicity of cyclosporine A was significantly augmented in the presence of the unconjugated bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) in P-gp positive cell lines, as compared to their taurine/glycine-conjugated counterparts, implicating P-gp in the molecular response. Overall this work identifies a novel mechanism by which gut microbial metabolites may influence drug accumulation and suggests a potential role for the microbial bile acid-deconjugating enzyme bile salt hydrolase (BSH) in ameliorating multidrug resistance through the generation of bile acid species with the capacity to access and inhibit P-gp ATPase. The physicochemical property of nonionization is suggested to underpin the preferential ability of unconjugated bile acids to attenuate the efflux of P-gp substrates and to sensitize tumorigenic cells to cytotoxic therapeutics in vitro. This work provides new impetus to investigate whether perturbation of the gut microbiota, and thereby the bile acid component of the intestinal metabolome, could alter drug pharmacokinetics in vivo. These findings may additionally contribute to the development of less toxic P-gp modulators, which could overcome MDR

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Gut microbiota-mediated bile acid metabolism: implications for oral drug absorption

In recent years, it has been elucidated that, in addition to host genetics, the gut microbiome must be considered as a source of pharmacokinetic variability. As newly emerging drug candidates trend toward low solubility and/or permeability, biopharmaceutical properties that prolong gastrointestinal residence time, and thereby microbial contact, identifying and manipulating the microbial processes influencing drug disposition will have fruitful consequences for personalized healthcare. To date, pharmacokinetic research at the host-microbe interface has been primarily focussed on effects on drug metabolism, with minimal consideration to the absorption process (as reviewed in Chapter I). Thus, this thesis investigates a potential mechanism, ‘microbial bile acid metabolism’, by which the intricate interplay between the host and gut bacteria may affect the pre-absorption behaviour and uptake of orally administered drugs. Bile salts have long been appreciated within the pharmaceutical field to be efficient solubilizers of lipophilic drugs. It is also now known that bile salts are important signalling molecules, with the potential to regulate xenobiotic-processing genes via bile acid-activated receptors (BARs). As the size and composition of the bile acid pool is regulated by gut bacterial bile acid metabolism, we propose that inter-individual differences in drug response may be partly attributed to variations in this specific microbial function. In the intestine, host synthesized tauro- or glyco-conjugated bile acids are sequentially deconjugated and 7α-dehydroxylated by microbial enzymes. These biotransformative reactions augment the diversity and alter the physicochemical properties of the bile acid pool. Herein, the effect of bile acid deconjugation and dehydroxylation on bile salt micelle solubilization capacity (Chapter II and III), supersaturated formulation stability (Chapter IV), drug-processing gene expression (Chapter V and VI), as well as passive and active transport mechanisms (Chapter III and V) was investigated. Bile acid conjugation and, in particular, hydroxylation state were determined to significantly influence the phase behaviour of poorly water-soluble drugs (PWSDs). Firstly, dihydroxy bile salt micelles were shown to possess a greater solubilization capacity for PWSDs than trihydroxy counterparts. Dihydroxy bile acids were also observed to be more efficient crystallization inhibitors, and thereby significantly improved the stability of supersaturated solutions of atazanavir, a weakly basic PWSD, relative to trihydroxy species. In addition, the crystallization onset of atazanavir in media designed to mimic a range of representative healthy subject intestinal fluids exhibited a bile salt concentration-dependence, further indicating that gut microbial activity may influence crystallization kinetics in vivo by regulating bile acid pool size. Collectively, these findings suggest that: (1) microbial bile acid metabolism may impact intraluminal drug behaviour, and (2) that close attention should be paid to the concentration and composition of bile salts used in simulated intestinal media when assessing both crystalline and supersaturating formulations to improve in vitro-in vivo predictiveness. This thesis has also illustrated that bile salt conjugation and hydroxylation state can influence the transcription of genes encoding proteins involved in drug disposition. Furthermore, this work identified a novel mechanism by which unconjugated dihydroxy bile acids can affect drug uptake through inhibition of P-glycoprotein ATPase activity. Overall, our research sheds new light on the multitude of mechanisms by which microbial bile acid metabolism may influence the drug absorption process. This effect might be most significant in disease states where gut microbiota alterations are exaggerated

Genomic epidemiology of SARS-CoV-2 in a university outbreak setting and implications for public health planning

AbstractWhole genome sequencing of SARS-CoV-2 has occurred at an unprecedented scale, and can be exploited for characterising outbreak risks at the fine-scale needed to inform control strategies. One setting at continued risk of COVID-19 outbreaks are higher education institutions, associated with student movements at the start of term, close living conditions within residential halls, and high social contact rates. Here we analysed SARS-CoV-2 whole genome sequences in combination with epidemiological data to investigate a large cluster of student cases associated with University of Glasgow accommodation in autumn 2020, Scotland. We identified 519 student cases of SARS-CoV-2 infection associated with this large cluster through contact tracing data, with 30% sequencing coverage for further analysis. We estimated at least 11 independent introductions of SARS-CoV-2 into the student population, with four comprising the majority of detected cases and consistent with separate outbreaks. These four outbreaks were curtailed within a week following implementation of control measures. The impact of student infections on the local community was short-term despite an underlying increase in community infections. Our study highlights the need for context-specific information in the formation of public health policy for higher educational settings.</jats:p