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Mapping human microbiome drug metabolism by gut bacteria and their genes
Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing evidence implicates the gut microbiome in this variability, the molecular mechanisms involved remain largely unknown. Here we show, by measuring the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs, that many drugs are chemically modified by microorganisms. We combined high-throughput genetic analyses with mass spectrometry to systematically identify microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents. These causal links between the gene content and metabolic activities of the microbiota connect interpersonal variability in microbiomes to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.
High-throughput genetic analyses combined with mass spectrometry reveal that the gene products of diverse human gut bacteria affect a wide range of oral drugs, as well as drug metabolism in mice.
Journal Article
Separating host and microbiome contributions to drug pharmacokinetics and toxicity
Anything humans swallow is exposed to the foraging and transforming activities of the gut microbiota. This applies to therapeutic drugs as well as food components and can be a major source of interpersonal variation in drug efficacy and toxicity. Zimmermann et al. found that individual drug responses depend on the genetics of an individual's microbiota. They explored the metabolism of nucleoside drugs (which are used as antivirals and antidepressants) in mice inoculated with a variety of mutant microbiota. They then modeled the pharmacokinetics in different body compartments and identified the host and microbe contributions. In some individuals, up to 70% of drug transformation can be ascribed to microbial metabolism. Science , this issue p. eaat9931 Genetic manipulation of drug metabolism in human gut commensal bacteria resolves host and microbiome contributions. The gut microbiota is implicated in the metabolism of many medical drugs, with consequences for interpersonal variation in drug efficacy and toxicity. However, quantifying microbial contributions to drug metabolism is challenging, particularly in cases where host and microbiome perform the same metabolic transformation. We combined gut commensal genetics with gnotobiotics to measure brivudine drug metabolism across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by these measurements, we built a pharmacokinetic model that quantitatively predicts microbiome contributions to systemic drug and metabolite exposure, as a function of bioavailability, host and microbial drug-metabolizing activity, drug and metabolite absorption, and intestinal transit kinetics. Clonazepam studies illustrate how this approach disentangles microbiome contributions to metabolism of drugs subject to multiple metabolic routes and transformations.
Journal Article
B vitamin acquisition by gut commensal bacteria
About the Authors: Emily E. Putnam Affiliation: Department of Microbial Pathogenesis and Microbial Sciences Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America ORCID logo http://orcid.org/0000-0002-3428-094X Andrew L. Goodman * E-mail: andrew.goodman@yale.edu Affiliation: Department of Microbial Pathogenesis and Microbial Sciences Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America ORCID logo http://orcid.org/0000-0001-7599-3471 Citation: Putnam EE, Goodman AL (2020) B vitamin acquisition by gut commensal bacteria. Given the wide range of strategies that bacteria encode for synthesis and transport of thiamine and the recent discovery of OMthi as a novel outer-membrane transporter of thiamine in a gut commensal, it is clear there is still much to learn about acquisition of this essential nutrient by microbes in the gut environment. Since vitamin B12 is a minority of the total cobamides present in the gut, variations of the transport machinery might be involved in acquisition of different types of cobamides or precursors [13, 14]. Because humans absorb vitamin B12 predominantly in the small intestine and B. thetaiotaomicron and other gut commensals are found predominantly in the large intestine, vitamin B12 piracy from intrinsic factor by microbes is unlikely to impact vitamin B12 availability for the host in most cases.
Journal Article
Public Insurance and Mortality
This paper provides new evidence that Medicaid’s introduction reduced infant and child mortality in the 1960s and 1970s. Mandated coverage of all cash welfare recipients induced substantial cross-state variation in the share of children immediately eligible for the program. Before Medicaid, higher- and lower-eligibility states had similar infant and child mortality trends. After Medicaid, public insurance utilization increased and mortality fellmore rapidly among children and infants in high-Medicaid-eligibility states. Mortality among nonwhite children on Medicaid fell by 20 percent, leading to a reduction in aggregate nonwhite child mortality rates of 11 percent.
Journal Article
Sphingolipids produced by gut bacteria enter host metabolic pathways impacting ceramide levels
Gut microbes are linked to host metabolism, but specific mechanisms remain to be uncovered. Ceramides, a type of sphingolipid (SL), have been implicated in the development of a range of metabolic disorders from insulin resistance (IR) to hepatic steatosis. SLs are obtained from the diet and generated by de novo synthesis in mammalian tissues. Another potential, but unexplored, source of mammalian SLs is production by Bacteroidetes, the dominant phylum of the gut microbiome. Genomes of
Bacteroides
spp. and their relatives encode serine palmitoyltransfease (SPT), allowing them to produce SLs. Here, we explore the contribution of SL-production by gut
Bacteroides
to host SL homeostasis. In human cell culture, bacterial SLs are processed by host SL-metabolic pathways. In mouse models,
Bacteroides
-derived lipids transfer to host epithelial tissue and the hepatic portal vein. Administration of
B. thetaiotaomicron
to mice, but not an SPT-deficient strain, reduces de novo SL production and increases liver ceramides. These results indicate that gut-derived bacterial SLs affect host lipid metabolism.
Ceramides are a type of sphingolipid (SL) that have been shown to play a role in several metabolic disorders. Here, the authors investigate the effect of SL-production by gut
Bacteroides
on host SL homeostasis and show that microbiome-derived SLs enter host circulation and alter ceramide production.
Journal Article
The Long-Term Stability of the Human Gut Microbiota
We know little about the stability of the constituent microbiota in the human gut or the extent to which the gut microbiota are a potential target for long-term health interventions. Faith et al. (p. 10.1126/science.1237439 ) analyzed the fecal microbiota of 37 individuals and found that, on average, 60% of bacterial strains remained stable for up to 5 years and many were estimated to remain stable for decades. Low-error sequencing data suggest that initial microbial colonizers of infant guts could persist over the life span of an individual. A low-error 16 S ribosomal RNA amplicon sequencing method, in combination with whole-genome sequencing of >500 cultured isolates, was used to characterize bacterial strain composition in the fecal microbiota of 37 U.S. adults sampled for up to 5 years. Microbiota stability followed a power-law function, which when extrapolated suggests that most strains in an individual are residents for decades. Shared strains were recovered from family members but not from unrelated individuals. Sampling of individuals who consumed a monotonous liquid diet for up to 32 weeks indicated that changes in strain composition were better predicted by changes in weight than by differences in sampling interval. This combination of stability and responsiveness to physiologic change confirms the potential of the gut microbiota as a diagnostic tool and therapeutic target.
Journal Article
Metabolic and fitness determinants for in vitro growth and intestinal colonization of the bacterial pathogen Campylobacter jejuni
Campylobacter jejuni is one of the leading infectious causes of food-borne illness around the world. Its ability to persistently colonize the intestinal tract of a broad range of hosts, including food-producing animals, is central to its epidemiology since most infections are due to the consumption of contaminated food products. Using a highly saturated transposon insertion library combined with next-generation sequencing and a mouse model of infection, we have carried out a comprehensive genome-wide analysis of the fitness determinants for growth in vitro and in vivo of a highly pathogenic strain of C. jejuni. A comparison of the C. jejuni requirements to colonize the mouse intestine with those necessary to grow in different culture media in vitro, combined with isotopologue profiling and metabolic flow analysis, allowed us to identify its metabolic requirements to establish infection, including the ability to acquire certain nutrients, metabolize specific substrates, or maintain intracellular ion homeostasis. This comprehensive analysis has identified metabolic pathways that could provide the basis for the development of novel strategies to prevent C. jejuni colonization of food-producing animals or to treat human infections.
Journal Article
Human nutrition, the gut microbiome and the immune system
Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.
Journal Article
A decade of advances in transposon-insertion sequencing
It has been 10 years since the introduction of modern transposon-insertion sequencing (TIS) methods, which combine genome-wide transposon mutagenesis with high-throughput sequencing to estimate the fitness contribution or essentiality of each genetic component in a bacterial genome. Four TIS variations were published in 2009: transposon sequencing (Tn-Seq), transposon-directed insertion site sequencing (TraDIS), insertion sequencing (INSeq) and high-throughput insertion tracking by deep sequencing (HITS). TIS has since become an important tool for molecular microbiologists, being one of the few genome-wide techniques that directly links phenotype to genotype and ultimately can assign gene function. In this Review, we discuss the recent applications of TIS to answer overarching biological questions. We explore emerging and multidisciplinary methods that build on TIS, with an eye towards future applications.In this Review, several experts discuss progress in the decade since the development of transposon-based approaches for bacterial genetic screens. They describe how advances in both experimental technologies and analytical strategies are resulting in insights into diverse biological processes.
Journal Article