Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota

Devlin, A. Sloan; Marcobal, Ángela; Dodd, Dylan; Nayfach, Stephen; Plummer, Natalie S.; Meyer, Tim; Pollard, Katherine S.; Sonnenburg, Justin L.; Fischbach, Michael A.

doi:10.1016/j.chom.2016.10.021

Cited by 215 publications

(156 citation statements)

References 42 publications

(45 reference statements)

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“…Whereas data presented here show protective effects of E. coli K12 versus K12ΔtnaA, recent data suggest that other intestinal eubacteria, including many Bacteroides and Lactobacillus species, likewise use TnaA to produce protective indole derivatives, including ICA and indole-3-carbinol (I3C)) (16,(48)(49)(50). Responsiveness to particular indoles may differ and be tuned to the precise complement of indoles produced by the microbiota.…”

Section: Discussioncontrasting

confidence: 55%

Indoles from commensal bacteria extend healthspan

Sonowal

Swimm

Sahoo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

139

154

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Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan. We show that indoles from commensal microbiota extend healthspan of diverse organisms, including Caenorhabditis elegans, Drosophila melanogaster, and mice, but have a negligible effect on maximal lifespan. Effects of indoles on healthspan in worms and flies depend upon the aryl hydrocarbon receptor (AHR), a conserved detector of xenobiotic small molecules. In C. elegans, indole induces a gene expression profile in aged animals reminiscent of that seen in the young, but which is distinct from that associated with normal aging. Moreover, in older animals, indole induces genes associated with oogenesis and, accordingly, extends fecundity and reproductive span. Together, these data suggest that small molecules related to indole and derived from commensal microbiota act in diverse phyla via conserved molecular pathways to promote healthy aging. These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans.C. elegans | aging | frailty | aryl hydrocarbon receptor | microbiota R ecent advances in health care have contributed to a significant increase in life expectancy of individuals, especially in developed countries, which predict an expansion of geriatric populations by as much as 350-fold over the next 40 y (1). However, extension of lifespan is often accompanied by increased frailty, and attendant increases in global healthcare expenditures are expected to be both massive and unsustainable (2). Such data highlight the need to develop means to extend healthspan, which is broadly defined as the length of time that an individual remains healthy and free of age-related infirmities (3, 4).Healthspan has often been convolved with lifespan, and extended healthspan has been associated with slowed onset of normal age-related changes (e.g., sarcopenia). Thus, mutations that extend lifespan might be expected to likewise extend healthspan. Recent studies in Caenorhabditis elegans indicate that, relative to wild-type animals, mutations that extend lifespan do indeed extend the period of youthfulness, in which animals are motile and resistant to bacterial infection (healthspan), but also extend the period of decrepitude or frailty, where animals are relatively immobile (5, 6) Other studies in C. elegans that take into account multiple measures of health, each normalized to maximal lifespan, indicate that mutations or conditions that extend lifespan minimally impact or ev...

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Section: Discussioncontrasting

confidence: 55%

Indoles from commensal bacteria extend healthspan

Sonowal

Swimm

Sahoo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

139

154

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“…In a recent study, a widely distributed family of tryptophanases in the gut commensal Bacteroides was identified as a primary and rate limiting source of indoxyl sulfate in human gut bacteria; moreover, modulating the content of the gut microbes harboring the tryptophanases was shown to substantially impact indoxyl sulfate levels in vivo. 138 In clinical studies, levels of this and other uremic toxins have been shown to be associated with angiographic coronary atherosclerosis severity. 139 Collectively, there is significant evidence suggesting the gut could be a target of treatment of CKD in conjunction with efforts to improve dialysis techniques to better remove microbially generated uremic toxins.…”

Section: Pathogenic Mechanism Of Gut Microbiota and Metabolites In Camentioning

confidence: 99%

Gut Microbiota in Cardiovascular Health and Disease

Tang

Kitai

Hazen

2017

Circulation Research

1,139

908

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Significant interest in recent years has focused on gut microbiota-host interaction because accumulating evidence has revealed that intestinal microbiota play an important role in human health and disease, including cardiovascular diseases. Changes in the composition of gut microbiota associated with disease, referred to as dysbiosis, have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity and type 2 diabetes mellitus. In addition to alterations in gut microbiota composition, the metabolic potential of gut microbiota has been identified as a contributing factor in the development of diseases. Recent studies revealed that gut microbiota can elicit a variety of effects on the host. Indeed, the gut microbiome functions like an endocrine organ, generating bioactive metabolites, that can impact host physiology. Microbiota interact with the host through a number of pathways, including the trimethylamine (TMA)/ trimethylamine N-oxide (TMAO) pathway, short-chain fatty acids pathway, and primary and secondary bile acids pathways. In addition to these “metabolism dependent” pathways, metabolism independent processes are suggested to also potentially contribute to CVD pathogenesis. For example, heart failure associated splanchnic circulation congestion, bowel wall edema and impaired intestinal barrier function are thought to result in bacterial translocation, the presence of bacterial products in the systemic circulation and heightened inflammatory state. These are believed to also contribute to further progression of heart failure and atherosclerosis. The purpose of the current review is to highlight the complex interplay between microbiota, their metabolites and the development and progression of cardiovascular diseases. We will also discuss the roles of gut microbiota in normal physiology and the potential of modulating intestinal microbial inhabitants as novel therapeutic targets.

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“…Therefore, this non-lethal approach may potentially improve cardiovascular outcomes in kidney disease patients by decreasing systemic TMAO concentrations. Genetic alteration of bacterial tryptophanase, which represents another non-lethal approach, may result in lower overall formation of indoxyl sulfate [95]. On the other hand, rifaximin is a lethal antibiotic that provides at least an acute decrease of TMAO concentrations in patients [96].…”

Section: Therapeutic Strategies To Target Microbial Toxinsmentioning

confidence: 99%

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

Prokopienko

Nolin

2017

Expert Review of Clinical Pharmacology

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Introduction Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease. Areas Covered This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed. Expert Commentary Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets.

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Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota

Cited by 215 publications

References 42 publications

Indoles from commensal bacteria extend healthspan

Indoles from commensal bacteria extend healthspan

Gut Microbiota in Cardiovascular Health and Disease

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

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