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      Impact of antimicrobial therapy on the gut microbiome

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          Abstract

          The gut microbiome is now considered an organ unto itself and plays an important role in health maintenance and recovery from critical illness. The commensal organisms responsible for the framework of the gut microbiome are valuable in protection against disease and various physiological tasks. Critical illness and the associated interventions have a detrimental impact on the microbiome. While antimicrobials are one of the fundamental and often life-saving modalities in septic patients, they can also pave the way for subsequent harm because of the resulting damage to the gut microbiome. Contributing to many of the non-specific signs and symptoms of sepsis, the balance between the overuse of antimicrobials and the clinical need in these situations is often difficult to delineate. Given the potency of antimicrobials utilized to treat septic patients, the effects on the gut microbiome are often rapid and long-lasting, in which case full recovery may never be observed. The overgrowth of opportunistic pathogens is of significant concern as they can lead to infections that become increasingly difficult to treat. Continued research to understand the disturbances within the gut microbiome of critically ill patients and their outcomes is essential to help develop future therapies to circumvent damage to, or restore, the microbiome. In this review, we discuss the impact of the antimicrobials often used for the treatment of sepsis on the gut microbiota.

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          Microbiota-mediated colonization resistance against intestinal pathogens.

          Commensal bacteria inhabit mucosal and epidermal surfaces in mice and humans, and have effects on metabolic and immune pathways in their hosts. Recent studies indicate that the commensal microbiota can be manipulated to prevent and even to cure infections that are caused by pathogenic bacteria, particularly pathogens that are broadly resistant to antibiotics, such as vancomycin-resistant Enterococcus faecium, Gram-negative Enterobacteriaceae and Clostridium difficile. In this Review, we discuss how immune- mediated colonization resistance against antibiotic-resistant intestinal pathogens is influenced by the composition of the commensal microbiota. We also review recent advances characterizing the ability of different commensal bacterial families, genera and species to restore colonization resistance to intestinal pathogens in antibiotic-treated hosts.
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            Human metabolic phenotype diversity and its association with diet and blood pressure.

            Metabolic phenotypes are the products of interactions among a variety of factors-dietary, other lifestyle/environmental, gut microbial and genetic. We use a large-scale exploratory analytical approach to investigate metabolic phenotype variation across and within four human populations, based on 1H NMR spectroscopy. Metabolites discriminating across populations are then linked to data for individuals on blood pressure, a major risk factor for coronary heart disease and stroke (leading causes of mortality worldwide). We analyse spectra from two 24-hour urine specimens for each of 4,630 participants from the INTERMAP epidemiological study, involving 17 population samples aged 40-59 in China, Japan, UK and USA. We show that urinary metabolite excretion patterns for East Asian and western population samples, with contrasting diets, diet-related major risk factors, and coronary heart disease/stroke rates, are significantly differentiated (P < 10(-16)), as are Chinese/Japanese metabolic phenotypes, and subgroups with differences in dietary vegetable/animal protein and blood pressure. Among discriminatory metabolites, we quantify four and show association (P < 0.05 to P < 0.0001) of mean 24-hour urinary formate excretion with blood pressure in multiple regression analyses for individuals. Mean 24-hour urinary excretion of alanine (direct) and hippurate (inverse), reflecting diet and gut microbial activities, are also associated with blood pressure of individuals. Metabolic phenotyping applied to high-quality epidemiological data offers the potential to develop an area of aetiopathogenetic knowledge involving discovery of novel biomarkers related to cardiovascular disease risk.
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              Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe.

              Toxins A and B are the primary virulence factors of Clostridium difficile. Since 2002, an epidemic of C difficile-associated disease with increased morbidity and mortality has been present in Quebec province, Canada. We characterised the dominant strain of this epidemic to determine whether it produces higher amounts of toxins A and B than those produced by non-epidemic strains. We obtained isolates from 124 patients from Centre Hospitalier Universitaire de Sherbrooke in Quebec. Additional isolates from the USA, Canada, and the UK were included to increase the genetic diversity of the toxinotypes tested. Isolate characterisation included toxinotyping, pulsed-field gel electrophoresis (PFGE), PCR ribotyping, detection of a binary toxin gene, and detection of deletions in a putative negative regulator for toxins A and B (tcdC). By use of an enzyme-linked immunoassay, we measured the in-vitro production of toxins A and B by epidemic strain and non-dominant strain isolates. The epidemic strain was characterised as toxinotype III, North American PFGE type 1, and PCR-ribotype 027 (NAP1/027). This strain carried the binary toxin gene cdtB and an 18-bp deletion in tcdC. We isolated this strain from 72 patients with C difficile-associated disease (58 [67%] of 86 with health-care-associated disease; 14 [37%] of 38 with community-acquired disease). Peak median (IQR) toxin A and toxin B concentrations produced in vitro by NAP1/027 were 16 and 23 times higher, respectively, than those measured in isolates representing 12 different PFGE types, known as toxinotype 0 (toxin A, median 848 microg/L [IQR 504-1022] vs 54 microg/L [23-203]; toxin B, 180 microg/L [137-210] vs 8 microg/L [5-25]; p<0.0001 for both toxins). The severity of C difficile-associated disease caused by NAP1/027 could result from hyperproduction of toxins A and B. Dissemination of this strain in North America and Europe could lead to important changes in the epidemiology of C difficile-associated disease.
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                Author and article information

                Journal
                J Antimicrob Chemother
                J. Antimicrob. Chemother
                jac
                Journal of Antimicrobial Chemotherapy
                Oxford University Press
                0305-7453
                1460-2091
                January 2019
                25 January 2019
                25 January 2019
                : 74
                : Suppl 1 , The Accelerate Pheno™ system for organism identification and rapid MIC determination
                : i6-i15
                Affiliations
                [1 ]Accelerate Diagnostics, Inc., Scientific Affairs, Tucson, AZ, USA
                [2 ]Amsterdam UMC, University of Amsterdam, Center for Experimental and Molecular Medicine, Amsterdam, The Netherlands
                [3 ]Amsterdam UMC, University of Amsterdam, Department of Medicine, Division of Infectious Diseases, Amsterdam, The Netherlands
                Author notes
                Corresponding author. Accelerate Diagnostics, 3950 South Country Club Road, Tucson, AZ 85714, USA. Tel: +1 520 365 3100; E-mail: abhalodi@ 123456axdx.com

                Tjitske S. R. van Engelen and Harjeet S. Virk authors contributed equally.

                Article
                dky530
                10.1093/jac/dky530
                6382031
                30690540
                48e6e2b4-dbac-4092-9690-22a073635e37
                © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 10
                Funding
                Funded by: Vidi
                Award ID: 91716475
                Funded by: Netherlands Organisation for Scientific Research 10.13039/501100003246
                Funded by: Marie Curie Skledowska Innovative Training Network
                Funded by: European Sepsis Academy
                Funded by: European Union’s Horizon 2020 programme
                Categories
                Supplement Papers

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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