Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study

Lankelma, Jacqueline M.; Cranendonk, D.R.; Belzer, Clara; Vos, Alex F. de; Vos, Willem M. de; Poll, Tom van der; Wiersinga, W. Joost

doi:10.1136/gutjnl-2016-312132

Cited by 72 publications

(68 citation statements)

References 47 publications

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“…Numerous in vivo studies have reported the similar phenomena as shown in our research that significantly decreased of Bacteroidetes and Firmicutes phyla and predominantly detected human intestinal microbiota from Proteobacteria phylum such as Pseudomonas and Klebsiella following vancomycin administration [9,10,15]. Some studies have also reported a drop in richness and alpha diversity and significant effect on beta diversity pursued by vancomycin exposure [9,36].…”

Section: Vancomycin Exposure Significantly Increased the Opportunistisupporting

confidence: 87%

Human disease-related pathways increasing with opportunistic pathogens bloom in intestinal microbiome after vancomycin exposure and restoration with fecal transplantation by simulator of the human intestinal microbial ecosystem (SHIME)

Liu

Wang

et al. 2019

Preprint

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Background: Antibiotics are growing reported to cause human intestinal microbial disorders with increasing abundances of opportunistic pathogens, and fecal microbiota transplantation (FMT) has been confirmed to restore the dysbiosis of gut flora in many kinds of intestinal disease. However, to date, few studies have focused on the bloomed opportunistic pathogens associated human disease-related pathways as well as antibiotic resistance genes (ARGs) after vancomycin exposure, and there is limited information on using FMT for restoration of intestinal microbiome affected by antibiotics. Methods: This study investigated effects of vancomycin on the opportunistic pathogens, human disease-related pathways as well as ARGs in human gut, and the restoration of intestinal microbiome by FMT. Using the simulator of the human intestinal microbial ecosystem (SHIME), two reactors (representing the ascending and descending colon, respectively) were inoculated with human intestinal microbiota from a healthy adult volunteer who did not suffer from gastrointestinal diseases or take any antibiotic in the previous six months. Samples were collected from the reactors at six-time points (before treatment, after seven days of individual 10 mg/L, 100 mg/L, 1000 mg/L vancomycin treatment, 14 days following the termination of vancomycin and 14 days following FMT). The intestinal microbiome composition and function were analyzed using 16S rRNA gene sequencing and High-throughput Quantitative PCR (HT-qPCR).Results: Vancomycin treatment substantially increased human disease-related pathways and decreased abundances of ARGs. Besides, the bloomed opportunistic pathogens including Achromobacter, Klebsiella, and Pseudomonas, caused by vancomycin exposure, were positively correlated with human disease-related pathways. The microbiota abundance and genes of human disease-related pathways and antibiotic resistance showed a remarkable return towards baseline after FMT, but not for natural recovery. Conclusions: These findings suggest that impacts of vancomycin on human gut are profound and FMT will be a promising strategy in clinical application that can restore the dysbiosis of gut microbiota, which may be valuable for directing future work.

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Section: Vancomycin Exposure Significantly Increased the Opportunistisupporting

confidence: 87%

Human disease-related pathways increasing with opportunistic pathogens bloom in intestinal microbiome after vancomycin exposure and restoration with fecal transplantation by simulator of the human intestinal microbial ecosystem (SHIME)

Liu

Wang

et al. 2019

Preprint

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“…Such dysbiosis occurs rapidly within days, leading to altered bacterial metabolism and impaired host proteome in mice and humans (Ferrer et al, 2014, Lichtman et al, 2016. Human microbiome reconstitution from antibiotic treatment is often slow and incomplete (Dethlefsen et al, 2008, Dethlefsen and Relman, 2011, Jernberg et al, 2007 and, in some cases, may take years to revert to naive configuration (Lankelma et al, 2017). Of note, studies in rodent models and humans suggest an association between antibiotic exposure, especially during early stages of life, and a host propensity for a variety of long-term disorders (Vangay et al, 2015), including obesity (Shao et al, 2017), allergy (Risnes et al, 2011, Hoskin-Parr et al, 2013, increased risk of autoimmunity (Arvonen et al, 2015), and inflammatory bowel disease (Virta et al, 2012, Kronman et al, 2012.…”

Section: Introductionmentioning

confidence: 99%

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT

Suez

Zmora

Zilberman-Schapira

et al. 2018

Cell

777

590

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Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.

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“…). At T = 0 hours all volunteers received an infusion of 2 ng/kg LPS (National Institute of Health Clinical Center) as described before . Two hours (T = 2) after infusion of LPS the intervention group received an autologous transfusion of either “fresh” or “stored” RBCs.…”

Section: Methodsmentioning

confidence: 99%

“…For the various time points, half a milliliter of heparinized whole blood was suspended in 0.5 mL RPMI‐ l ‐glutamine (Gibco, Thermo Fisher Scientific) in a sterile 24‐well cell culture plate. The suspensions were stimulated ex vivo with 100 ng/mL LPS ( Escherichia coli , O111:B4, ultrapure, Sigma), 10 µg/mL lipotheic acid (LTA; InvivoGen), or solely RPMI‐ l ‐glutamine as control as described . LPS is the endotoxin of Gram‐negative bacteria and a TLR4 ligand.…”

Section: Methodsmentioning

confidence: 99%

Transfusion of 35‐day‐stored red blood cells does not alter lipopolysaccharide tolerance during human endotoxemia

et al. 2017

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BACKGROUND: Transfusion-related immunomodulation (TRIM) encompasses immunosuppressive and proinflammatory effects induced by red blood cell (RBC) transfusion. Changes that occur during storage in the RBC product have been hypothesized to underlie TRIM, mediated by tolerance of toll-like receptors (TLR). We investigated whether transfusion of 35-day-stored autologous RBCs alters cytokine production in response to stimulation with lipopolysaccharide (LPS) or lipotheic acid (LTA), in a clinically relevant model of endotoxemia. STUDY DESIGN AND METHODS:Eighteen volunteers received 2 ng/kg LPS intravenously, followed by normal saline or 2-or 35-day-stored autologous RBC transfusion. Before LPS, before transfusion, and 6 hours after transfusion blood was collected to measure cytokine gene expression. Whole blood was used for ex vivo stimulation with LPS and LTA, after which cytokine levels were measured with enzyme-linked immunosorbent assay. RESULTS:In vivo LPS induced a biphasic response in cytokine mRNA with peak values 2 hours after LPS infusion. Storage time of RBC transfusion did not influence cytokine mRNA levels. In vivo infusion of LPS resulted in tolerance for ex vivo stimulation with LPS and LTA. However, transfusion of either fresh or stored RBCs did not further affect the capacity to produce cytokines after ex vivo stimulation. CONCLUSION:In a clinically relevant model of human endotoxemia, autologous transfusion of 35-day-stored RBCs does not influence cytokine mRNA levels nor does it change the capacity of white blood cells in whole blood to produce cytokines after ex vivo stimulation with LPS or LTA. License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. MATERIALS AND METHODSAll procedures have been reviewed and approved by the Academic Medical Center Medical Ethical Committee and are according to the Declaration of Helsinki including good clinical practice. The study has been registered at the Dutch Trial Register (NTR4455). All enrolled volunteers provided written informed consent before enrollment. Subjects and designThis study is part of a larger study on the influence of storage time of RBCs on transfusion-related acute lung injury. 21 In short, a total of 18 healthy volunteers, ages 18 to 35 years old, were included in our open-label randomized controlled study. Volunteers were screened at the Academic Medical Center. To be included an unremarkable medical history as well as physical examination was required. Participants were not allowed to participate in another intervention trial during the course of our study. Randomization and blood donationVolunteers were randomly assigned into one of three groups: six volunteers received 2-day-stored (fresh) autologous RBC transfusion, six received 35-day-stored (stored) autologous RBC transfusion, and six volunteers were infused with 350 mL of 0.9% NaCl as endotoxemic control. Depending on group allocation, the volunteers donated 1 uni...

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Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study

Abstract: ClinicalTrials.gov (NCT02127749; Pre-results).

Cited by 72 publications

References 47 publications

Human disease-related pathways increasing with opportunistic pathogens bloom in intestinal microbiome after vancomycin exposure and restoration with fecal transplantation by simulator of the human intestinal microbial ecosystem (SHIME)

Human disease-related pathways increasing with opportunistic pathogens bloom in intestinal microbiome after vancomycin exposure and restoration with fecal transplantation by simulator of the human intestinal microbial ecosystem (SHIME)

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT

Transfusion of 35‐day‐stored red blood cells does not alter lipopolysaccharide tolerance during human endotoxemia

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