Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment: a randomized trial of preterm infants

AbstractAntibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the Routine Early Antibiotic use in SymptOmatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 hours after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.

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Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants

Scientific Reports ◽

10.1038/s41598-021-80982-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jordan T. Russell ◽

J. Lauren Ruoss ◽

Diomel de la Cruz ◽

Nan Li ◽

Catalina Bazacliu ◽

...

Keyword(s):

Preterm Infants ◽

Gut Microbiome ◽

Antibiotic Use ◽

Intestinal Microbiome ◽

Preterm Neonates ◽

Gamma Aminobutyric Acid ◽

Microbiome Diversity ◽

Infant Gut Microbiome ◽

Stool Samples ◽

To Receive

AbstractAntibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.Trial Registration This project is registered at clinicaltrials.gov under the name “Antibiotic ‘Dysbiosis’ in Preterm Infants” with trial number NCT02784821.

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A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants

BMC Microbiology ◽

10.1186/s12866-021-02230-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Christophe Lay ◽

Collins Wenhan Chu ◽

Rikky Wenang Purbojati ◽

Enzo Acerbi ◽

Daniela I. Drautz-Moses ◽

...

Keyword(s):

Risk Factor ◽

Gut Microbiome ◽

Reference Group ◽

Mode Of Delivery ◽

Controlled Study ◽

Double Blind ◽

Lipopolysaccharide Biosynthesis ◽

Infant Gut Microbiome ◽

Stool Samples ◽

The Impact

Abstract Background The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). In a double-blind randomized controlled study, 153 infants born by elective C-section received an infant formula supplemented with either synbiotic, prebiotics, or unsupplemented from birth until 4 months old. Vaginally born infants were included as a reference group. Stool samples were collected from day 3 till week 22. Multi-omics were deployed to investigate the impact of mode of delivery and nutrition on the development of the infant gut microbiome, and uncover putative biological mechanisms underlying the role of a compromised microbiome as a risk factor for NCD. Results As early as day 3, infants born vaginally presented a hypoxic and acidic gut environment characterized by an enrichment of strict anaerobes (Bifidobacteriaceae). Infants born by C-section presented the hallmark of a compromised microbiome driven by an enrichment of Enterobacteriaceae. This was associated with meta-omics signatures characteristic of a microbiome adapted to a more oxygen-rich gut environment, enriched with genes associated with reactive oxygen species metabolism and lipopolysaccharide biosynthesis, and depleted in genes involved in the metabolism of milk carbohydrates. The synbiotic formula modulated expression of microbial genes involved in (oligo)saccharide metabolism, which emulates the eco-physiological gut environment observed in vaginally born infants. The resulting hypoxic and acidic milieu prevented the establishment of a compromised microbiome. Conclusions This study deciphers the putative functional hallmarks of a compromised microbiome acquired during C-section birth, and the impact of nutrition that may counteract disturbed microbiome development. Trial registration The study was registered in the Dutch Trial Register (Number: 2838) on 4th April 2011.

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The Microbiota Diversity Following Antibiotic Treatment of Clostridium Difficile Infection

10.21203/rs.3.rs-52869/v1 ◽

2020 ◽

Author(s):

Dana Binyamin ◽

Orna Nitzan ◽

Maya Azrad ◽

Zohar Hamo ◽

Omry Koren ◽

...

Keyword(s):

Clostridium Difficile ◽

Gut Microbiota ◽

Antibiotic Treatment ◽

Gut Microbiome ◽

Diarrheal Disease ◽

Medical Center ◽

Disease Onset ◽

Intestinal Microbiome ◽

Rrna Gene ◽

Stool Samples

Abstract Background: Clostridium difficile (C. difficile) is a major nosocomial pathogen that infects the human gut and can cause diarrheal disease. A dominant risk factor is antibiotic treatment that disrupts the normal gut microbiota. The aim of the study was to examine the correlation between antibiotic treatment received prior to C. difficile infection (CDI) onset and patient gut microbiota.Methods: Stool samples were collected from patients with CDI, presenting at the Baruch Padeh Medical Center Poriya, Israel. Demographic and clinical information, including previous antibiotic treatments, was collected from patient charts, and CDI severity score was calculated. Bacteria were isolated from stool samples, and gut microbiome was analyzed by sequencing the 16S rRNA gene using the Illumina MiSeq platform and QIIME2.Results: In total, 84 patients with C. difficile infection were enrolled in the study; all had received antibiotics prior to disease onset. Due to comorbidities, 46 patients (55%) had received more than one class of antibiotics. The most common class of antibiotics used was cephalosporins (n=44 cases). The intestinal microbiota of the patients was not uniform. Differences in intestinal microbiome were influenced by the different combinations of antibiotics that the patients had received (p = 0.022)Conclusions: The number of different antibiotics administered has a major impact on the CDI patients gut microbiome, mainly on bacterial richness.

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Microbiota diversity following antibiotic treatment of Clostridium difficile infection

10.21203/rs.3.rs-30391/v1 ◽

2020 ◽

Author(s):

Dana Binyamin ◽

Orna Nitzan ◽

Maya Azrad ◽

Zohar Hamo ◽

Omry Koren ◽

...

Keyword(s):

Clostridium Difficile ◽

Gut Microbiota ◽

Antibiotic Treatment ◽

Gut Microbiome ◽

Diarrheal Disease ◽

Medical Center ◽

Disease Onset ◽

Intestinal Microbiome ◽

Rrna Gene ◽

Stool Samples

Abstract Background: Clostridium difficile (C. difficile) is a major nosocomial pathogen that infects the human gut and can cause C. difficile infection (CDI), a diarrheal disease. A dominant risk factor is antibiotic treatment, which disrupts the normal gut microbiota. The aim of the study was to examine the correlation between antibiotic treatment received prior to CDI onset and patient gut microbiota during the infection.Methods: Stool samples were collected from patients with CDI, presenting at the Baruch Padeh Medical Center Poriya, Israel. Demographic and clinical information, including previous antibiotic treatments, was collected from patient charts, and CDI severity score was calculated. Bacteria were isolated from stool samples, and gut microbiome was analyzed by sequencing the 16S rRNA gene, using the Illumina MiSeq platform and QIIME2.Results: In total, 84 patients with CDI were enrolled in the study; all had received antibiotics prior to disease onset. Due to comorbidities, 46 patients (55%) received more than one class of antibiotics. The most common class of antibiotics used was cephalosporins (n=44 cases). The intestinal microbiota of the patients was not uniform. Differences in intestinal microbiome were influenced by the different numbers of antibiotics families that the patients received (p = 0.022)Conclusions: The number of different antibiotics amount has a major impact on the gut microbiome of CDI patients, particularly on its bacterial richness.

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Physical Activity Shapes the Intestinal Microbiome and Immunity of Healthy Mice but Has No Protective Effects against Colitis in MUC2−/− Mice

mSystems ◽

10.1128/msystems.00515-20 ◽

2020 ◽

Vol 5 (5) ◽

Author(s):

Mehrbod Estaki ◽

Douglas W. Morck ◽

Sanjoy Ghosh ◽

Candice Quin ◽

Jason Pither ◽

...

Keyword(s):

Physical Activity ◽

Gut Microbiome ◽

Short Chain Fatty Acids ◽

Intestinal Microbiome ◽

Protective Effects ◽

Immune Markers ◽

Murine Colitis ◽

Intestinal Mucus ◽

Chemically Induced ◽

Inflammatory Bowel

Perturbation in the gut microbial ecosystem has been associated with various diseases, including inflammatory bowel disease. Habitual physical activity, through its ability to modulate the gut microbiome, has recently been shown to prophylactically protect against chemically induced models of murine colitis. Here, we (i) confirm previous reports that physical activity has limited but significant effects on the gut microbiome of mice and (ii) show that such changes are associated with anti-inflammatory states in the gut, such as increased production of beneficial short-chain fatty acids and lower levels of proinflammatory immune markers implicated in human colitis; however, we also show that (iii) these physical activity-derived benefits are completely lost in the absence of a healthy intestinal mucus layer, a hallmark phenotype of human colitis.

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The Microbiome and p-Inulin in Hemodialysis: A Feasibility Study

Kidney360 ◽

10.34067/kid.0006132020 ◽

2021 ◽

pp. 10.34067/KID.0006132020

Author(s):

Dominic S. Raj ◽

Michael B. Sohn ◽

David M. Charytan ◽

Jonathan Himmelfarb ◽

T. Alp Ikizler ◽

...

Keyword(s):

Feasibility Study ◽

Gut Microbiome ◽

Post Treatment ◽

Intestinal Microbiome ◽

Maintenance Hemodialysis ◽

Sample Collection ◽

Microbiome Composition ◽

Stool Samples ◽

Pre Treatment ◽

End Stage

Background: The intestinal microbiome is an appealing target for interventions in end-stage kidney disease (ESKD) because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. Methods: Multi-center, non-randomized, crossover feasibility study of maintenance hemodialysis patients consisting of 3 phases: pre-treatment (8 weeks), treatment during which the prebiotic, p-inulin (Prebiotin®), was administered at a dose of 8 gm twice daily (12 weeks), and post-treatment (8 weeks). Stool samples were collected 1-2 times/week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal RNA sequencing and metabolomic profiling. Results: Eleven of the 13 participants completed the 28-week study. Inter-participant variability was greater than intra-participant variability for microbiome composition (p<0.001 by UniFrac distances), and metabolomic composition (p<0.001 by Euclidean distances). p-Inulin was well-tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pre-treatment to post-treatment was evident by the overall shifts in weighted UniFrac distances (p=0.004) and a progressive decrease in prevalence of high intra-class correlations indicating an increase in intra-participant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident. Conclusions: The intra-participant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies.

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29. Rapid Restoration of Bile Acid Compositions After Treatment with Investigational Microbiota-based Therapeutic RBX2660 for Recurrent clostrioides Difficile Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa417.028 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S15-S16

Author(s):

Nicky Ferdyan ◽

Romeo Papazyan ◽

Dana Walsh ◽

Sarah Klein ◽

Steve Qi ◽

...

Keyword(s):

Bile Acid ◽

Lithocholic Acid ◽

Recurrence Risk ◽

Intestinal Microbiome ◽

Phase 2 Trial ◽

Liquid Chromatography Tandem Mass ◽

Rapid Restoration ◽

Stool Samples ◽

Double Blinded ◽

To Receive

Abstract Background Recurrent Clostrioides difficile infection (rCDI) is a public health threat associated with intestinal microbiome disruption (dysbiosis), which is postulated to increase CDI recurrence risk via disruption of bile acid(BA)-mediated resistance to C. difficile colonization. RBX2660 is an investigational microbiota-based therapeutic in clinical development for reducing rCDI recurrence. Herein, we assessed BA composition among participants in a Phase 2 trial of RBX2660 for rCDI. Methods In a double-blinded trial (PUNCH CD2), rCDI participants were randomized to receive RBX2660 or placebo. Primary efficacy was defined as absence of CDI recurrence at 8 weeks after the last study treatment. Participants were asked to provide stool samples before (baseline) and up to 24 months after treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 36 BAs from a total of 167 participant stool samples from 47 participants. Participant-matched samples at baseline and 1, 4, and 8 weeks were compared with a linear mixed effects model. Results Primary BAs predominated at baseline but were significantly reduced (p< .02) as early as 1 week after treatment and remained so to 24 months. Concurrently, secondary BAs, most notably deoxycholic acid (DCA) and lithocholic acid (LCA), were significantly increased (p< .01) after treatment and remained so throughout. Moreover, increases in DCA and LCA were associated with treatment response (p=.05 and p< .01, respectively), recognizing the limited sample size of treatment failures. Observed BA changes coincided with changes in taxonomic compositions—a shift from Gammaproteobacteria and Bacilli predominance before treatment to Clostridia and Bacteroidia predominance after treatment. Figure 1: BA restoration of successfully-treated participants Conclusion In a trial of RBX2660 for rCDI, participant BA compositions significantly changed from before to after treatment, remained so for at least two years, and correlated with treatment outcome. The resulting predominance of secondary BAs coincided with microbiome compositional changes. Because secondary BA are thought to repress C. difficile colonization, these changes may partly explain how RBX2660 reduced CDI recurrence. Continued evaluation of RBX2660 for rCDI is underway. Disclosures Romeo Papazyan, PhD, Ferring Pharmaceuticals (Employee) Dana Walsh, PhD, Rebiotix Inc. (Employee) Steve Qi, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc. (Employee) Karthik Srinivasan, PhD, Ferring Pharmaceuticals (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee)

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Indirect Effect of Azithromycin Use on the Intestinal Microbiome Diversity of Untreated Children: A Randomized Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz061 ◽

2019 ◽

Vol 6 (3) ◽

Cited By ~ 2

Author(s):

Catherine E Oldenburg ◽

Ali Sié ◽

Boubacar Coulibaly ◽

Lucienne Ouermi ◽

Clarisse Dah ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Controlled Trial ◽

Randomized Trial ◽

Indirect Effect ◽

Controlled Trial ◽

Antibiotic Use ◽

Intestinal Microbiome ◽

Randomized Controlled ◽

Microbiome Diversity

Abstract Cohabiting children may share components of their intestinal microbiome. We evaluated whether receipt of azithromycin in one sibling confers changes to the intestinal microbiome in an untreated sibling compared with placebo in a randomized controlled trial. We found no evidence of an indirect effect of antibiotic use in cohabiting children. Clinical Trials Registrations: NCT03187834.

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Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales

PLoS ONE ◽

10.1371/journal.pone.0244763 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0244763

Author(s):

James K. Carter ◽

Dipankar Bhattacharya ◽

Joshua N. Borgerding ◽

M. Isabel Fiel ◽

Jeremiah J. Faith ◽

...

Keyword(s):

Gut Microbiome ◽

Severe Form ◽

Intestinal Microbiome ◽

Independent Effect ◽

Alcoholic Fatty Liver ◽

Nash Model ◽

Microbiome Diversity ◽

Primary Driver ◽

Alcoholic Fatty Liver Disease

Background & aim Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease. Methods The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome. Results There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales. Conclusions We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.

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Effect of Environmental Exposures on the Gut Microbiota from Early Infancy to Two Years of Age

Microorganisms ◽

10.3390/microorganisms9102140 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2140

Author(s):

Kameron Y. Sugino ◽

Tengfei Ma ◽

Nigel Paneth ◽

Sarah S. Comstock

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Gut Microbiome ◽

Linear Models ◽

Antibiotic Use ◽

Temporal Variations ◽

Milk Intake ◽

Microbiome Composition ◽

Infant Gut Microbiome ◽

Over Time

The gut microbiota undergoes rapid changes during infancy in response to early-life exposures. We have investigated how the infant gut bacterial community matures over time and how exposures such as human milk and antibiotic treatment alter gut microbiota development. We used the LonGP program to create predictive models to determine the contribution of exposures on infant gut bacterial abundances from one month to two years of age. These models indicate that infant antibiotic use, human milk intake, maternal pre-pregnancy BMI, and sample shipping time were associated with changes in gut microbiome composition. In most infants, Bacteroides, Lachnospiraceae unclassified, Faecalibacterium, Akkermansia, and Phascolarctobacterium abundance increased rapidly after 6 months, while Escherichia, Bifidobacterium, Veillonella, and Streptococcus decreased in abundance over time. Individual, time-varying, random effects explained most of the variation in the LonGP models. Multivariate association with linear models (MaAsLin) displayed partial agreement with LonGP in the predicted trajectories over time and in relation to significant factors such as human milk intake. Multiple factors influence the dynamic changes in bacterial composition of the infant gut. Within-individual differences dominate the temporal variations in the infant gut microbiome, suggesting individual temporal variability is an important feature to consider in studies with a longitudinal sampling design.

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