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Subtherapeutic antibiotics alter the murine colonic microbiome and early life adiposity

ABSTRACT: Early life exposure to antibiotics alters the gut microbiome. These alterations lead to changes in metabolic homeostasis and an increase in host adiposity. We used microarrays to identify metabolic genes that may be up- or down-regulated secondary to antibiotic exposure. Low dose antibiotics have been widely used as growth promoters in the agricultural industry since the 1950’s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we hypothesized that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy (STAT) to young mice and evaluated changes in the composition and capabilities of the gut microbiome. STAT administration increased adiposity in young mice and altered hormones related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids (SCFA), increases in colonic SCFA levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early life murine metabolic homeostasis through antibiotic manipulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE38880 | GEO | 2012/07/01

SECONDARY ACCESSION(S): PRJNA169135

REPOSITORIES: GEO

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Subtherapeutic antibiotics alter the murine colonic microbiome and early life adiposity

Project description:Early life exposure to antibiotics alters the gut microbiome. These alterations lead to changes in metabolic homeostasis and an increase in host adiposity. We used microarrays to identify metabolic genes that may be up- or down-regulated secondary to antibiotic exposure. Low dose antibiotics have been widely used as growth promoters in the agricultural industry since the 1950’s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we hypothesized that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy (STAT) to young mice and evaluated changes in the composition and capabilities of the gut microbiome. STAT administration increased adiposity in young mice and altered hormones related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids (SCFA), increases in colonic SCFA levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early life murine metabolic homeostasis through antibiotic manipulation. C57BL6 mice were divided into low-dose penicillin or control groups. Given antibiotics via drinking water after weaning. Sacrificed and liver sections collected for RNA extraction.

2012-06-30 | E-GEOD-38880 | biostudies-arrayexpress

Xenobiotics shape the physiology and gene expression of the active human gut microbiome

Project description:The human gut is colonized by trillions of microorganisms that influence human health and disease through the metabolism of xenobiotics, including therapeutic drugs and antibiotics. The diversity and metabolic potential of the human gut microbiome have been extensively characterized, but it remains unclear which microorganisms are active and which perturbations can influence this activity. Here, we use flow cytometry, 16S rRNA gene sequencing, and metatranscriptomics to demonstrate that the human gut contains distinctive subsets of active and damaged microorganisms, primarily composed of Firmicutes, which display marked temporal variation. Short-term exposure to a panel of xenobiotics resulted in significant changes in the physiology and gene expression of this active microbiome. Xenobiotic-responsive genes were found across multiple bacterial phyla, encoding novel candidate proteins for antibiotic resistance, drug metabolism, and stress response. These results demonstrate the power of moving beyond DNA-based measurements of microbial communities to better understand their physiology and metabolism. RNA-Seq analysis of the human gut microbiome during exposure to antibiotics and therapeutic drugs.

2012-10-30 | E-GEOD-38151 | biostudies-arrayexpress

Antibiotic-induced microbiome perturbations are associated with significant alterations to colonic mucosal immunity in rhesus macaques

Project description:The diverse bacterial communities that colonize the gastrointestinal tract play an essential role in maintaining immune homeostasis through the production of critical metabolites such as short chain fatty acids (SCFA), and this can be disrupted by antibiotic use. However, few studies have addressed the effects of specific antibiotics longitudinally on the microbiome and immunity. We evaluated the effects of four specific antibiotics; enrofloxacin, cephalexin, paromomycin, and clindamycin; in healthy female rhesus macaques. All antibiotics disrupted the microbiome, including reduced abundances of fermentative bacteria and increased abundances of potentially pathogenic bacteria, including Enterobacteriaceae in stool, and decreased Helicobacteraceae in the colon. This was associated with decreased SCFAs, indicating altered bacterial metabolism. Importantly, antibiotic use also substantially altered local immune responses, including increased neutrophils and Th17 cells in the colon. Furthermore, we observed increased soluble-CD14 in plasma, indicating microbial translocation. These data provide a longitudinal evaluation of antibiotic-induced changes to the composition and function of colonic bacterial communities, associated with specific alterations in mucosal and systemic immunity.

2020-03-01 | GSE143729 | GEO

Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine

Project description:Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that male mice with their gut microbiome depleted by nonabsorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference across a range of doses (2.5-15 mg/kg), have decreased locomotor sensitization to morphine, and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to high-dose morphine (20 mg/kg × 7 days). Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders

2023-05-18 | GSE232836 | GEO

Interactions of erythromycin and an antibiotic-mixture to the gut microbiome of juvenile rainbow trout

Project description:Erythromycin (ERY) is a commonly used antibiotic that can be found in wastewater effluents globally. Due to the mechanisms by which they kill and prevent bacterial growth, antibiotics can have significant unwanted impacts on the fish gut microbiome. The overall objective of this project was to assess the effects of erythromycin and an antibiotic mixture on fish gut microbiomes. The project was split into two experiments to assess gut microbiome in response to exposure with ERY alone or in mixture with other common antibiotics. The objectives of experiment 1 were to understand uptake and depuration of ERY in juvenile rainbow trout (RBT) over a 7 d uptake followed by a 7 d depuration period using three concentrations of ERY. Furthermore, throughout the study changes in gut microbiome response were assessed. In experiment 2, a follow-up study was conducted using an identical experimental design to assess the impacts of an antibiotic-mixture (ERY, ampicillin, metronidazole, and ciprofloxacin at 100 µg/g each). Here, three matrices were analyzed, with gut collected for 16s metabarcoding, plasma for untargeted metabolomics, and brain for mRNA-seq analysis. ERY was depurated from the fish relatively quickly and gut microbiome dysbiosis was observed at 7 d after exposure, with a slight recovery after the 7 d depuration period. A greater number of plasma metabolites was dysregulated at 14 d compared to 7 d revealing temporality compared to gut microbiome dysbiosis. Furthermore, several transformation products of antibiotics and biomarker metabolites were observed in plasma due to antibiotic exposure. Brain transcriptome revealed only slight alterations due to antibiotic exposure. The results of these studies will help inform aquaculture practitioners and risk assessors when assessing the potential impacts of antibiotics in fish feed and the environment, with implications for host health.

2024-02-07 | GSE253746 | GEO

The effect of antibiotic mediated gut microbiome perturbation on ileal gene expression in NOD mice.

Project description:The early life microbiome plays important roles in host immunological and metabolic development. Because type 1 diabetes (T1D) incidence has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota that predisposes to disease. Using NOD mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and T reg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating T1D onset in NOD mice.

2016-05-20 | GSE81648 | GEO

Xenobiotics shape the physiology and gene expression of the active human gut microbiome

2012-10-30 | GSE38151 | GEO

Gut microbiota transplantation in conventional mice

Project description:Gut microbiota dysbiosis characterizes systemic metabolic alteration, yet its causality is debated. To address this issue, we transplanted antibiotic-free conventional wild-type mice with either dysbiotic (“obese”) or eubiotic (“lean”) gut microbiota and fed them either a NC or a 72%HFD. We report that, on NC, obese gut microbiota transplantation reduces hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non-transplanted mice. Of note, this phenotype is blunted in conventional NOD2KO mice. By contrast, lean microbiota transplantation did not affect hepatic gluconeogenesis. In addition, obese microbiota transplantation changed both gut microbiota and microbiome of recipient mice. Interestingly, hepatic gluconeogenesis, PEPCK and G6Pase activity were reduced even once mice transplanted with the obese gut microbiota were fed a 72%HFD, together with reduced fed glycaemia and adiposity compared to non-transplanted mice. Notably, changes in gut microbiota and microbiome induced by the transplantation were still detectable on 72%HFD. Finally, we report that obese gut microbiota transplantation may impact on hepatic metabolism and even prevent HFD-increased hepatic gluconeogenesis. Our findings may provide a new vision of gut microbiota dysbiosis, useful for a better understanding of the aetiology of metabolic diseases. all livers are from NC-fed mice only.

2017-03-16 | GSE81318 | GEO

Physiomimetic model of the human Gut-Liver axis for studies of inflammatory diseases

Project description:Association between the microbiome, IBD and liver diseases are known, yet cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver and circulating Treg/Th17 cells, we modeled progression of ulcerative colitis (UC) ex vivo. We show that microbiome-derived short-chain fatty acids (SCFA) may either improve or worsen disease severity, depending on the activation state of CD4 T cells. Employing a multiomic approach, we found SCFA reduced innate activation of the UC gut and increased hepatic metabolism. However, during acute T cell-mediated inflammation, SCFA exacerbate CD4 T cell effector function leading to gut barrier disruption and liver damage. These paradoxical findings underscore the emerging utility of human physiomimetic technology in combination with systems immunology to study causality and temporal facets of gut-liver axis related diseases where animal models might leave ambiguity.

2021-06-03 | GSE135428 | GEO

Cecal transcriptome by Next Generation Sequencing of WT C57Bl/6 mice treated with water (vehicle) or with antibiotics (AIMD) to induce microbiome depletion .

Project description:Antibiotic induced microbiome depletion (AIMD) has been used frequently to study the role of the gut microbiome in pathological conditions. However, unlike germ-free mice, the effects of AIMD on host metabolism is unknown. We investigated the effects of AIMD in normal-chow fed mice to understand its effects on gut homeostasis, luminal signaling, and metabolism. We show that AIMD, which decreases luminal Firmicutes and Bacteroidetes species, decreases baseline serum glucose levels, reduces glucose surge in a tolerance test, and improves insulin sensitivity without altering adiposity. These occur in the setting of decreased luminal short-chain fatty acids (SCFAs), especially butyrate, and secondary bile acid (BA) pool, which affects whole-body BA metabolism. In mice, AIMD alters cecal gene expression and gut GLP-1 signaling. Extensive tissue remodeling and decreased availability of SCFAs shift colonocyte metabolism toward glucose utilization. Hence, AIMD alters whole-body glucose homeostasis by potentially shifting colonocyte energy utilization from SCFAs to glucose.

2018-07-07 | GSE114818 | GEO

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