Dataset Information

Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks.

ABSTRACT: OBJECTIVE:Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited. DESIGN:Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network. RESULTS:We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments. CONCLUSIONS:In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics.

SUBMITTER: Morgun A

PROVIDER: S-EPMC5166700 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks.

Morgun Andrey A Dzutsev Amiran A Dong Xiaoxi X Greer Renee L RL Sexton D Joseph DJ Ravel Jacques J Schuster Martin M Hsiao William W Matzinger Polly P Shulzhenko Natalia N

Gut 20150122 11

<h4>Objective</h4>Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited.<h4>Design</h4>Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes a ...[more]

PMID: 25614621

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Project description:With the widespread use of antibiotics, more attention has been paid to their side effects. We paid extra attention to the impact of antibiotics on children's bodies. Therefore, we analyzed the characteristic changes in the gut microbiota of children after antibiotic treatment to explore the pathogenesis of antibiotic-associated diseases in more depth and to provide a basis for diagnosis and treatment. We recruited 28 children with bronchopneumonia in the western district of Zhuhai, China, and divided them into three treatment groups based on antibiotic type. We took stool samples from children before and 3-5 days after antibiotic treatment. 16S rRNA gene sequencing was used to analyze the effects of antibiotic therapy on the gut microbiota of children. Continuous nonparametric data are represented as median values and analyzed using the Wilcoxon rank-sum test. While alpha diversity analysis found no significant changes in the mean abundance of the gut microbiota of children after a short course of antibiotic treatment, beta diversity analysis demonstrated significant changes in the composition and diversity of the gut microbiota of children even after a short course of antibiotic therapy. We also found that meloxicillin sulbactam can inhibit the growth of Proteobacteria, Bacteroidetes, and Verrucomicrobia, ceftriaxone inhibits Verrucomicrobia and Bacteroides, and azithromycin inhibits Fusobacteria, Actinobacteria, Proteobacteria, and Verrucomicrobia. We further performed a comparative analysis at the genus level and found significantly different clusters in each group. Finally, we found that azithromycin had the greatest effect on the metabolic function of intestinal microbiota, followed by ceftriaxone, and no significant change in the metabolic process of intestinal microbiota after meloxicillin sulbactam treatment. Antibiotic treatment significantly affects the diversity of intestinal microbiota in children, even after a short course of antibiotic treatment. Different classes of antibiotics affect diverse microbiota primarily, leading to varying alterations in metabolic function. Meanwhile, we identified a series of intestinal microbiota that differed significantly after antibiotic treatment. These groups of microbiota could be used as biomarkers to provide an additional basis for diagnosing and treating antibiotic-associated diseases.

Project description:The microbiome is important to all animals, including poultry, playing a critical role in health and performance. Low-dose antibiotics have historically been used to modulate food production animals and their microbiome. Identifying alternatives to antibiotics conferring similar modulatory properties has been elusive. The purpose of this study was to determine if a host-tailored probiotic could recapitulate effects of a low-dose antibiotic on host response and the developing microbiome. Over 13 days of life, turkey poults were supplemented continuously with a low-dose antibiotic or oral supplementation of a prebiotic with or without two different probiotics (8 cage units, n = 80 per group). Gastrointestinal bacterial and fungal communities of poults were characterized by 16S rRNA gene and ITS2 amplicon sequencing. Localized and systemic host gene expression was assessed using transcriptome sequencing (RNA-Seq), kinase activity was assessed by avian-specific kinome peptide arrays, and performance parameters were assessed. We found that development of the early-life microbiome of turkey poults was tightly ordered in a tissue- and time-specific manner. Low-dose antibiotic and turkey-tailored probiotic supplementation, but not nontailored probiotic supplementation, elicited similar shifts in overall microbiome composition during development compared to controls. Treatment-induced bacterial changes were accompanied by parallel shifts in the fungal community and host gene expression and enhanced performance metrics. These results were validated in pen trials that identified further additive effects of the turkey-tailored probiotic combined with different prebiotics. Alternative approaches to low-dose antibiotic use in poultry are feasible and can be optimized utilizing the indigenous poultry microbiome. Similar approaches may also be beneficial for humans.IMPORTANCE Alternative approaches are greatly needed to reduce the need for antibiotic use in food animal production. This study utilized a pipeline for the development of a host-tailored probiotic to enhance performance in commercial turkeys and modulate their microbiota, similar to the effects of low-dose antibiotic administration. We determined that a host-tailored probiotic, developed in the context of the commercial turkey gut microbiome, was more effective at modulating these parameters than a nontailored probiotic cocktail. Furthermore, the host-tailored probiotic mimicked many of the effects of a low-dose antibiotic growth promoter. Surprisingly, the effects of the antibiotic growth promoter and host-tailored probiotic were observed across kingdoms, illustrating the coordinated interkingdom effects of these approaches. This work suggests that tailored approaches to probiotic development hold promise for modulating the avian host and its microbiota.

Dataset Information

Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks.

Publications

Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks.

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