Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production

ABSTRACT Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the d...

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Autores principales:	Shuai Wang, Ayah El-Fahmawi, David A. Christian, Qun Fang, Enrico Radaelli, Longfei Chen, Megan C. Sullivan, Ana M. Misic, Jodi A. Ellringer, Xing-Quan Zhu, Sebastian E. Winter, Christopher A. Hunter, Daniel P. Beiting
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	gut microbiota microbiome Toxoplasma dysbiosis nitric oxide Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d2ef25ef76e04b01ad8ae75f8454e93f
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spelling	oai:doaj.org-article:d2ef25ef76e04b01ad8ae75f8454e93f2021-11-15T15:55:24ZInfection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production10.1128/mBio.00935-192150-7511https://doaj.org/article/d2ef25ef76e04b01ad8ae75f8454e93f2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00935-19https://doaj.org/toc/2150-7511ABSTRACT Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that Toxoplasma infection induces a dysbiosis dominated by Enterobacteriaceae and an increased potential for nitrate respiration. In vivo experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of Enterobacteriaceae in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Enterobacteriaceae. Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with T. gondii, in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology. IMPORTANCE Toxoplasma gondii is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with Toxoplasma—as well as numerous other pathogens—is the overgrowth of Escherichia coli or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.Shuai WangAyah El-FahmawiDavid A. ChristianQun FangEnrico RadaelliLongfei ChenMegan C. SullivanAna M. MisicJodi A. EllringerXing-Quan ZhuSebastian E. WinterChristopher A. HunterDaniel P. BeitingAmerican Society for Microbiologyarticlegut microbiotamicrobiomeToxoplasmadysbiosisnitric oxideMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	gut microbiota microbiome Toxoplasma dysbiosis nitric oxide Microbiology QR1-502
spellingShingle	gut microbiota microbiome Toxoplasma dysbiosis nitric oxide Microbiology QR1-502 Shuai Wang Ayah El-Fahmawi David A. Christian Qun Fang Enrico Radaelli Longfei Chen Megan C. Sullivan Ana M. Misic Jodi A. Ellringer Xing-Quan Zhu Sebastian E. Winter Christopher A. Hunter Daniel P. Beiting Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production
description	ABSTRACT Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that Toxoplasma infection induces a dysbiosis dominated by Enterobacteriaceae and an increased potential for nitrate respiration. In vivo experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of Enterobacteriaceae in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Enterobacteriaceae. Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with T. gondii, in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology. IMPORTANCE Toxoplasma gondii is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with Toxoplasma—as well as numerous other pathogens—is the overgrowth of Escherichia coli or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.
format	article
author	Shuai Wang Ayah El-Fahmawi David A. Christian Qun Fang Enrico Radaelli Longfei Chen Megan C. Sullivan Ana M. Misic Jodi A. Ellringer Xing-Quan Zhu Sebastian E. Winter Christopher A. Hunter Daniel P. Beiting
author_facet	Shuai Wang Ayah El-Fahmawi David A. Christian Qun Fang Enrico Radaelli Longfei Chen Megan C. Sullivan Ana M. Misic Jodi A. Ellringer Xing-Quan Zhu Sebastian E. Winter Christopher A. Hunter Daniel P. Beiting
author_sort	Shuai Wang
title	Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production
title_short	Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production
title_full	Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production
title_fullStr	Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production
title_full_unstemmed	Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production
title_sort	infection-induced intestinal dysbiosis is mediated by macrophage activation and nitrate production
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d2ef25ef76e04b01ad8ae75f8454e93f
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Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production

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