Antibiotic-Induced Disruption of Gut Microbiota Alters Local Metabolomes and Immune Responses

ORIGINAL RESEARCH published: 24 April 2019 doi: 10.3389/fcimb.2019.00099 Antibiotic-Induced Disruption of Gut Microbiota Alters Local Metabolomes and Immune Responses Lin Sun 1,2 , Xiaoyan Zhang 1 , Yuxiao Zhang 1 , Kai Zheng 1 , Qiaoyan Xiang 1 , Ning Chen 1 , Zhiyun Chen 1 , Nan Zhang 1 , Junping Zhu 1 and Qiushui He 1,3* 1 Department of Medical Microbiology, Capital Medical University, Beijing, China, 2 Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China, 3 Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland Edited by: Shai Bel, Bar-Ilan University, Israel Reviewed by: Xiaoming Bian, University of Georgia, United States Jiangwen Jiang, Zhejiang University School of Medicine, China *Correspondence: Qiushui He Specialty section: This article was submitted to Microbiome in Health and Disease, a section of the journal Frontiers in Cellular and Infection Microbiology Received: 20 November 2018 Accepted: 25 March 2019 Published: 24 April 2019 Citation: Sun L, Zhang X, Zhang Y, Zheng K, Xiang Q, Chen N, Chen Z, Zhang N, Zhu J and He Q (2019) Antibiotic-Induced Disruption of Gut Microbiota Alters Local Metabolomes and Immune Responses. Front. Cell. Infect. Microbiol. 9:99. doi: 10.3389/fcimb.2019.00099 Gut microbiome plays an essential role in modulating host immune responses. However, little is known about the interaction of microbiota, their metabolites and relevant inflammatory responses in the gut. By treating the mice with three different antibiotics (enrofloxacin, vancomycin, and polymixin B sulfate), we aimed to investigate the effects of different antibiotics exposure on gut microbiota, microbial metabolism, inflammation responses in the gut, and most importantly, pinpoint the underlying interactions between them. Although the administration of different antibiotics can lead to different effects on mouse models, the treatment did not affect the average body weight of the mice. A heavier caecum was observed in vancomycin treated mice. Treatment by these three antibiotics significantly up-regulated gene expression of various cytokines in the colon. Enrofloxacin treated mice seemed to have an increased Th1 response in the colon. However, such a difference was not found in mice treated by vancomycin or polymixin B sulfate. Vancomycin treatment induced significant changes in bacterial composition at phylum and family level and decreased richness and diversity at species level. Enrofloxacin treatment only induced changes in composition at family presenting as an increase in Prevotellaceae and Rikenellaceae and a decrease in Bacteroidaceae. However, no significant difference was observed after polymixin B sulfate treatment. When compared with the control group, significant metabolic shift was found in the enrofloxacin and vancomycin treated group. The metabolic changes mainly occurred in Valine, leucine, and isoleucine biosynthesis pathway and beta-Alanine metabolism in enrofloxacin treated group. For vancomycin treatment metabolic changes were mainly found in beta-Alanine metabolism and Alanine, aspartate and glutamate metabolism pathway. Moreover, modifications observed in the microbiota compositions were correlated with the metabolite concentrations. For example, concentration of pentadecanoic acid was positively correlated with richness of Rikenellaceae and Prevotellaceae and negatively correlated with Enterobacteriaceae. This study suggests that the antibiotic-induced changes in gut microbiota might contribute to the inflammation responses through the alternation of metabolic status, providing a novel insight regarding a complex network that integrates the different interactions between gut microbiota, metabolic functions, and immune responses in host. Keywords: gut microbiome, microbial metabolite, immune response, cytokine, antibiotic, co-correlation analysis Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 April 2019 | Volume 9 | Article 99 Sun et al. Gut Microbiota and Immune Responses INTRODUCTION alternation of inflammation responses, especially the expression of key cytokines in the colon, (iv) identify the similar or specific changes induced by different antibiotics at the above three level, and (v) the most importantly, pinpoint the underlying interactions between microbiota, their metabolites and the host immunity. The results obtained will provide an important basis for clinical relevance of microbiome in human health and disease. The gut microbiome plays an essential role in health and disease of the host. It is well-documented that gut microbiome aids the host in modulating immune responses and protecting against pathogens (Holmes et al., 2011). It also provides beneficial biological functions via production of vitamin and short-chain fatty acids (SCFAs) (Kasubuchi et al., 2015). Disturbing the balance between the host and microbial community can impair these homeostasis and finally result in a series of diseases. Therefore, a better understanding of the mechanistic roles the gut microbiota play in the regulation of host metabolic and immunological functions will provide useful information on the complex host-gut relationship. Antibiotics have been used as a useful tool to manipulate the gut microbiome, because they cannot only change the structure of host microbial communities but also their function in the gut (Ferrer et al., 2017). Therefore, antibiotics provide a good insight into the potential cause of the microbiota-dependent changes and help us to better understand the host-microbiome crosstalk. In order to explore role of antibiotic on the host’s gut microbial function, different antibiotics are used in previous studies, including broad-spectrum or antibiotic cocktails which are targeted at both Gram-negative and Gram-positive bacteria (Rodrigues et al., 2017; Strzepa et al., 2017), mono-antibiosis specific to Gram-positive (Mikkelsen et al., 2015) or Gramnegative bacteria (Oh et al., 2014). In addition, it has also been certificated that antibiotic-induced alternations in gut microbiota are associated with glucose tolerance (Rodrigues et al., 2017), body weight and bone growth (Mikkelsen et al., 2015), and gut microbiome diversity (Nobel et al., 2015). However, there is less attention received on the effects of different kinds of antibiotic usage on the host’s gut microbial function. The antibiotics, usually prescribed for infections, can also target commensal microbiota. Because of their different mechanisms in killing or inhibiting growth of bacteria, antibiotics may have differing effects on composition and richness of gut bacteria. For example, continuous use of therapeutic-dose ampicillin induces microbial dysbiosis and caused enhanced production of NF-κB in the colon tissues of a mouse model (Shi et al., 2018). Antibiotic cocktails which composed of vancomycin, neomycin, a (...truncated)