Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats

Suzana Stanisavljević,Neda Đedović,Sanja Mihajlović,Nataša Golić,Đorđe Miljković,Bojan Jevtić,Katarina Veljović,Aleksa Čepić,Svetlana Bojić,Miljana Momčilović,Milica Lazarević,Marija Mostarica Stojković

doi:10.1038/s41598-018-37505-7

Abstract

Gut microbiota dysbiosis has been considered the essential element in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Antibiotics were administered orally to Dark Agouti (DA) rats early in their life with the aim of perturbing gut microbiota and investigating the effects of such intervention on the course of EAE. As a result, the diversity of the gut microbiota was reduced under the influence of antibiotics. Mainly, Firmicutes and Actinobacteria were replaced by Proteobacteria and Bacteroidetes, while decreased proportions of Clostridia and Bacilli classes were accompanied by an increase in Gamma-Proteobacteria in antibiotic-treated animals. Interestingly, a notable decrease in the Helicobacteraceae, Spirochaetaceae and Turicibacteriaceae was scored in antibiotic-treated groups. Also, levels of short chain fatty acids were reduced in the faeces of antibiotic-treated rats. Consequently, aggravation of EAE, paralleled with stronger immune response in lymph nodes draining the site of immunization, and increased inflammation within the CNS, were observed in antibiotic-treated DA rats. Thus, the alteration of gut microbiota leads to an escalation of CNS-directed autoimmunity in DA rats. The results of this study indicate that antibiotic use in early life may have subsequent unfavourable effects on the regulation of the immune system.

Highlights

The intestinal microbiota has become increasingly appreciated as an important, if not the major external factor of immune response regulation[1,2]
EAE-susceptible Dark Agouti (DA) rats were treated with antibiotics early in their lifetime and, as a consequence, their gut microbiota was disturbed and production of short chain fatty acids (SCFA) reduced
Gravid DA rats were treated with antibiotics in drinking water starting two weeks before giving birth

Summary

Introduction

The intestinal microbiota has become increasingly appreciated as an important, if not the major external factor of immune response regulation[1,2]. A rising number of observational, clinical, and epidemiologic studies focused on children and antibiotics use show that antibiotic exposure-related dysbiosis of intestinal microbiota increases the risks for various diseases such as obesity, diabetes, inflammatory bowel diseases, celiac disease, allergies and asthma[14]. Studies that explore the autoimmunity-related effects of antibiotics on intestinal microbiota are valuable for assessing the potential risks of antibiotic use. EAE-susceptible Dark Agouti (DA) rats were treated with antibiotics early in their lifetime and, as a consequence, their gut microbiota was disturbed and production of SCFA reduced. When challenged with encephalitogenic immunization later in their lives, at the time when gut microbiota dysbiosis was no longer evident, the rats that had been treated with antibiotics had more severe EAE in comparison to their untreated counterparts. The increased severity of EAE was paralleled with increased Th1 and Th17 activity and decreased Treg in immune compartments and within the CNS

Methods

Results

Conclusion