title: Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice.
abstract: Environmental factors clearly influence the pathogenesis of Type 1 diabetes, an autoimmune disease. We have studied gut microbiota as important environmental agents that could affect the initiation or progression of type 1 diabetes especially in the prenatal period. We used neomycin, targeting mainly Gram negative or vancomycin, targeting mainly Gram positive bacteria, to treat pregnant NOD mothers and to study autoimmune diabetes development in their offspring. Neomycin-treated offspring were protected from diabetes, while vancomycin-treated offspring had accelerated diabetes development, and both antibiotics caused distinctly different shifts in gut microbiota composition compared with the offspring from untreated control mice. Our study demonstrated that neomycin treatment of pregnant mothers leads to generation of immune-tolerogenic antigen-presenting cells (APCs) in the offspring and these APCs had reduced specific autoantigen-presenting function both in vitro and in vivo. Moreover, the protection from diabetes mediated by tolerogenic APCs was vertically transmissible to the second generation. In contrast, more diabetogenic inflammatory T cells were found in the lymphoid organs of the offspring from the vancomycin-treated pregnant mothers. This change however was not transmitted to the second generation. Our results suggested that prenatal exposure to antibiotic influenced gut bacterial composition at the earliest time point in life and is critical for consequent education of the immune system. As different bacteria can induce different immune responses, understanding these differences and how to generate self-tolerogenic APCs could be important for developing new therapy for type 1 diabetes.
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Youjia
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D001419:Bacteria / Q000145:classification / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology*; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007107:Immune System / Q000187:drug effects* / Q000196:embryology / Q000276:immunology; D015994:Incidence; D016688:Mice, Inbred NOD; D009355:Neomycin / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D012336:RNA, Ribosomal, 16S; D014640:Vancomycin; D009355:Neomycin
keywords: Antibiotic treatment; Gut microbiota; Type 1 diabetes