Long-term Impacts of Early Life Antibiotic Exposure on Intestinal Microbiota and Metabolic Disease

• Author / Creator

  Li, Jiaying

• Although genetic factors, diet choices and sedentary lifestyle have long been considered main risk contributors for obesity and diabetes mellitus, years of study show that these factors cannot fully explain the increasing rate of worldwide metabolic disease. Epidemiological studies in recent years have correlated antibiotic exposure in early life with long-lasting metabolic consequences, particularly central obesity. Experimental evidence for this relationship has not been provided, and the cellular and molecular mechanisms are not clearly defined. The overall objective of this study was to explore the association between early life antibiotic treatment and modified programming of gastrointestinal tract and pancreas development that predispose to metabolic disease. A piglet model for the human infant was developed by administering therapeutic doses of amoxicillin to newborn piglets through the first 2 postnatal weeks and examining the immediate and long-term consequences of the treatment. Changes of microbial composition and microbial product sensing were examined during the period of this study. Likewise, glucose regulation, pancreatic development and gene expression levels to the related pathways were assessed. Study 1 demonstrated that early life antibiotic treatment altered pancreatic development, β-cell function, and modestly impaired glucose tolerance. Shifted microbial composition to a specific direction, alteration of SCFA metabolism in large intestine and LPS activities in circulation further confirmed our hypothesis that early exposure to antibiotics may programme pancreatic and intestinal development via microbial metabolites that play a causal role in metabolic disorder pathogenesis. This is the first experimental evidence linking therapeutic antibiotics in the early life period to islet development and function later in life. The observed variations in vivo and in isolated islets support the epidemiological evidence and indicate further study on the relationship between early life microbiota and long-term metabolic status is warranted. In addition, as metabolic disease is usually triggered by multiple environmental factors and the outcomes of some programming effects will only show in certain conditions, a westernized diet or high fat diet is likely to faster or exacerbate the outcomes of antibiotic programming effects. Therefore, study 2 evaluated the suitability of pig as a model of high fat diet induced metabolic syndrome. This pig model developed central obesity and impaired glucose control during oral glucose tolerance test and secreted less plasma insulin during the test within 5 weeks of high fat feeding. This study provides important experimental evidence supporting epidemiological studies relating early life antibiotics and metabolic outcomes, as well as a metabolic challenge model to support future research.

• Subjects / Keywords

  • Obesity
  • Early life programming
  • Gut microbiota
  • Antibiotics
  • Metabolic disease
  • Diabetes

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3RV0DB74

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.