Abstract
Background: The human gut microbiota is the densest most complex community of microorganisms found in the human body. The microbiota can be considered our second genome and it makes a significant contribution to human biology, development, and health. Negative alterations of the gut microbiota, called dysbiosis, is associated with a broad range of diseases ranging from metabolic disorders, such as obesity, to autoimmune diseases, and even neurodevelopmental disorders resulting in behavioral differences. The brain is dependent on the gut microbiota for essential metabolic products for normal neurological function making the gut microbiota not only essential for gut health but also mental health. The shaping and colonization of the gut microbiome starts at birth and the use of antibiotic agents antenatally, perinatally, and in the infant disrupt the normal establishment of the gut microbiota and even a single course of antibiotics can cause permanent aberrations in metabolism and immunity. Antibiotics, through their effect on the gut microbiota, have been shown to influence host appetite and metabolism, affect behavior and have been linked to childhood obesity. While antibiotics play an essential role in clinical practice it has become increasingly evident that their use is not without risks, especially during infancy, when the microbiota is being established, antibiotics can be harmful.
Aim and Methods: The aim of this thesis is to investigate the influence of antibiotics on gut microbiota, development, and health. In particular to gain further insight into the host-microbiota interplay and the consequences for interrupting this natural balance with antibiotics, specifically on early life development, gut barrier integrity, feeding behavior and weight changes. To this end Wistar rats are used as an animal model and treated with antibiotics and Next Generation Sequencing (NGS) is used to profile the gut microbial communities. In the first animal experiment (Paper I) adult female rats receive different antibiotic classes to study the effects on the commensal gut microbial community and impact on intestinal integrity depending on the antibiotic administered. In the second animal study (Paper II), intergenerational transmission of bacteria and the metabolic consequences of exposing neonate Wistar rats to an antibiotic-perturbed low-diversity microbiota from birth until weaning, without exposing the pups directly to antibiotics, was examined. The aim is to show a connection between a few community changes of the transmitted gut microbiome at birth, which disappeared over time, can result in long-lasting physical and behavioral changes induced by changed satiety and facilitated by bacterial products. In the unpublished data (Manuscript I) a link between an antibiotic altered microbiome and social behavior is examined. Throughout this thesis multi-disciplinary approaches are applied to understand the microbial profiles and host physiology, including profiling of the microbial composition (16S rRNA gene based), culturing, determination of microbial metabolites, host physiological measurements, gene expression analysis, measurements of the intestinal integrity and Spearman’s rank correlation is performed to integrate findings from different approaches.
Major Findings: The main findings of this thesis can be summarized as follows.
• Antibiotics can directly or indirectly disrupt the gut barrier and antibiotic-induced changes in microbiota can be linked to alterations in intestinal permeability, but changes in permeability do not always result from major changes in microbiota and vice versa.
• Early-life exposure to an antibiotic-perturbed low-diversity microbiota is sufficient to cause changes in body weight persisting into adulthood and antibiotics can have a protective effect that reduce the risk of overweight by preventing the transfer of the obesogenic microbiota from the mother during delivery.
• Peripartum antibiotic treatment of rat dams can cause a delay in successional microbiota development and sustained lower adult body weight in offspring, reflected in significantly reduced epididymal fat pats, concordant with lower feed intake, decreased levels of cecal SCFA, as well as increased colonic expression of satiety hormone genes at weaning.
• Even when early life gut microbial changes disappear, permanent physical changes, such as sustained lower adult body weight, can remain, indicative of “metabolic programming”.
• Peripartum antibiotics can change eating behavior but no conclusive effect on the social behavior of rats was seen, likely due to a too small experimental group as well as a small effect size if any.
Conclusion: This thesis contributes with important new findings on antibiotics effect on the gut microbiome and how they influence gut permeability, development in antibiotics perturbed offspring and eating behavior. There is a growing awareness of the importance of the gut microbiota on health and disease, and this work provides further insight into the host-microbiota interplay and the consequences for interrupting this natural balance with antibiotics, especially on early life development, gut barrier integrity, feeding behavior and weight changes. Coupled with an expanding knowledge of satiety and host-metabolic regulatory properties of antibiotics and their effect on the gut microbiota, the knowledge generated in this thesis may form the basis for future strategies to support healthy gut microbiota development and appropriate use of antibiotics in early life and during pregnancies.
Aim and Methods: The aim of this thesis is to investigate the influence of antibiotics on gut microbiota, development, and health. In particular to gain further insight into the host-microbiota interplay and the consequences for interrupting this natural balance with antibiotics, specifically on early life development, gut barrier integrity, feeding behavior and weight changes. To this end Wistar rats are used as an animal model and treated with antibiotics and Next Generation Sequencing (NGS) is used to profile the gut microbial communities. In the first animal experiment (Paper I) adult female rats receive different antibiotic classes to study the effects on the commensal gut microbial community and impact on intestinal integrity depending on the antibiotic administered. In the second animal study (Paper II), intergenerational transmission of bacteria and the metabolic consequences of exposing neonate Wistar rats to an antibiotic-perturbed low-diversity microbiota from birth until weaning, without exposing the pups directly to antibiotics, was examined. The aim is to show a connection between a few community changes of the transmitted gut microbiome at birth, which disappeared over time, can result in long-lasting physical and behavioral changes induced by changed satiety and facilitated by bacterial products. In the unpublished data (Manuscript I) a link between an antibiotic altered microbiome and social behavior is examined. Throughout this thesis multi-disciplinary approaches are applied to understand the microbial profiles and host physiology, including profiling of the microbial composition (16S rRNA gene based), culturing, determination of microbial metabolites, host physiological measurements, gene expression analysis, measurements of the intestinal integrity and Spearman’s rank correlation is performed to integrate findings from different approaches.
Major Findings: The main findings of this thesis can be summarized as follows.
• Antibiotics can directly or indirectly disrupt the gut barrier and antibiotic-induced changes in microbiota can be linked to alterations in intestinal permeability, but changes in permeability do not always result from major changes in microbiota and vice versa.
• Early-life exposure to an antibiotic-perturbed low-diversity microbiota is sufficient to cause changes in body weight persisting into adulthood and antibiotics can have a protective effect that reduce the risk of overweight by preventing the transfer of the obesogenic microbiota from the mother during delivery.
• Peripartum antibiotic treatment of rat dams can cause a delay in successional microbiota development and sustained lower adult body weight in offspring, reflected in significantly reduced epididymal fat pats, concordant with lower feed intake, decreased levels of cecal SCFA, as well as increased colonic expression of satiety hormone genes at weaning.
• Even when early life gut microbial changes disappear, permanent physical changes, such as sustained lower adult body weight, can remain, indicative of “metabolic programming”.
• Peripartum antibiotics can change eating behavior but no conclusive effect on the social behavior of rats was seen, likely due to a too small experimental group as well as a small effect size if any.
Conclusion: This thesis contributes with important new findings on antibiotics effect on the gut microbiome and how they influence gut permeability, development in antibiotics perturbed offspring and eating behavior. There is a growing awareness of the importance of the gut microbiota on health and disease, and this work provides further insight into the host-microbiota interplay and the consequences for interrupting this natural balance with antibiotics, especially on early life development, gut barrier integrity, feeding behavior and weight changes. Coupled with an expanding knowledge of satiety and host-metabolic regulatory properties of antibiotics and their effect on the gut microbiota, the knowledge generated in this thesis may form the basis for future strategies to support healthy gut microbiota development and appropriate use of antibiotics in early life and during pregnancies.
Original language | English |
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Place of Publication | Kgs. Lyngby |
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Publisher | Technical University of Denmark |
Number of pages | 137 |
Publication status | Published - 2022 |