Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Fröhlich, E.
Analysis of gut microbiota-brain communication
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Autor*innen der Med Uni Graz:
- Fröhlich Esther Eleonore
- Betreuer*innen:
- Farzi Aitak
- Gorkiewicz Gregor
- Holzer Peter
- Stadlbauer-Köllner Vanessa
- Altmetrics:
- Abstract:
- The concept of the gut-brain axis, the bidirectional communication between gut and brain, has been supported by many experimental and clinical studies. This model has recently been expanded by including the gut microbiota as a critical node in the communication between the gut and brain. The communication between gut and brain involves neuronal, hormonal and immune routes. Some microbial components, like lipopolysaccharide, have been shown to activate the immune system, leading to alterations in anxiety, depression and social behavior. Clinical observations that the intestinal microbiota profile is altered in many neurologic and psychiatric disorders and diseases have given rise to the hypothesis that a disordered microbiota (dysbiosis) is a pathogenetic factor in these pathologies. As animal models raised in the absence of germs (germ-free) exhibit physiological differences compared to their colonized counterparts, antibiotic treatment gained appreciation as an approach for studying dysbiosis and causality in microbiota-host interactions. However, so far no standardized model of antibiotic-induced dysbiosis has been established. Moreover, the different models have not been characterized in detail, mostly concentrating on single aspects of changes in microbial composition. To shed more light on the communication between intestinal microbiota and brain function, an antibiotic-induced dysbiosis model was established in adult male C57BL/7N mice and characterized in great depth, including microbiome analysis of colon tissue and luminal content, metabolome analysis of colonic luminal content and plasma, mRNA expression pattern in colon and brain tissue, histologic evaluation of the small and large intestine, and assessment of emotional, affective and cognitive behavior. In addition, as behavioral sequelae of flagellin have been little studied, the effects of this bacterial protein with regard to anxiety-like and social behavior were investigated in adult male C57BL/7N mice. In the antibiotic regimen, mice were treated for 11 days with an antibiotic mix consisting of five antibiotics. This treatment induced marked dysbiosis that was associated with a significant disruption of the microbial community structure and load in the gut. Furthermore, dysbiosis altered the metabolite profile of the colonic content and plasma without inducing overt inflammation. Whereas anxiety- and depression-like behavior remained unaltered, antibiotic-induced dysbiosis impaired novel object recognition memory but had no impact on spatial memory. In addition, expression of neuronal signaling molecules was markedly altered in the brain of antibiotic-treated mice. The intestinal microbiota is the main source of bacterial components in the body. Some of these molecules can bind to receptors of the innate immune system and thereby elicit immune responses. As activation of the immune system has been shown to be involved in the pathogenesis of psychiatric disorders like anxiety, I was interested to know whether administration of flagellin would elicit behavioral alterations in mice. However, intraperitoneal injection of flagellin (200µg/kg) from Salmonella typhimurium had no consistent impact on anxiety-like and social behavior. In summary, these results add important information on the communication between the gut microbiota and the brain at several levels of the gut-brain axis, using distinct molecular, biochemical and neurobiological methods. In particular, the data of this dissertation show that antibiotic-induced dysbiosis in mice impairs cognition, an effect in which alterations of the metabolite profile and changes in the cerebral expression of signaling molecules may play an important role. In addition, several molecular and functional alterations of antibiotic-induced dysbiosis are to some extent similar to those found in germ-free mice.