Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Farzi, A.
Effects of immune modulation on brain function and behaviour in the context of the microbiota–gut–brain axis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2015. pp.
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- Autor*innen der Med Uni Graz:
- Farzi Aitak
- Betreuer*innen:
- Enzinger Christian
- Gorkiewicz Gregor
- Holzer Peter
- Altmetrics:
- Abstract:
- Pro-inflammatory cytokines have been demonstrated to be causally involved in the pathogenesis of psychiatric disorders including major depression and anxiety. While various mechanisms may underlie the increased prevalence of heightened immune markers in psychiatric patients, the microbial community of the intestinal tract, the intestinal microbiota, has emerged as a potential source of immune activating agents being capable of affecting systemic immunity. Bacterial cell wall components activate the immune system by binding to specialized receptors including Toll-like receptors (TLRs) and nuclear-binding domain (NOD)-like receptors (NLRs). The outer membrane component of Gram-negative bacteria, lipopolysaccharide (LPS), is commonly known as a strong immune activator, activating TLR4 and leading to behavioural signs of sickness, anxiety and depression. While the immune activating potency of NOD agonists is less marked, they are able to prime immune cells augmenting LPS-induced cytokine production. As the behavioural sequelae of NOD and TLR4 co-activation have been little studied, the effects of the NOD1 agonist FK565 and the NOD2 agonist muramyl dipeptide (MDP), alone and in combination with LPS, were investigated in C57BL/6N mice with regard to immune and brain activity markers. In addition, the effects of a disturbance of the intestinal microbiota by oral antibiotics targeting Gram-positive, Gram-negative and/or anaerobic microorganisms on anxiety and depression-like behaviour as well as learning and memory were investigated. While the NOD agonists under study given alone had only minor behavioural effects, intraperitoneal injection of FK565 (0.001 or 0.003 mg/kg) or MDP (1 or 3 mg/kg) 4 h before LPS (0.1 or 0.83 mg/kg) significantly aggravated and prolonged the LPS-evoked sickness behaviour as revealed by a decrease in locomotion, exploration, food intake and body temperature. The exacerbated behavioural response was accompanied by elevated plasma and cerebral levels of pro-inflammatory cytokines (IFN-¿, IL-1ß, IL-6, TNF-a) as well as raised plasma levels of kynurenine. Immunohistochemical labelling of c-Fos, a marker indicating changes in activity within neurons, indicated that NOD2 synergism with TLR4 modulated activation of cerebral nuclei relevant to the sickness response. The main source of TLR and NOD agonists in the body is the intestinal microbiota. For this reason I was interested in examining the behavioural effects of an antibiotic-induced dysbiosis of the gut microbiota. Administration of various antibiotics revealed that a combination of ampicillin (2 mg/ml), bacitracin (5 mg/ml), meropenem (1 mg/ml), neomycin (5 mg/ml) and vancomycin (0.3 mg/ml) administered via the drinking water depleted the colonic microbiota and exerted anxiolytic and depressogenic effects, while impairing learning and memory. At the same time, however, addition of the antibiotics to the drinking water resulted in a decrease in fluid intake and body weight. In summary, these results demonstrate that NOD1 or NOD2 synergizes with TLR4 in aggravating the immune-related and behavioural responses to peripheral immune activation. Furthermore, depletion of the intestinal microbiota succeeded in inducing behavioural changes comparable to those seen in germ-free mice. However, a causal involvement of the microbiota on the behavioural alterations cannot be warranted from the current results, due to potential side effects of the antibiotic treatment.