Associations between the use of antibiotics and altered brain function and mental illness are now well evidenced from animal models and clinical trials. Based on these findings, emerging research efforts have largely focused on how high-dose antibiotic- mediated perturbations of the gut microbiota result in altered neurophysiological and behavioural outcomes. However, these studies have not investigated whether antibiotics also act directly on the host nervous system. My central hypothesis is that high-dose antibiotics, as used in experimental models testing the modulatory role of the gut microbiome, can induce pathophysiological outcomes by direct interaction with enteric neuronal circuits.
I designed two sets of experiments to characterize the acute effect of high-dose antibiotics on gut motility and gut-brain neuronal signalling. The first experimental study aimed to determine whether acute exposure of the gastrointestinal tract to high-dose antibiotics directly modulates enteric neurons, with consequences for gut motility. To test this, I used enteric nervous system dependent motility reflexes, ex vivo, as an index of putative effects on the intestinal nervous system. The results of these experiments have shown that luminal antibiotics alter oral to anal propulsive peristalsis in a system where such motility is dependent on the enteric nervous system. The second study aimed to test whether these local effects modulate brain function and behaviour by altering responses of vagal afferent pathways. I performed single-unit recordings from the mesenteric nerve bundle in ex vivo preparations to test this research question. The results suggest that antibiotics can increase activity of extrinsic vagal afferent neurons largely through cholinergic synapses with myenteric IPANs.
The present work offers significant therapeutic implications, although its main relevance is in the interpretation of the experimental use of high-dose antibiotics on animal models and where effects on behaviour and the nervous system are attributed solely to alterations in the microbiome. / Thesis / Master of Science (MSc) / Little is known about the mechanisms by which high-dose antibiotics produce changes in gut-brain signalling to negatively affect brain functions and behaviour. Although the general consensus is that these changes are caused by antibiotic-mediated perturbations of the gut microbiota, whether high-dose antibiotics also act directly on the nervous system remains a topic of debate. I have hypothesized that high-dose antibiotics, as used in experimental models associating pathophysiological outcomes to gut microbial changes, also produce adverse effects by direct modulation of enteric neuronal circuits. Indeed, our findings suggest that high-dose antibiotics directly signal to enteric neurons, which locally regulate gut motility reflexes and can transmit that information further to vagal neurons, to influence homeostatic regulation of brain functions and behaviour. This work offers novel therapeutic potential for antibiotics and advises careful interpretation of studies that have attributed effects of high-dose antibiotics solely to alterations in the gut microbiome.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/23700 |
| Date | January 2018 |
| Creators | Delungahawatta, Thilini |
| Contributors | Kunze, Wolfgang, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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