The Enteric Neural Circuitry Activated During Bacterial-toxin Induced Diarrhoea
The enteric neural circuits include intrinsic sensory neurons, interneurons, excitatory and inhibitory motor neurons, and secretomotor neurons. These are organised so that they form simple feed-forward circuits and more complex feedback loops capable of generating complex motor patterns. It is our aim to characterise the dynamic properties of these neural circuits and how they are affected by the contents of the gastrointestinal tract including nutrients after a meal, the metabolic products of the gut microbiome and toxins produced by diarrhoea producing bacteria.
Specific projects in 2014-2015 include:
(a) Comparison of the effects on enteric neural circuits of two major diarrhoea-producing bacterial toxins – cholera toxin (CT) and toxin A (TcdA) of Clostridium difficile (CDiff).
Common enteric neural circuits have been implicated in diarrhoeal diseases, including irritable bowel syndrome (IBS) and bacterial disease. The exotoxins of bacteria Vibrio cholera and C. difficile induce epidemic disease in the form of rapid and irresolvable hypersecretion which potentially leads to human death in developing and developed countries respectively. We have found that both exotoxins increase the excitability of enteric neurons and are now investigating specific subtypes, underlying mechanisms and the pathophysiological consequences for both water and salt secretion and intestinal motor patterns. The goal is to develop a new theory of how diarrhoea is produced and identify novel sites for therapeutic intervention.
(b) The gut can "taste" food, so does it "smell" it?
This project aims to identify motor patterns of mouse small intestine induced by odorants incorporated in a meal and the mechanisms by which odorants act.
(c) Understanding the enteric neural circuits in mouse and identifying regional differences in the gastrointestinal tract.
There is now significant interest in examining the mouse ENS due to availability of transgenic models, particularly those related to enteric neuropathies. More detailed work has been done in guinea-pig but there are significant species differences.
(d) Understanding sex differences in gastrointestinal pathophysiologies.
There are known sex differences in some gut disorders, for example IBS is more common in women than in men. Our work with CT shows that there are major differences between male and female mice in the effects of this toxin and that these are related to mucosal serotonin, this project aims to examine the mechanisms behind this.
(e) Involvement of gut microbiota in the regulation of intestinal functions..
Our gut epithelial layer is the residence of a diverse variety of microbes collectively known as the gut microbiota. Major metabolic products of several gut bacteria species include γ-amino butyric acid (GABA), which is best known as an inhibitory transmitter in the brain but is also found in some enteric neurons. We are investigating the effects of luminal GABA on the enteric neural circuitry as a first step in investigation of how the gut microbiota affect intestinal functions.
Dr Jaime Foong and Ms Rachel Gwynne
Dr Kulmira Nurgali (Victoria University)
Prof Henrik Sjövall (Göteborg University)
A/Pr Tor Savidge (Baylor College of Medicine, Houston)
Prof Helen Cox (King's College Medical School, London)