Novel insights into early life stress-induced dysfunction of the gut-brain axis

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Collins, James M.
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University College Cork
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Visceral pain, a debilitating hallmark of disorders of gut-brain axis interactions such as irritable bowel syndrome, has a major impact on quality of life. Given the increasing prevalence of irritable bowel syndrome over the past number of years, as well as a lack of effective treatments for disorders of visceral pain, new strategies need to be undertaken to develop successful interventions. The use of both dietary and pharmacological interventions to reduce visceral pain has yielded some promising results, however, these require further investigation. There is also a pressing need to unravel the mechanisms behind the aetiology of these disorders. In this thesis, we focused on prenatal and postnatal stress-induced dysfunction of the gut-brain axis and provide novel insights into the factors that modulate the visceral pain response. Firstly, the potential of CL-316243, a pharmacological intervention, and milk fat globule membrane (MFGM), a dietary intervention, as potential novel strategies to ameliorate visceral hypersensitivity resultant from exposure to stress in the early postnatal period were assessed. Specifically, using Sprague Dawley rats exposed to maternal separation (MS) for 3 hours per day from postnatal day 2-12, a well-established rodent model of early life stress, we administered either CL-316243 via the oral route or MFGM in the diet to assess their efficacy in ameliorating MS-induced visceral hypersensitivity. Here, we report that both interventions were successful in reducing MS-induced visceral hypersensitivity and this occurred independently of changes at the level of central serotonergic signalling and secretomotor activity (CL-316243), or the enteric nervous system and intestinal permeability (MFGM). xiii Next, we investigated the role of female sex hormones and the gut microbiota as modulators of visceral sensitivity using female germ-free mice. Here, we observed that the oestrous cycle modulated the visceral pain response in a microbiota-dependent manner and ovariectomy resulted in visceral hypersensitivity in conventional animals only. We then assessed alterations in the immune profiles of pre-adolescent rats and the consequent impact of MS. Here, we reported modest pre-adolescent changes in the plasma immune profile and spleen weight in male rats, with no changes seen in the gut immune profile at this same timepoint. Finally, we propose the use of several biological markers of systemic inflammation and gastrointestinal permeability as indicators of prenatal maternal stress during the second trimester of healthy pregnancies. The utilisation of these biomarkers could help to negate or prevent the deleterious impacts of early life stress both on foetal development and maternal health. Overall, the results of this thesis provide novel insights into early life stress-induced dysfunction of the gut-brain axis as well as potential therapeutic strategies.
Early life stress , Maternal separation , Visceral pain , Milk fat globule membrane , Beta 3-adrenoceptor , Gut-brain axis
Collins, J. M. 2022. Novel insights into early life stress-induced dysfunction of the gut-brain axis. PhD Thesis, University College Cork.