Devereaux, Jeannie ORCID: https://orcid.org/0000-0003-3214-2938 (2023) Behavioural changes associated with chronic intestinal inflammation: correlation with the changes in tryptophan metabolism in the gut and brain. PhD thesis, Victoria University.

Abstract

Context and purpose of the research project: Inflammatory bowel disease (IBD) encapsulates a chronic and systemic disorder characterised by recurring episodes of inflammation within the gastrointestinal tract. IBD incorporates two primary diseases, namely ulcerative colitis and Crohn’s disease. It results in altered motility, ulcer formation, bleeding, diarrhoea, abdominal pain, increased morbidity and is linked with depression and anxiety. IBD's symptomatic burden has a psychosocial negative impact on emotional functioning, and it is believed that negative emotions influence biological disease progression and behavioural changes. Our study hypothesises that depressive and anxiety-like behaviours in IBD patients might be side effects of chronic intestinal inflammatory responses, possibly related to tryptophan metabolism. Method: This thesis investigated the relationship between behavioural changes and energy metabolism, focusing on the tryptophan synthesis model in the distal colon and brain of the Winnie mouse with colitis. The Winnie mouse model, which has a Muc2 missense mutation, exhibits a close synteny of its genome with ulcerative colitis. Using indirect calorimetry, various aspects, including food and water intake, energy metabolism, sleep patterns, and spontaneous physical activity of the Winnie mouse, were assessed. Depressive and anxiety-like behaviours were evaluated utilising rodent behavioural tests. In addition, the study employed RNA-sequencing for cytokine activity and immunohistochemistry in the mouse's brain to detect inflammation and structural changes. RNA-sequencing and metabolomics mapped the pathways of glycolysis/gluconeogenesis, fatty acid ß-oxidation, and tryptophan de novo NAD+ synthesis in the distal colons and brains of the Winnie mouse. This aimed to clarify the pathophysiology of colitis in relation to behavioural changes. Major conclusions drawn: Indirect calorimetry results indicated that the Winnie mouse consumed less food and water, exhibited perturbed metabolic profiles, showed diminished glucose and lipid oxidation, a paramount indicator of metabolic health, decreased spontaneous physical activity, a hallmark of decreased energy, and increased sleep. Behavioural tests revealed depressive and anxiety-like behaviours, manifested by decreased grooming, a fundamental self-care activity, and reduced exploratory tendencies, a key behavioural metric. Comprehensive gene expression analysis of the distal colon identified disruptions in energy metabolism, integral detoxification processes, and tryptophan de novo NAD+ biosynthesis correlating with inflammation. Notably, the transcriptomes of Winnie mice and human IBD showed significant homologous similarities. Elevated levels of multiple tryptophan metabolites were detected in the colons of Winnie mice, indicating inflammation, compromised detoxification pathways, disrupted metabolism, and altered motility. Brain tryptophan metabolites, key neurotransmitter precursors, showed reduced levels, indicating diminished serotonergic pathway activity and nicotinamide production, central elements that are known to contribute to depression and behavioural changes. Immunohistochemistry revealed changes in brain structure of the Winnie mouse evidenced by altered expression of high mobility group box 1 protein, glial fibrillary acidic protein, myelin basic protein, transmembrane protein 119, and neuronal nuclei. In Winnie mice brains, pro-inflammatory cytokines increased, while anti-inflammatory cytokines, essential protective agents, decreased. These changes in cytokine activity, glycolysis, and tryptophan metabolism gene expressions, forming a cohesive pattern, correlated with reduced exploratory behaviour, depression, anxiety-like behaviours and behavioural changes, thus supporting the hypothesis.

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