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Elucidating the impact of Westernised diet on intestinal inflammation - from patient’s perspectives to in vitro and in vivo models
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Date
2024
Authors
Hanrahan, Naomi
Journal Title
Journal ISSN
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Publisher
University College Cork
Published Version
Abstract
The westernisation of societies during the 19th and 20th centuries has coincided with the rise of multiple non-communicable diseases, including Inflammatory Bowel Diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD), and obesity. Western dietary patterns, characterised by increased consumption of processed foods, saturated fats, and refined sugars, alongside a reduction in whole foods, fruits, and vegetables, have distinct effects on the small intestine. Given the small intestine's critical role in overall host homeostasis, alterations in its function can lead to detrimental effects on nutritional status, either through hyper- or hypo-absorption of nutrients, both of which are implicated in disease development. This thesis investigates the interplay between dietary patterns, patient perspectives, and molecular mechanisms affecting the intestinal epithelium in IBD, with a specific focus on CD and its association with the Western diet and obesity.
An Irish study employing a mixed-methods approach, integrating patient-reported data from an online questionnaire, insights from a patient collaborator panel (PCP), and experimental models was conducted. Our investigation within an Irish cohort suggests that western dietary habits are more prevalent among individuals with active IBD, particularly in those with active CD, which may result in significantly reduced micronutrient intake, often well below European food safety authorities (EFSA) recommendations. Additionally, we identified body mass index (BMI) as elevated in the active CD group, indicating a possible association between diet-obesity-and active CD. However, the panel emphasised that: dietary tolerance is reduced in active disease and the focus is on simple foods to restore energy, however, many other factors, including dietary support, will affect what people can and will eat. The PCP advocated for multidisciplinary support outside of crisis to manage their IBD.
Crohn’s disease is solely ileal targeting in one third of diagnosed individuals, and inflammation in the terminal ileum is associated with altered metabolic and lipid associated pathways. Mechanistic studies highlighted that lipid metabolism in intestinal epithelial cells modulates inflammatory and oxidative responses, providing protective effects in specific contexts, which is in alignment with the literature. However, in vivo studies highlight that High-fat-diet (HFD) impacts Paneth cell responses in the distal small intestine, processes which are highly implicated in ileal CD. Innovative models, including apical-out organoids, provided novel platforms to study dietary impacts on the small intestine under both baseline and inflammatory conditions, in the context of ileal CD and western diet components.
PDLIM2, a regulator of inflammation and metabolism, was found to influence host-microbe dialogue in the small intestine without inducing inflammation in a global knockout model. PDLIM2-deficiency appears to increase overall microbial diversity and mitigate some of the usual negative effects of HFD on the microbiota, and possibly alters intestinal gluconeogenesis or host glucose and lipid processing, although deficient animals do not gain more weight. PDLIM2-deficiency causes strong induction of WDFY1, a TLR3/4 adapter, and increases in transcriptional expression of other viral-associated protein Ifitm3, but organoids are not rendered divergently sensitised to viral stimuli. Furthermore, PDLIM2-deficiency causes significant changes in metabolic intermediates such as oleic acid, phospholipids and glycerophsphocholine, many of which have cross-over interactions with viral signalling in the small intestine. PDLIM2 does not appear altered in ileal Crohn’s, and further investigation of western diet-induced changes in WT and PDLIM2KO organoid models, ensuring specific enteroendocrine cell subsets (L and K cells) are present, is warranted for obesity-specific investigations.
Taken together, our data suggests that diet alone does not cause intestinal inflammation. Instead, it may serve as a marker along the path of accumulating environmental insults that contribute to disease development in the intestinal tract of genetically susceptible hosts. The small intestinal epithelium plays key roles in both metabolic processes related to obesity and in inflammatory and defence mechanisms in ileal Crohn’s disease. Given the high complexity of interactions in the gastrointestinal tract, a more targeted and in-depth investigation is warranted moving forward. These findings highlight the intricate relationship between diet, intestinal biology, and patient experiences, providing insights into broader disease management strategies for IBD and related intestinal disorders.
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Keywords
Inflammatory bowel disease , Obesity , Diet , Small intestine , Intestinal organoids , Preclinical models , PDLIM2
Citation
Hanrahan, N. 2024. Elucidating the impact of Westernised diet on intestinal inflammation - from patient’s perspectives to in vitro and in vivo models. PhD Thesis, University College Cork.