The Gut Milieu in Cystic Fibrosis: Identifying Mechanisms of Disease and Exploring Therapeutic Targets [thesis]

Michael Coffey
Gastrointestinal disease in cystic fibrosis (CF) begins In Utero and continues throughout life. Intestinal dysbiosis and inflammation have been observed in children with CF, however, the mechanisms linking them, and clinical implications are poorly understood. The intestinal tract as a therapeutic target is relatively underexplored. The overarching hypothesis is the intestinal milieu (bacteria, viruses and host-expressed proteins) is altered in children with CF compared to healthy controls
more » ... and these changes have implications for intestinal inflammation and clinical outcomes. This thesis presents a series of observational studies characterising alterations in the intestinal milieu in children with CF, with a focus on identifying mechanisms for inflammation, disease, influences on clinical outcomes and potential therapeutic strategies. This thesis presents a novel research program commenced to address the limitations of current microbiome research and explore the gut-lung and gut-brain axes. This thesis demonstrates that in children with CF: (i) the intestinal milieu is structurally and functionally altered compared to HC, (ii) pro-inflammatory microbiota and bacteriophage lysins are increased in abundance, (iii) Ruminococcaceae may be beneficial for growth and lung function, (iv) upstream regulators for intestinal inflammation include interferon gamma, tumour necrosis factor (TNF) 5 and transglutaminase 2, and (v) xanthine dehydrogenase/oxidase (generates reactive oxygen species) negatively correlate with growth measures. Several potential strategies warranting further investigation for intestinal disease in children with CF include: (i) probiotics, (ii) short-chain fatty acid sources, (iii) antioxidants (e.g. glutathione), (iv) lactotransferrin, (v) TNF inhibitors, and (vi) amino acids (e.g. phenylalanine). A systematic review of probiotics for people with CF revealed low-quality evidence suggestive that probiotics may be beneficial to the health of children and adults with CF, however they are associated w [...]
doi:10.26190/unsworks/21821 fatcat:uvmk5lsnqzbvhpcfcdohy5pe2e