Investigating the metabolic function of the gut microbiota in colorectal carcinogenesis via choline metabolism
File(s)
Author(s)
Bi, Yang
Type
Thesis
Abstract
Colorectal cancer (CRC) stands as the third most frequently diagnosed cancer globally. This thesis delves into the intricate relationship between CRC pathogenesis and the gut microbiota, emphasising the microbiota's role in converting dietary components into oncologic or tumour-suppressive metabolites, thereby influencing CRC development. TMAO, a metabolite derived from both dietary choline and carnitine, emerges as a pivotal intermediate marker connecting dietary choices and gut microbial metabolism to CRC risk.
Gut microbiota plays a crucial role in TMA and TMAO metabolism. Using 1H-NMR spectroscopy, the study explores the TMA-producing ability of choline and carnitine on Enterobacteriaceae isolates. Identifying three Klebsiella isolates with robust TMA-producing capability, the subsequent investigation involves assessing their colonisation ability and pro-carcinogenic effects in wild-type and ApcMin/+ mice. Despite successful colonisation in antibiotic-treated mice, the Klebsiella isolates did not significantly impact TMA concentrations or induce global metabolic changes in intestinal tissues, faeces, or urine. This observation prompts further investigation on dietary manipulations to alter TMA concentrations.
This thesis then shifts its focus to the role of TMAO in CRC development in FabplCre;Apc15lox/+ mice, employing targeted and non-targeted metabolomics, flow cytometry, and RNA-seq. Contrary to expectations, TMAO exhibits anti-tumour effects in a sex-specific manner, particularly pronounced in male mice. These effects are associated with the downregulation of the pro-inflammatory cytokine TNF-α from immune cells like CD8+, CD4+, and Natural Killer cells in colonic tissues.
In summary, this thesis provides valuable insights into the intricate interplay between microbial choline metabolism and CRC risk, unravelling unexpected findings that challenge conventional assumptions regarding the role of TMAO in CRC development.
Gut microbiota plays a crucial role in TMA and TMAO metabolism. Using 1H-NMR spectroscopy, the study explores the TMA-producing ability of choline and carnitine on Enterobacteriaceae isolates. Identifying three Klebsiella isolates with robust TMA-producing capability, the subsequent investigation involves assessing their colonisation ability and pro-carcinogenic effects in wild-type and ApcMin/+ mice. Despite successful colonisation in antibiotic-treated mice, the Klebsiella isolates did not significantly impact TMA concentrations or induce global metabolic changes in intestinal tissues, faeces, or urine. This observation prompts further investigation on dietary manipulations to alter TMA concentrations.
This thesis then shifts its focus to the role of TMAO in CRC development in FabplCre;Apc15lox/+ mice, employing targeted and non-targeted metabolomics, flow cytometry, and RNA-seq. Contrary to expectations, TMAO exhibits anti-tumour effects in a sex-specific manner, particularly pronounced in male mice. These effects are associated with the downregulation of the pro-inflammatory cytokine TNF-α from immune cells like CD8+, CD4+, and Natural Killer cells in colonic tissues.
In summary, this thesis provides valuable insights into the intricate interplay between microbial choline metabolism and CRC risk, unravelling unexpected findings that challenge conventional assumptions regarding the role of TMAO in CRC development.
Version
Open Access
Date Issued
2023-06-30
Date Awarded
2024-04-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Li, Jia
Marchesi, Julian
Sponsor
European Research Council
Chinese Scholarship Council
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)