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@PHDTHESIS{Wortmann:977573,
author = {Wortmann, Esther},
othercontributors = {Clavel, Thomas and Hornef, Mathias Walter and Blank, Lars
M.},
title = {{T}argeting the gut microbiota to investigate the role of
secondary bile acids in colorectal cancer},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2024-00801},
pages = {1 Online-Ressource : Illustrationen},
year = {2023},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University 2024; Dissertation, RWTH Aachen University, 2023},
abstract = {Colorectal cancer (CRC) is one of the most fatal cancer
types worldwide. The production of secondary bile acids
(SBAs) by gut bacteria has been linked to CRC. However,
proof of causality and mechanistic insights in vivo are
scarce. We used several animal models, microbiota-targeted
approaches, and multi-omics techniques to address these
points. First, we performed faecal microbiota transplants
from APC1311/+ pigs to germfree Apc1638N/+ mice to
investigate if a CRC phenotype can be transferred by the
microbiota. The microbiota of mice colonised with stool from
the pigs that were fed a diet high in red meat and lard (RL)
clustered separately from that of recipient mice that
received the control (CTRL) microbiota. Microbiota structure
of CTRL recipients was more affected by the cholic acid
supplemented diet compared to RL recipients, suggesting that
the RL microbiota was more resistant to bile acid (BA)
stress. Most lesions were found in the small intestine of
Apc1638N/+ mice, with no significant differences due to
colonisation type. Second, germfree wild type mice fed a
high-fat diet were colonised with a synthetic community with
or without the bacterial species Extibacter muris, which
produces SBAs by 7α-dehydroxylation. Carcinogenesis was
induced by AOM/DSS treatment. Mice with E. muris had
significantly more tumours compared to those mice without E.
muris. Third, to assess host responses to SBAs in the gut,
we tested the effects of E. muris on the colonic epithelium
in gnotobiotic Apc1638N/+ mice colonised with the minimal
microbial consortium OMM12, using single-cell RNA
sequencing. Colonisation with E. muris (OMM12+E) was
associated with a higher fraction of absorptive enterocytes,
characterised by high expression of multiple BA transporters
and receptors, and a lower fraction of cell clusters
classified as goblet cells. PROGENy analysis revealed
upregulation of hypoxia, NFκB, and the tumor suppressor p53
pathway in OMM12+E mice. Finally, we tested whether the BA
scavenger colestyramine (COL) could improve disease by
reducing the bacterial production of SBAs when added to the
diet of APC1311/+ pigs. RL diet feeding lead to enhanced
cell proliferation and lower goblet cell numbers in the
distal colon, and to increased T cell infiltration in the
proximal colon. These effects were counteracted by COL
supplementation in the diet. COL also counteracted the
following effects of the RL diet on the microbiota: lower
Shannon effective counts in the caecum, high relative
abundance of Bacillota and a low fraction of Bacteroidota,
and increased levels of Lactobacillus johnsonii (SOTU1).
Additionally, the COL diet also lead to significantly higher
levels of conjugated primary BAs and SBAs, especially in the
caecum and colon, while levels of individual SBA species
were not significantly affected. We conclude that
physiological levels of microbially produced SBA, especially
DCA, promote early events of tumorigenesis under high fat
diet conditions, potentially by affecting epithelial cells
types and gene expression. Our results highlight the complex
interactions between diet, microbiota, and the host in CRC
development and point at the importance of consuming diets
that limit microbial SBA production.},
cin = {525500-2 ; 922510 / 161710 / 160000 / 525500-3 ; 922620 ;
922610},
ddc = {570},
cid = {$I:(DE-82)525500-2_20140620$ / $I:(DE-82)161710_20140620$ /
$I:(DE-82)160000_20140620$ / $I:(DE-82)525500-3_20140620$},
pnm = {DFG project 395357507 - SFB 1371: Microbiome Signatures --
Funktionelle Relevanz des Mikrobioms im Verdauungstrakt
(395357507)},
pid = {G:(GEPRIS)395357507},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2024-00801},
url = {https://publications.rwth-aachen.de/record/977573},
}
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