Role of bile acids in colon carcinogenesis

Nguyen, Thi Phuong; Ung, Trong Thuan; Kim, Nam Ho; Jung, Young Do

doi:10.12998/wjcc.v6.i13.577

Cited by 114 publications

(83 citation statements)

References 106 publications

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“…There are diverse signals involved in the carcinogenesis mechanism of bile acids, with a major role of epidermal growth factor receptor, and its down-stream signaling, involving mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor kappa-light-chain-enhancer of activated B cells. Bile acids regulate numerous genes including the human leukocyte antigen class I gene, p53, matrix metalloprotease, urokinase plasminogen activator receptor, Cyclin D1, cyclooxygenase-2, interleukin-8, and miRNAs of cancer cells [57].…”

Section: Discussionmentioning

confidence: 99%

Alterations in Gastric Microbial Communities are Associated with Risk of Gastric Cancer in a Korean Population: A Case-Control Study

Gunathilake

Lee²,

Choi

et al. 2020

Preprint

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Background: Although recent studies have reported the potential role of microbiome in GC, little is known about the microbial dysbiosis and their functions in GC. This study aimed to observe the associations between the alterations in gastric microbial communities and GC risk.Results: The study participants included 268 GC patients and 288 controls. DNA was extracted from gastric biopsies, and 16S rRNA gene analysis was performed to assign into bacterial taxa. Linear discriminant analysis (LDA) effect size (LEfSe) was used to identify differentially abundant taxa and pathways. Compositionality corrected by renormalization and permutation (CCREPE) was applied to derive microbial dysbiosis index (MDI). Microbiota metabolic pathways were analyzed using Phylogenetic Investigation of Communities by Reconstruction of Observed States (PICRUSt) based on the Kyoto Encyclopedia of Genes and Genomes (KEGG). Based on LEfSe, Streptococcus_NCVM and Prevotella melaninogenica species were highly enriched in GC cases and controls, respectively. Those who are in the third tertile of Prevotella melaninogenica showed a significantly decreased risk of GC in total (odds ratio (OR): 0.91, 95% confidence interval (CI): 0.38-0.96, p-trend=0.071). In the cladogram, class Bacilli was phylogenetically enriched in GC cases while phylum Actinobacteria, class Actinobacteria were phylogenetically related in the controls. MDI was significantly higher for the GC cases compared to the healthy controls in the female population (p=0.002). Females, those who are in the third tertile of the MDI showed a significantly increased risk of GC (OR: 2.66, 95% CI: 1.19-5.99, p-trend=0.017; model II). There was a significant inverse correlation between MDI and Shannon index for the total population (R=-0.83, p<0.001). Secondary bile acid synthesis and biosynthesis of ansamycins pathways were highly abundant in cases and controls, respectively.Conclusion: There is a significantly higher MDI in GC cases than controls and further, MDI is significantly positively associated with GC risk in the female population. Biosynthesis of ansamycins is a critical function which is highly enriched in healthy controls. Further microbiome studies are needed to confirm the findings of the current study.

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Section: Discussionmentioning

confidence: 99%

Alterations in Gastric Microbial Communities are Associated with Risk of Gastric Cancer in a Korean Population: A Case-Control Study

Gunathilake

Lee²,

Choi

et al. 2020

Preprint

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“…Contrarily, high physiological levels of secondary BA have been associated with colorectal cancer patients [43]. Due to their detergent-like properties, chronic exposure to higher concentration of BAs can damage cell membrane and induce pro-inflammatory pathways resulting in activation of ROS and genomic instability of colonic cellular DNA [44][45][46][47][48]. However, as IBD comprises of heterogeneous population of subtypes, inter-individual variation of gut microbiota and their expression potential among similar population further complicates the generalization and validation of bile acids needed to restore the bile acid pool across IBD cohorts [49].…”

Section: Discussionmentioning

confidence: 99%

Metagenomic analysis of bile salt biotransformation in the human gut microbiome

Das

Marcišauskas

et al. 2019

Preprint

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Background: In the biochemical milieu of human colon, bile acids act as signaling mediators between the host and its gut microbiota. Biotransformation of primary to secondary bile acids have been known to be involved in the immune regulation of human physiology. Several 16S amplicon-based studies with inflammatory bowel disease (IBD) subjects were found to have an association with the level of fecal bile acids. However, a detailed investigation of all the bile acid biotransformation genes involved in the secondary bile acid metabolism has not been performed. Results: Here, we report a comprehensive analysis of the bile acid biotransformation genes and their distribution at the phyla level. Based on the analysis of shotgun metagenomes, we found that the IBD subjects harbored a significantly lower abundance of these genes compared to the healthy controls. Majority of these genes originated from Firmicutes in comparison to other phyla. From metabolomics data, we found that the IBD subjects were measured with a significantly low level of secondary bile acids and high levels of primary bile acids compared to that of the healthy controls. Conclusions: Our bioinformatics-driven approach of identifying bile acid biotransformation genes predicts the bile salt biotransformation potential in the gut microbiota of IBD subjects. The functional level of dysbiosis likely contributes to the variation in the bile acid pool. This study sets the stage to envisage potential solutions to modulate the gut microbiome with the objective to restore the bile acid pool in the gut.

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“…In addition, bile acids are also substrates of OATP4A1, which are taken up by the mucosa cells for further metabolism to prevent their accumulation in the colonic lumen. This observation has been hypothesized to be beneficial as certain bile acids can promote carcinogenesis in the colon (11). OATP4A1 can also transport steroid hormone precursors such as estrone sulfate, which has been demonstrated to increase cell proliferation following its metabolization to 17β-estradiol, the most biologically active estrogen.…”

Section: Two Common Polymorphic Variants Of Oatp4a1mentioning

confidence: 99%

Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer

et al. 2020

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Genetic variations in the organic-anion-transporting polypeptide (OATP)-encoding solute carrier of organic anions (SLCO) genes can promote cancer development and progression. The overexpression of solute carrier organic anion transporter family member 4A1 (OATP4A1), a transporter for steroid hormones, prostaglandins, and bile acids, has been previously associated with tumor recurrence and progression in colorectal cancer (CRC). Therefore, the present study aimed to investigate the association between 2 frequent single nucleotide polymorphisms (SNPs) in SLCO4A1 (rs34419428, R70Q; rs1047099G, V78I) and CRC predisposition. Following restriction fragment length polymorphism-PCR analysis in 178 patients with CRC [Union for International Cancer Control (UICC) stage I/II] and 65 healthy controls, no significant difference was observed in allele frequency and the number of heterozygous/homozygous individuals between the groups. Notably, the R70Q minor allele was identified to be associated with the V78I minor allele in the genome. Comparing of the individual genotypes of CRC patients to clinical data, including sex, UICC-stage and relapse revealed no increased risk for CRC. In addition, the OATP4A1 immunoreactivity assay in paraffin-embedded CRC and adjacent non-tumorous mucosa sections, examined using quantitative microscopy image analysis, did not reveal any association with these polymorphisms. No significant differences were observed in the expression levels, localization, and sodium fluorescein transport capacity among the OATP4A1 variants, which was studied using functional assays in Sf9-insect and A431 tumor cells overexpressing the 2 single and a double mutant OATP4A1 SNP variants. These results suggested that the 2 most frequent polymorphisms located in the first intracellular loop of OATP4A1 do not associate with CRC predisposition and tumor recurrence. They are unlikely to affect the outcome of CRC in patients.

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Role of bile acids in colon carcinogenesis

Cited by 114 publications

References 106 publications

Alterations in Gastric Microbial Communities are Associated with Risk of Gastric Cancer in a Korean Population: A Case-Control Study

Alterations in Gastric Microbial Communities are Associated with Risk of Gastric Cancer in a Korean Population: A Case-Control Study

Metagenomic analysis of bile salt biotransformation in the human gut microbiome

Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer

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