Serrated neoplasia in the colorectum: gut microbiota and molecular pathways

Kang, Xing; Zhang, Ru; Kwong, Thomas N.Y.; Lui, Rashid N.; Wu, William Ka Kei; Sung, Joseph J.Y.; Yu, Jun; Wong, Sunny H.

doi:10.1080/19490976.2020.1863135

Cited by 14 publications

(13 citation statements)

References 83 publications

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“…Azoxymethane (AOM) 26 mice develop hyperproliferative colonic mucosa, aberrant crypt foci (ACF), and eventually carcinomas 27 . An AOM-dextran sulfate sodium 28 model is widely used to study colitis-associated colon cancer 29 . We next investigated the role of VDR in regulating Claudin-5 expression in the development of cancer using an AOM/DSS treated mouse models ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis

et al. 2022

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Tight junctions are essential for barrier integrity, inflammation, and cancer. Vitamin D and the vitamin D receptor (VDR) play important roles in colorectal cancer (CRC). Using the human CRC database, we found colonic VDR expression was low and significantly correlated with a reduction of Claudin-5 mRNA and protein. In the colon of VDR ΔIEC mice, deletion of intestinal VDR led to lower protein and mRNA levels of Claudin-5. Intestinal permeability was increased in the VDR −/− colon cancer model. Lacking VDR and a reduction of Claudin-5 are associated with an increased number of tumors in the VDR −/− and VDR ΔIEC mice. Furthermore, gain and loss functional studies have identified CLDN-5 as a downstream target of VDR. We identified the Vitamin D response element (VDRE) binding sites in a reporter system showed that VDRE in the Claudin-5 promoter is required for vitamin D 3 -induced Claudin-5 expression. Conditional epithelial VDR overexpression protected against the loss of Claudin-5 in response to inflammation and tumorigenesis in vivo . We also reported fecal VDR reduction in a colon cancer model. This study advances the understanding of how VDR regulates intestinal barrier functions in tumorigenesis and the possibility for identifying new biomarker and therapeutic targets to restore VDR-dependent functions in CRC.

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Section: Resultsmentioning

confidence: 99%

Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis

et al. 2022

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“…Until now, a precise list of microorganisms involved in dMMR CRC has remained elusive. A recent study linked CRC microflora to tumor CMS via 16S rRNA analysis ( Kang et al, 2021 ). The study revealed that the relative abundances of Fusobacteria and Bacteroidetes were enriched in CMS1, while Firmicutes and Proteobacteria were decreased.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota distinct between colorectal cancers with deficient and proficient mismatch repair: A study of 230 CRC patients

Jin

Shi

et al. 2022

Front. Microbiol.

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Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) exhibit heterogeneous tumor characteristics, distinct responses to immunotherapy, and different survival outcomes. However, it is unclear whether gut microbiota is distinct between CRCs with different MMR status. In this study, we used immunohistochemistry for four major MMR proteins to determine the MMR status in 230 CRC patients. The gut microbiota was profiled in cancerous and adjacent normal tissues by using bacterial 16S rRNA sequencing. The differences in microbiota diversity, composition and related metabolic pathways between patients with dMMR and pMMR CRCs were explored. Linear discriminant analysis effect size (LEfSe) analysis was further applied to validate the significant taxonomic differences at the genus level. In our study cohort, dMMR status was identified in 29 of 230 (12.61%) tumors. The richness (alpha-diversity) of gut microbiome in dMMR tumor tissue was higher compared with pMMR tumor tissues. The microbial community composition (beta-diversity) between the two groups was significantly different. The dMMR group was enriched considerably for some microbiota, including Fusobacteria, Firmicutes, Verrucomicrobia, and Actinobacteria at the phylum level and Fusobacterium, Akkermansia, Bifidobacterium, Faecalibacterium, Streptococcus, and Prevotella bacteria at the genus level. However, the pMMR group was dominated by Proteobacteria at the phylum level and Serratia, Cupriavidus and Sphingobium at the genus level. Moreover, a wide variety of microbiota associated functional pathways were observed with different MMR status. KEGG pathway analysis indicated a higher abundance of the biosynthesis and metabolic pathways of glycan and nucleotide, cell growth and death pathways, genetic replication and repair pathways in dMMR samples compared with the pMMR group. These findings demonstrate that CRC patients with different MMR status have distinct gut bacterial community richness, compositions and related metabolic pathways, suggesting basis that may explain the effectiveness of immunotherapy in dMMR tumors.

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“…Ma et al reported that colorectal tumor apoptosis is induced by sitosterol through promoting gut microbiota to produce SCFAs which display antiproliferative effects on human colorectal cancer cells via gene expression inhibition [ 26 ]. Also, the intestinal flora may promote serrated lesions through EGFR signaling, the induction of cellular proliferation, the activation of a tumor immunosuppressive microenvironment, and the induction of an inflammatory response [ 27 ]. ROC analysis suggested that Faecalibacterium , Collinsella, and Bacteroides may be potential biomarkers for CRC.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive analysis of the microbiota composition and host driver gene mutations in colorectal cancer

Yuan

Tao

Wang³

et al. 2022

Invest New Drugs

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Studies of both, microbiota and target therapy associated with gene mutations in colorectal cancer, (CRC) have attracted increasing attention. However, only a few of them analyzed the combined effects on CRC. we analyzed differences in intestinal microbiota of 44 colorectal cancer patients and 20 healthy controls (HC) using 16S rRNA gene sequencing of fecal samples. For 39 of the CRC patients, targeted Next Generation Sequencing (NGS) was carried out at formalin fixed paraffin embedded (FFPE) samples to identify somatic mutation profiles. Compared to the HC group, the microbial diversity of CRC patients was significantly lower. In the CRC group, we found a microbiome that was significantly enriched for strains of Bifidobacterium, Bacteroides, and Megasphaera whereas in the HC group the abundance of Collinsella, Faecalibacterium, and Agathobacter strains was higher. Among the mutations detected in the CRC group, the APC gene had the highest mutation rate (77%, 30/39). We found that the KRAS mutant type was closely associated with Faecalibacterium, Roseburia, Megamonas, Lachnoclostridium, and Harryflintia. Notably, Spearman correlation analysis showed that KRAS mutations were negatively correlated with the existence of Bifidobacterium and positively correlated with Faecalibacterium. By employing 16S rRNA gene sequencing, we identified more unique features of microbiota profiles in CRC patients. For the first time, our study showed that gene mutations could directly be linked to the microbiota composition of CRC patients. We hypothesize that the effect of a targeted colorectal cancer therapy is also closely related to the colorectal flora, however, this requires further investigation.

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Serrated neoplasia in the colorectum: gut microbiota and molecular pathways

Cited by 14 publications

References 83 publications

Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis

Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis

Gut microbiota distinct between colorectal cancers with deficient and proficient mismatch repair: A study of 230 CRC patients

A comprehensive analysis of the microbiota composition and host driver gene mutations in colorectal cancer

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