Changes in gut microbiota and plasma inflammatory factors across the stages of colorectal tumorigenesis: a case-control study

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Abstract

Background

Colorectal cancer (CRC) is a common malignant gastrointestinal tumor. In China, CRC is the 5th most commonly diagnosed cancer. The vast majority of CRC cases are sporadic and evolve with the adenoma-carcinoma sequence. There is mounting evidence indicating that gut microbiota and inflammation play important roles in the development of CRC although study results are not entirely consistent. In the current study, we investigated the changes in the CRC-associated bacteria and plasma inflammatory factors and their relationships based on data from a case-control study of Han Chinese. We included 130 initially diagnosed CRC patients, 88 advanced colorectal adenoma patients (A-CRA), 62 patients with benign intestinal polyps and 130 controls.

Results

Fecal microbiota composition was obtained using 16S ribosomal DNA (16S rDNA) sequencing. PCOA analysis showed structural differences in microbiota among the four study groups ( P = 0.001, Unweighted Unifrac). Twenty-four CRC-associated bacteria were selected by a two-step statistical method and significant correlations were observed within these microbes. CRC-associated bacteria were found to change with the degree of malignancy. Plasma C-reactive protein (CRP) and soluble tumor necrosis factor II (sTNFR-II) displayed significant differences among the four study groups and increased with adenoma-carcinoma sequence. The correlations of CRP and sTNFR-II with several CRC-associated microbes were also explored.

Conclusions

CRC-associated species and plasma inflammatory factors tended to change along the adenoma-carcinoma sequence. Several CRC-associated bacteria were correlated with CRP and sTNFR-II. It is likely that gut microbiome and inflammation gradually form a microenvironment that is associated with CRC development.

Electronic supplementary material

The online version of this article (10.1186/s12866-018-1232-6) contains supplementary material, which is available to authorized users.

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Most cited references 22

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Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity.

Melanie Schirmer, Sanne Smeekens, Hera Vlamakis … (2016)

Gut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP), we investigate how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulations in healthy humans. We observe microbiome-cytokine interaction patterns that are stimulus specific, cytokine specific, and cytokine and stimulus specific. Validation of two predicted host-microbial interactions reveal that TNFα and IFNγ production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism and tryptophan degradation to tryptophol. Besides providing a resource of predicted microbially derived mediators that influence immune phenotypes in response to common microorganisms, these data can help to define principles for understanding disease susceptibility. The three HFGP studies presented in this issue lay the groundwork for further studies aimed at understanding the interplay between microbial, genetic, and environmental factors in the regulation of the immune response in humans. PAPERCLIP.

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Gut mucosal microbiome across stages of colorectal carcinogenesis

Geicho Nakatsu, Xiangchun Li, Haokui Zhou … (2015)

Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired samples of adenoma and adenoma-adjacent mucosae, 52 paired samples of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired samples shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC.

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Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth

V De Simone, E Franzè, G Ronchetti … (2014)

Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in the neoplastic areas. These data suggest that strategies aimed at the cotargeting of STAT3/NF-kB activation and interaction between them might represent an attractive and novel approach to combat CRC.

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Author and article information

Contributors

Yongzhen Zhang: zhangyongzhen2014@yeah.net

Xin Yu: yux15@fudan.edu.cn

Enda Yu: Endayu2010@126.com

Na Wang: na.wang@fudan.edu.cn

Quancai Cai:

ORCID: http://orcid.org/0000-0002-0163-1942

qccai@smmu.edu.cn

Qun Shuai: qunshuai999@163.com

Feihu Yan: feihuyan@yeah.net

Lufang Jiang: jianglufang@fudan.edu.cn

Hexing Wang: wanghexing@fudan.edu.cn

Jianxiang Liu: jxliu@shmu.edu.cn

Yue Chen: ychen@uottawa.ca

Zhaoshen Li: zhaoshenli56@gmail.com

Qingwu Jiang: jiangqw@fudan.edu.cn

Journal

Journal ID (nlm-ta): BMC Microbiol

Journal ID (iso-abbrev): BMC Microbiol

Title: BMC Microbiology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2180

Publication date (Electronic): 29 August 2018

Publication date PMC-release: 29 August 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 92

Affiliations

[1 ]ISNI 0000 0004 0369 1599, GRID grid.411525.6, Department of Gastroenterology, , Changhai Hospital, Naval Medical University, ; 168 Changhai Road, Shanghai, 200433 China

[2 ]The 92914th Military Hospital of PLA, Shanghai, China

[3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, , Fudan University, ; 130 Dong’an Road, Shanghai, 200032 China

[4 ]ISNI 0000 0004 0369 1599, GRID grid.411525.6, Department of General Surgery, , Changhai Hospital, Naval Medical University, ; Shanghai, 200032 China

[5 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, School of Epidemiology and Public Health, , University of Ottawa Faculty of Medicine, ; Ottawa, Canada

Author information

Quancai Cai http://orcid.org/0000-0002-0163-1942

Article

Publisher ID: 1232

DOI: 10.1186/s12866-018-1232-6

PMC ID: 6114884

PubMed ID: 30157754

SO-VID: e07610ea-0576-4917-8368-bcd75b3a7fad

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 October 2017

Date accepted : 15 August 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81473045

Award ID: 81273154

Award Recipient : Quancai Cai

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ScienceOpen disciplines: Microbiology & Virology

Keywords: colorectal cancer (crc),gut microbiota,plasma inflammatory factors,correlation analysis

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ScienceOpen disciplines: Microbiology & Virology

Keywords: colorectal cancer (crc), gut microbiota, plasma inflammatory factors, correlation analysis

Changes in gut microbiota and plasma inflammatory factors across the stages of colorectal tumorigenesis: a case-control study

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Role of Microbes in Soil Fertility and Human Health

Most cited references 22

Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity.

Gut mucosal microbiome across stages of colorectal carcinogenesis

Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth

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