Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice

Background: Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown. Methods: Azoxymethane (AOM)-treated, ApcMin/+ and germ-free mice were gavaged with feces from obese individuals and control subjects respective...

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Main Authors: Kang, Xing, Ng, Siu-Kin, Liu, Changan, Lin, Yufeng, Zhou, Yunfei, Kwong, Thomas N. Y., Ni, Yunbi, Lam, Thomas Y. T., Wu, William K. K., Wei, Hong, Sung, Joseph Jao Yiu, Yu, Jun, Wong, Sunny Hei
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2023
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Online Access:https://hdl.handle.net/10356/169288
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spelling sg-ntu-dr.10356-1692882023-07-16T15:37:49Z Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice Kang, Xing Ng, Siu-Kin Liu, Changan Lin, Yufeng Zhou, Yunfei Kwong, Thomas N. Y. Ni, Yunbi Lam, Thomas Y. T. Wu, William K. K. Wei, Hong Sung, Joseph Jao Yiu Yu, Jun Wong, Sunny Hei Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Obesity Microbiota Background: Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown. Methods: Azoxymethane (AOM)-treated, ApcMin/+ and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated. Findings: Conventional AOM-treated and ApcMin/+ mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth. Interpretation: Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC. Nanyang Technological University Published version We would like to thank National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065- 18GF), RGC-GRF Hong Kong (14110819, 14111621), NTU Start-Up Grant (021337-00001), Centre for Microbiome Medicine, and Wang Lee Wah Memorial Fund for their support of this study. 2023-07-11T05:46:50Z 2023-07-11T05:46:50Z 2023 Journal Article Kang, X., Ng, S., Liu, C., Lin, Y., Zhou, Y., Kwong, T. N. Y., Ni, Y., Lam, T. Y. T., Wu, W. K. K., Wei, H., Sung, J. J. Y., Yu, J. & Wong, S. H. (2023). Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice. EBioMedicine, 93, 104670-. https://dx.doi.org/10.1016/j.ebiom.2023.104670 2352-3964 https://hdl.handle.net/10356/169288 10.1016/j.ebiom.2023.104670 37343363 2-s2.0-85162148859 93 104670 en 021337-00001 EBioMedicine © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Obesity
Microbiota
spellingShingle Science::Medicine
Obesity
Microbiota
Kang, Xing
Ng, Siu-Kin
Liu, Changan
Lin, Yufeng
Zhou, Yunfei
Kwong, Thomas N. Y.
Ni, Yunbi
Lam, Thomas Y. T.
Wu, William K. K.
Wei, Hong
Sung, Joseph Jao Yiu
Yu, Jun
Wong, Sunny Hei
Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
description Background: Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown. Methods: Azoxymethane (AOM)-treated, ApcMin/+ and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated. Findings: Conventional AOM-treated and ApcMin/+ mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth. Interpretation: Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Kang, Xing
Ng, Siu-Kin
Liu, Changan
Lin, Yufeng
Zhou, Yunfei
Kwong, Thomas N. Y.
Ni, Yunbi
Lam, Thomas Y. T.
Wu, William K. K.
Wei, Hong
Sung, Joseph Jao Yiu
Yu, Jun
Wong, Sunny Hei
format Article
author Kang, Xing
Ng, Siu-Kin
Liu, Changan
Lin, Yufeng
Zhou, Yunfei
Kwong, Thomas N. Y.
Ni, Yunbi
Lam, Thomas Y. T.
Wu, William K. K.
Wei, Hong
Sung, Joseph Jao Yiu
Yu, Jun
Wong, Sunny Hei
author_sort Kang, Xing
title Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
title_short Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
title_full Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
title_fullStr Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
title_full_unstemmed Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
title_sort altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice
publishDate 2023
url https://hdl.handle.net/10356/169288
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