Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context
Summary: 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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423002359 |
| _version_ | 1797798669793099776 |
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| author | Xing Kang Siu-Kin Ng Changan Liu Yufeng Lin Yunfei Zhou Thomas N.Y. Kwong Yunbi Ni Thomas Y.T. Lam William K.K. Wu Hong Wei Joseph J.Y. Sung Jun Yu Sunny H. Wong |
| author_facet | Xing Kang Siu-Kin Ng Changan Liu Yufeng Lin Yunfei Zhou Thomas N.Y. Kwong Yunbi Ni Thomas Y.T. Lam William K.K. Wu Hong Wei Joseph J.Y. Sung Jun Yu Sunny H. Wong |
| author_sort | Xing Kang |
| collection | DOAJ |
| description | Summary: 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. Funding: This work was funded by 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), and NTU Start-Up Grant (021337-00001). |
| first_indexed | 2024-03-13T04:08:21Z |
| format | Article |
| id | doaj.art-6eff480801eb40048ceea1cc3ee5cdd7 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-13T04:08:21Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6eff480801eb40048ceea1cc3ee5cdd72023-06-21T06:58:32ZengElsevierEBioMedicine2352-39642023-07-0193104670Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in contextXing Kang0Siu-Kin Ng1Changan Liu2Yufeng Lin3Yunfei Zhou4Thomas N.Y. Kwong5Yunbi Ni6Thomas Y.T. Lam7William K.K. Wu8Hong Wei9Joseph J.Y. Sung10Jun Yu11Sunny H. Wong12Department of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Lee Kong Chian School of Medicine, Nanyang Technological University, SingaporeDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, ChinaDepartment of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China; Department of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Corresponding author. Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore.Department of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China; Corresponding author. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.Department of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Corresponding author. Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore.Summary: 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. Funding: This work was funded by 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), and NTU Start-Up Grant (021337-00001).http://www.sciencedirect.com/science/article/pii/S2352396423002359ObesityMicrobiotaColorectal cancerPro-inflammationGut barrier |
| spellingShingle | Xing Kang Siu-Kin Ng Changan Liu Yufeng Lin Yunfei Zhou Thomas N.Y. Kwong Yunbi Ni Thomas Y.T. Lam William K.K. Wu Hong Wei Joseph J.Y. Sung Jun Yu Sunny H. Wong Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context EBioMedicine Obesity Microbiota Colorectal cancer Pro-inflammation Gut barrier |
| title | Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context |
| title_full | Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context |
| title_fullStr | Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context |
| title_full_unstemmed | Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context |
| title_short | Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceResearch in context |
| title_sort | altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in miceresearch in context |
| topic | Obesity Microbiota Colorectal cancer Pro-inflammation Gut barrier |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423002359 |
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