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Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects.
Gastroenterology. 2020 09; 159(3):969-983.e4.G

Abstract

BACKGROUND & AIMS

Alterations in the intestinal microbiota affect development of colorectal cancer and drug metabolism. We studied whether the intestinal microbiota affect the ability of aspirin to reduce colon tumor development in mice.

METHODS

We performed studies with APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium to induce colorectal carcinogenesis. Some mice were given antibiotics to deplete intestinal microbes, with or without aspirin, throughout the entire experiment. Germ-free mice were studied in validation experiments. Colon tissues were collected and analyzed by histopathology, quantitative reverse-transcription polymerase chain reaction, and immunoblots. Blood samples and gut luminal contents were analyzed by liquid chromatography/mass spectrometry and an arylesterase activity assay. Fecal samples were analyzed by 16S ribosomal RNA gene and shotgun metagenome sequencing.

RESULTS

Administration of aspirin to mice reduced colorectal tumor number and load in APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium that had been given antibiotics (depleted gut microbiota), but not in mice with intact microbiota. Germ-free mice given aspirin developed fewer colorectal tumors than conventionalized germ-free mice given aspirin. Plasma levels of aspirin were higher in mice given antibiotics than in mice with intact gut microbiota. Analyses of luminal contents revealed that aerobic gut microbes, including Lysinibacillus sphaericus, degrade aspirin. Germ-free mice fed L sphaericus had lower plasma levels of aspirin than germ-free mice that were not fed this bacterium. There was an inverse correlation between aspirin dose and colorectal tumor development in conventional mice, but this correlation was lost with increased abundance of L sphaericus. Fecal samples from mice fed aspirin were enriched in Bifidobacterium and Lactobacillus genera, which are considered beneficial, and had reductions in Alistipes finegoldii and Bacteroides fragili, which are considered pathogenic.

CONCLUSIONS

Aspirin reduces development of colorectal tumors in APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium, depending on the presence of intestinal microbes. L sphaericus in the gut degrades aspirin and reduced its chemopreventive effects in mice. Fecal samples from mice fed aspirin were enriched in beneficial bacteria, with reductions in pathogenic bacteria.

Authors+Show Affiliations

State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.Macau Institute for Applied Research in Medicine and Health, State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.Macau Institute for Applied Research in Medicine and Health, State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.Department 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, China.Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.Microbiome Research Centre, St George & Sutherland Clinical School, University of New South Wales, Sydney, Australia.State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: junyu@cuhk.edu.hk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32387495

Citation

Zhao, Risheng, et al. "Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce Its Bioavailability and Chemopreventive Effects." Gastroenterology, vol. 159, no. 3, 2020, pp. 969-983.e4.
Zhao R, Coker OO, Wu J, et al. Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects. Gastroenterology. 2020;159(3):969-983.e4.
Zhao, R., Coker, O. O., Wu, J., Zhou, Y., Zhao, L., Nakatsu, G., Bian, X., Wei, H., Chan, A. W. H., Sung, J. J. Y., Chan, F. K. L., El-Omar, E., & Yu, J. (2020). Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects. Gastroenterology, 159(3), 969-e4. https://doi.org/10.1053/j.gastro.2020.05.004
Zhao R, et al. Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce Its Bioavailability and Chemopreventive Effects. Gastroenterology. 2020;159(3):969-983.e4. PubMed PMID: 32387495.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects. AU - Zhao,Risheng, AU - Coker,Olabisi Oluwabukola, AU - Wu,Jianlin, AU - Zhou,Yunfei, AU - Zhao,Liuyang, AU - Nakatsu,Geicho, AU - Bian,Xiqing, AU - Wei,Hong, AU - Chan,Anthony W H, AU - Sung,Joseph J Y, AU - Chan,Francis K L, AU - El-Omar,Emad, AU - Yu,Jun, Y1 - 2020/05/06/ PY - 2019/07/17/received PY - 2020/04/22/revised PY - 2020/05/01/accepted PY - 2020/5/11/pubmed PY - 2021/4/16/medline PY - 2020/5/11/entrez KW - Anti-Inflammatory KW - Chemoprevention KW - Colon Cancer KW - Microbiome SP - 969 EP - 983.e4 JF - Gastroenterology JO - Gastroenterology VL - 159 IS - 3 N2 - BACKGROUND & AIMS: Alterations in the intestinal microbiota affect development of colorectal cancer and drug metabolism. We studied whether the intestinal microbiota affect the ability of aspirin to reduce colon tumor development in mice. METHODS: We performed studies with APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium to induce colorectal carcinogenesis. Some mice were given antibiotics to deplete intestinal microbes, with or without aspirin, throughout the entire experiment. Germ-free mice were studied in validation experiments. Colon tissues were collected and analyzed by histopathology, quantitative reverse-transcription polymerase chain reaction, and immunoblots. Blood samples and gut luminal contents were analyzed by liquid chromatography/mass spectrometry and an arylesterase activity assay. Fecal samples were analyzed by 16S ribosomal RNA gene and shotgun metagenome sequencing. RESULTS: Administration of aspirin to mice reduced colorectal tumor number and load in APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium that had been given antibiotics (depleted gut microbiota), but not in mice with intact microbiota. Germ-free mice given aspirin developed fewer colorectal tumors than conventionalized germ-free mice given aspirin. Plasma levels of aspirin were higher in mice given antibiotics than in mice with intact gut microbiota. Analyses of luminal contents revealed that aerobic gut microbes, including Lysinibacillus sphaericus, degrade aspirin. Germ-free mice fed L sphaericus had lower plasma levels of aspirin than germ-free mice that were not fed this bacterium. There was an inverse correlation between aspirin dose and colorectal tumor development in conventional mice, but this correlation was lost with increased abundance of L sphaericus. Fecal samples from mice fed aspirin were enriched in Bifidobacterium and Lactobacillus genera, which are considered beneficial, and had reductions in Alistipes finegoldii and Bacteroides fragili, which are considered pathogenic. CONCLUSIONS: Aspirin reduces development of colorectal tumors in APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium, depending on the presence of intestinal microbes. L sphaericus in the gut degrades aspirin and reduced its chemopreventive effects in mice. Fecal samples from mice fed aspirin were enriched in beneficial bacteria, with reductions in pathogenic bacteria. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/32387495/Aspirin_Reduces_Colorectal_Tumor_Development_in_Mice_and_Gut_Microbes_Reduce_its_Bioavailability_and_Chemopreventive_Effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(20)30596-5 DB - PRIME DP - Unbound Medicine ER -