A Gnotobiotic Mouse Model Demonstrates That Dietary Fiber Protects against Colorectal Tumorigenesis in a Microbiota- and Butyrate-Dependent Manner

Donohoe, Dallas R.; Holley, Darcy; Collins, Leonard B.; Montgomery, Stephanie A.; Whitmore, Alan C.; Hillhouse, Andrew; Curry, Kaitlin P.; Renner, Sarah W.; Greenwalt, Alicia; Ryan, Elizabeth P.; Godfrey, Virginia; Heise, Mark T.; Threadgill, Deborah S.; Han, Anna; Swenberg, James A.; Threadgill, David W.; Bultman, Scott J.

doi:10.1158/2159-8290.cd-14-0501

Cited by 367 publications

(315 citation statements)

References 39 publications

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“…Epigenetic modulators, such as HDAC2 overexpression, were associated with colorectal cancer progression, and a selective HDAC2 inhibitor was reported to prevent colorectal cancer tumorigenesis in both AOM/DSS mouse models and Apc Min/þ mice (33). A recent study shows that gut microbiota could ferment dietary fiber into butyrate, a class I and II HDAC inhibitor, to exert chemopreventive effect on colorectal cancer in gnotobiotic mouse models (34), suggesting that HDACs are potential targets for colorectal cancer prevention. In addition, epidemiology study suggests that statins attenuated the risk of colorectal cancer (35).…”

Section: Clin Cancer Res; 22(16) August 15 2016mentioning

confidence: 99%

Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor

Wei

Lin

Tseng

et al. 2016

Clinical Cancer Research

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Purpose: Colorectal cancer is a worldwide cancer with rising annual incidence. Inflammation is a well-known cause of colorectal cancer carcinogenesis. Metabolic inflammation (metaflammation) and altered gut microbiota (dysbiosis) have contributed to colorectal cancer. Chemoprevention is an important strategy to reduce cancer-related mortality. Recently, various polypharmacologic molecules that dually inhibit histone deacetylases (HDAC) and other therapeutic targets have been developed.Experimental Design: Prevention for colitis was examined by dextran sodium sulfate (DSS) mouse models. Prevention for colorectal cancer was examined by azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models. Immunohistochemical staining was utilized to analyze the infiltration of macrophages and neutrophils and COX-II expression in mouse tissue specimens. The endotoxin activity was evaluated by Endotoxin Activity Assay Kit.Results: We synthesized a statin hydroxamate that simultaneously inhibited HDAC and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Its preventive effect on colitis and colitis-associated colorectal cancer in mouse models was examined. Oral administration of this statin hydroxamate could prevent acute inflammation in the DSS-induced colitis and AOM/ DSS-induced colorectal cancer with superior activity than the combination of lovastatin and SAHA. It also reduced proinflammatory cytokines, chemokines, expression of COX-II, and cyclin D1 in inflammation and tumor tissues, as well as decreasing the infiltration of macrophages and neutrophils in tumor-surrounding regions. Stemness of colorectal cancer and the release of endotoxin in AOM/DSS mouse models were also attenuated by this small molecule.Conclusions: This study demonstrates that the polypharmacological HDAC inhibitor has promising effect on the chemoprevention of colorectal cancer, and serum endotoxin level might serve as a potential biomarker for its chemoprevention. Clin Cancer Res; 22(16); 4158-69. Ó2016 AACR.

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Section: Clin Cancer Res; 22(16) August 15 2016mentioning

confidence: 99%

Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor

Wei

Lin

Tseng

et al. 2016

Clinical Cancer Research

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“…As these agents may have a profound systemic immune effect, it has been suggested that diarrhea could potentially be inflammatory in nature (8)(9)(10). The role of gut microbiota in immune-related inflammation [e.g., through lipopolysaccharides (LPS) or fermentation of butyrates in colonocytes] provides motivation to investigate the relationship between the microbiota and VEGF-TKI-induced diarrhea (11,12). As a first step, we focus on demonstrating that patients with VEGF-TKI-induced diarrhea have a different microbiota population than patients without diarrhea.…”

Section: Introductionmentioning

confidence: 99%

Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor–Tyrosine Kinase Inhibitors

Pal

et al. 2015

Clinical Cancer Research

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Purpose: Diarrhea occurs in approximately half of patients with metastatic renal cell carcinoma (mRCC) receiving vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKI). We evaluated the relationship between VEGF-TKI–related diarrhea and stool microbiota. Experimental Design: Stool samples were collected from 20 mRCC patients receiving VEGF-TKIs. 16S rRNA sequencing was used to characterize the stool bacteriomic profiling of patients. Assay validation with Salmonella typhimurium spike-in experiments suggested greatest speciation with use of the V5 region. Results: Higher levels of Bacteroides spp. and lower levels of Prevotella spp. were found in patients with diarrhea. In addition, patients receiving VEGF-TKIs with mRCC appeared to have less relative abundance of Bifidobacterium spp. as compared with previous reports based on healthy subjects. Conclusions: We have thus demonstrated interplay between microbiota and VEGF-TKI–induced diarrhea. Further studies are warranted to evaluate the potential causative role of preexisting dysbiosis in VEGF-TKI–related diarrhea. Clin Cancer Res; 21(23); 5286–93. ©2015 AACR.

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“…Microbiota could have a key role in fiber fermentation into bioactive metabolite short-chain fatty acids; thus, their role should not be overlooked. In gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium, it was shown that dietary fiber could have a potent tumor-suppressive effect in a microbiota-and butyrate-dependent manner (Donohoe et al 2014).…”

Section: Dietary Fibers Short-chain Fatty Acids and Butyratementioning

confidence: 99%

“…Gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium demonstrated that dietary fiber protects against colorectal carcinoma in a microbiota-dependent and butyrate-dependent manner (Donohoe et al 2014). Due to high aerobic glycolysis by malignant tumors (Warburg effect), butyrate is metabolized less in tumors where it accumulates and functions as an HDAC inhibitor, stimulating histone acetylation, inhibiting cell proliferation, and inducing apoptosis in cancer cells (Donohoe et al 2014).…”

Section: Dietary Fibers Short-chain Fatty Acids and Butyratementioning

confidence: 99%

“…Due to high aerobic glycolysis by malignant tumors (Warburg effect), butyrate is metabolized less in tumors where it accumulates and functions as an HDAC inhibitor, stimulating histone acetylation, inhibiting cell proliferation, and inducing apoptosis in cancer cells (Donohoe et al 2014). These findings suggest that probiotic/prebiotic strategies could modulate endogenous natural HDAC inhibitors, such as butyrate, for anticancer chemoprevention.…”

Section: Dietary Fibers Short-chain Fatty Acids and Butyratementioning

confidence: 99%

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Epigenetic Impact of Bioactive Dietary Compounds in Cancer Chemoprevention

Šupić

Wagner

Magić

2016

Critical Dietary Factors in Cancer Chemoprevention

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Epigenetic changes refer to modifications caused by heritable but potentially reversible changes in gene expression not coded in the DNA sequence. Evidence has been provided that various environmental factors and dietary bioactive compounds contribute to cancer development through epigenetic mechanisms. The main mechanisms of epigenetic control in mammals are DNA methylation, histone modifications, and RNA silencing through noncoding RNAs. The inhibition of DNA methyltransferases (DNMTs) involved in DNA methylation of CpG-rich regions of gene promoters and various enzymes involved in the chromatin condensation such as histone deacetylases (HDACs) have been recognized as potent strategies for cancer therapy and chemoprevention. Treatments using natural compounds such as green tea polyphenols, soy isoflavones, curcumin, resveratrol, isothiocyanates, and butyrate (an intestinal product from dietary fiber) modulate DNMT or HDAC gene expression and/or protein levels and activities, indicating that natural compounds could have strong potential to reverse epigenetic changes, without the adverse toxic effects associated with synthetic epigenetic inhibitors used in chemotherapy. Further characterization of the chemopreventive properties of various dietary bioactive compounds is warranted to potentially establish the clinical utility of dietary factors as anticancer compounds either alone or in combination with other dietary factors or clinically relevant therapeutics. Moreover, these characterizations are useful for personalized dietary recommendations and chemopreventive strategies for reducing cancer incidence.

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A Gnotobiotic Mouse Model Demonstrates That Dietary Fiber Protects against Colorectal Tumorigenesis in a Microbiota- and Butyrate-Dependent Manner

Cited by 367 publications

References 39 publications

Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor

Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor

Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor–Tyrosine Kinase Inhibitors

Epigenetic Impact of Bioactive Dietary Compounds in Cancer Chemoprevention

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