Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases

Han, Anna; Bennett, Natalie E.; Bettaieb, Ahmed; Whelan, Jay; Donohoe, Dallas R.

doi:10.18632/oncotarget.25546

Cited by 39 publications

(19 citation statements)

References 53 publications

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“…Interestingly, the higher amount of butyric acid in CRC patients could depend also by the fact that cancerous colonocytes prefer the glucose utilization as primary energy source instead of oxidize butyrate and recently, Anna Han and coll. have demonstrated that butyrate decreased its own oxidation in cancerous colonocytes[52].…”

Section: Discussionmentioning

confidence: 99%

Evaluation and comparison of short chain fatty acids composition in gut diseases

Niccolai

Baldi

Ricci

et al. 2019

WJG

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BACKGROUNDAn altered (dysbiosis) and unhealthy status of the gut microbiota is usually responsible for a reduction of short chain fatty acids (SCFAs) concentration. SCFAs obtained from the carbohydrate fermentation processes are crucial in maintaining gut homeostasis and their determination in stool samples could provide a faster, reliable and cheaper method to highlight the presence of an intestinal dysbiosis and a biomarker for various gut diseases. We hypothesize that different intestinal diseases, such as celiac disease (CD), adenomatous polyposis (AP) and colorectal cancer (CRC) could display a particular fecal SCFAs’ signature.AIMTo compare the fecal SCFAs’ profiles of CD, AP, CRC patients and healthy controls, using the same analytical method.METHODSIn this cross-sectional study, we defined and compared the SCFAs’ concentration in fecal samples of 9 AP, 16 CD, 19 CRC patients and 16 healthy controls (HC). The SCFAs’ analysis were performed using a gas-chromatography coupled with mass spectrometry method. Data analysis was carried out using Wilcoxon rank-sum test to assess pairwise differences of SCFAs’ profiles, partial least squares-discriminate analysis (PLS-DA) to determine the status membership based on distinct SCFAs’ profiles, and Dirichlet regression to determine factors influencing concentration levels of SCFAs.RESULTSWe have not observed any difference in the SCFAs’ amount and composition between CD and healthy control. On the contrary, the total amount of SCFAs was significantly lower in CRC patients compared to HC (P = 0.044) and CD (P = 0.005). Moreover, the SCFAs’ percentage composition was different in CRC and AP compared to HC. In detail, HC displayed higher percentage of acetic acid (P value = 1.3 × 10-6) and a lower amount of butyric (P value = 0.02192), isobutyric (P value = 7.4 × 10-5), isovaleric (P value = 0.00012) and valeric (P value = 0.00014) acids compared to CRC patients. AP showed a lower abundance of acetic acid (P value = 0.00062) and higher percentages of propionic (P value = 0.00433) and isovaleric (P value = 0.00433) acids compared to HC. Moreover, AP showed higher levels of propionic acid (P value = 0.03251) and a lower level of isobutyric acid (P value = 0.00427) in comparison to CRC. The PLS-DA model demonstrated a significant separation of CRC and AP groups from HC, although some degree of overlap was observed between CRC and AP.CONCLUSIONAnalysis of fecal SCFAs shows the potential to provide a non-invasive means of diagnosis to detect patients with CRC and AP, while CD patients cannot be discriminated from healthy subjects.

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Section: Discussionmentioning

confidence: 99%

Evaluation and comparison of short chain fatty acids composition in gut diseases

Niccolai

Baldi

Ricci

et al. 2019

WJG

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“…In colonocytes, butyrate is oxidased to produce ATP; in cancer cells butyrate cannot be metabolized due to the Warburg effect and thus accumulates and enters into the nucleous where it inhibits HDACs [26]. In colorectal cancer cells, butyrate has been shown to decrease the expression of short chain acyl-CoA dehydrogenase, which catalyses oxidation of butyrate [187,188].…”

Section: Discussionmentioning

confidence: 99%

Effects of Intestinal Microbial–Elaborated Butyrate on Oncogenic Signaling Pathways

2019

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The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals.

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“…The increase in colonic butyrate production in resveratrol-treated CRC mice was interesting given the fact that previous reports show butyrate not only increases Treg production [56,57], but the HDAC inhibiting activities of this SCFA have been implicated as a key mechanism in which it exerts anti-inflammatory and anti-cancer properties [58][59][60], including in colorectal cancer models [61]. With this in mind, studies were performed to examine the ability of resveratrol and BUT to suppress HDACs in vitro and in the CRC in vivo model and how this correlated with increased Treg production.…”

Section: Resveratrol and But Inhibit Hdacs In Vivo And In Vitromentioning

confidence: 96%

Alterations in the Gut Microbiome and Suppression of Histone Deacetylases by Resveratrol Are Associated with Attenuation of Colonic Inflammation and Protection Against Colorectal Cancer

Alrafas

Busbee

Chitrala

et al. 2020

JCM

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Inflammatory bowel disease (IBD) is known to significantly increase the risk for development of colorectal cancer (CRC), suggesting inflammation and cancer development are closely intertwined. Thus, agents that suppress inflammation may prevent the onset of cancer. In the current study, we used resveratrol, an anti-inflammatory stilbenoid, to study the role of microbiota in preventing inflammation-driven CRC. Resveratrol treatment in the azoxymethane (AOM) and dextran sodium sulphate (DSS) CRC murine model caused an increase in anti-inflammatory CD4 + FOXP3 + (Tregs) and CD4 + IL10 + cells, a decrease in proinflammatory Th1 and Th17 cells, and attenuated CRC development. Gut microbial profile studies demonstrated that resveratrol altered the gut microbiome and short chain fatty acid (SCFA), with modest increases in n-butyric acid and a potential butyrate precursor isobutyric acid. Fecal transfer from resveratrol-treated CRC mice and butyrate supplementation resulted in attenuation of disease and suppression of the inflammatory T cell response. Data also revealed both resveratrol and sodium butyrate (BUT) were capable of inhibiting histone deacetylases (HDACs), correlating with Treg induction. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed increased expression of Treg-specific transcription factor FoxP3 or anti-inflammatory IL-10 resulted in an increase in 5-year survival of patients with CRC. These data suggest that alterations in the gut microbiome lead to an anti-inflammatory T cell response, leading to attenuation of inflammation-driven CRC.

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Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases

Cited by 39 publications

References 53 publications

Evaluation and comparison of short chain fatty acids composition in gut diseases

Evaluation and comparison of short chain fatty acids composition in gut diseases

Effects of Intestinal Microbial–Elaborated Butyrate on Oncogenic Signaling Pathways

Alterations in the Gut Microbiome and Suppression of Histone Deacetylases by Resveratrol Are Associated with Attenuation of Colonic Inflammation and Protection Against Colorectal Cancer

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