The Role of Diet Related Short-Chain Fatty Acids in Colorectal Cancer Metabolism and Survival: Prevention and Therapeutic Implications

: Colorectal Cancer (CRC) is a major cause of cancer-related death worldwide. CRC increased risk has been associated with alterations in the intestinal microbiota, with decreased production of Short Chain Fatty Acids (SCFAs). SCFAs produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch. While colonocytes use the three major SCFAs, namely acetate, propionate and butyrate, as energy sources, transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit increased sensitivity to SCFAs, thus indicating they play an important role in cell homeostasis. Manipulation of SCFA levels in the intestine, through changes in microbiota, has therefore emerged as a potential preventive/therapeutic strategy for CRC. Interest in understanding SCFAs mechanism of action in CRC cells has increased in the last years. Several SCFA transporters like SMCT-1, MCT-1 and aquaporins have been identified as the main transmembrane transporters in intestinal cells. Recently, it was shown that acetate promotes plasma membrane re-localization of MCT-1 and triggers changes in the glucose metabolism. SCFAs induce apoptotic cell death in CRC cells, and further mechanisms have been discovered, including the involvement of lysosomal membrane permeabilization, associated with mitochondria dysfunction and degradation. : In this review, we will discuss the current knowledge on the transport of SCFAs by CRC cells and their effects on CRC metabolism and survival. The impact of increasing SCFA production by manipulation of colon microbiota on the prevention/therapy of CRC will also be addressed.

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Fecal Short-Chain Fatty Acids Are Not Predictive of Colonic Tumor Status and Cannot Be Predicted Based on Bacterial Community Structure

mBio ◽

10.1128/mbio.01454-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 5

Author(s):

Marc A. Sze ◽

Begüm D. Topçuoğlu ◽

Nicholas A. Lesniak ◽

Mack T. Ruffin ◽

Patrick D. Schloss

Keyword(s):

Colorectal Cancer ◽

Fatty Acids ◽

16S Rrna ◽

16S Rrna Gene ◽

Sequence Data ◽

Short Chain Fatty Acids ◽

Tumor Burden ◽

Short Chain ◽

Rrna Gene ◽

Chain Fatty Acids

ABSTRACT Colonic bacterial populations are thought to have a role in the development of colorectal cancer with some protecting against inflammation and others exacerbating inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory properties and are produced in large quantities by colonic bacteria that produce SCFAs by fermenting fiber. We assessed whether there was an association between fecal SCFA concentrations and the presence of colonic adenomas or carcinomas in a cohort of individuals using 16S rRNA gene and metagenomic shotgun sequence data. We measured the fecal concentrations of acetate, propionate, and butyrate within the cohort and found that there were no significant associations between SCFA concentration and tumor status. When we incorporated these concentrations into random forest classification models trained to differentiate between people with healthy colons and those with adenomas or carcinomas, we found that they did not significantly improve the ability of 16S rRNA gene or metagenomic gene sequence-based models to classify individuals. Finally, we generated random forest regression models trained to predict the concentration of each SCFA based on 16S rRNA gene or metagenomic gene sequence data from the same samples. These models performed poorly and were able to explain at most 14% of the observed variation in the SCFA concentrations. These results support the broader epidemiological data that questions the value of fiber consumption for reducing the risks of colorectal cancer. Although other bacterial metabolites may serve as biomarkers to detect adenomas or carcinomas, fecal SCFA concentrations have limited predictive power. IMPORTANCE Considering that colorectal cancer is the third leading cancer-related cause of death within the United States, it is important to detect colorectal tumors early and to prevent the formation of tumors. Short-chain fatty acids (SCFAs) are often used as a surrogate for measuring gut health and for being anticarcinogenic because of their anti-inflammatory properties. We evaluated the fecal SCFA concentrations of a cohort of individuals with different colonic tumor burdens who were previously analyzed to identify microbiome-based biomarkers of tumors. We were unable to find an association between SCFA concentration and tumor burden or use SCFAs to improve our microbiome-based models of classifying people based on their tumor status. Furthermore, we were unable to find an association between the fecal community structure and SCFA concentrations. Our results indicate that the association between fecal SCFAs, the gut microbiome, and tumor burden is weak.

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IDDF2019-ABS-0090 Carboxylomics profiles delineate short-chain fatty acids in colorectal cancer diagnosis and prognosis

10.1136/gutjnl-2019-iddfabstracts.25 ◽

2019 ◽

Author(s):

Jian-Lin Wu ◽

Xiqing Bian ◽

Na Li

Keyword(s):

Colorectal Cancer ◽

Fatty Acids ◽

Cancer Diagnosis ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Diagnosis And Prognosis ◽

Cancer Diagnosis And Prognosis ◽

Chain Fatty Acids

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Pilot Study on the Forehead Skin Microbiome and Short Chain Fatty Acids Depending on the SC Functional Index in Korean Cohorts

Microorganisms ◽

10.3390/microorganisms9112216 ◽

2021 ◽

Vol 9 (11) ◽

pp. 2216

Author(s):

Haryung Park ◽

Karina Arellano ◽

Yuri Lee ◽

Subin Yeo ◽

Yosep Ji ◽

...

Keyword(s):

Fatty Acids ◽

Skin Barrier ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Skin Barrier Function ◽

Skin Microbiome ◽

Dry Skin ◽

Pathogen Invasion ◽

The Impact ◽

Chain Fatty Acids

Dry skin is one of the indicators of a compromised skin barrier. An intact skin barrier is not only important to reserve the hydration within the epidermal tissue but also to protect our skin from environmental stressors and inhibit pathogen invasion; damage to the skin barrier may lead to inflammatory skin diseases. Some microbial metabolites such as short chain fatty acids may inhibit or destroy harmful bacteria and regulate the host immune system. The impact of the skin microbiome and short chain fatty acids on skin barrier function was studied in two groups of 75 participants each. The cohort was equally divided in dry and moist skin types, based on stratum corneum (SC) functionality index (SCFI), reflecting the ratio of transepidermal water loss (TEWL). A dry group represents a low SCFI and a moist group a high SCFI. Compared with the dry skin group, propionate and Cutibacterium levels (previously known as Propionibacterium acnes) were significantly higher (p < 0.001) in the moist group. Levels of Cutibacterium were negatively correlated with those of Staphylococcus (p <0.0001) in both dry and moist groups. The moist group also had a significantly higher propionate concentration (p < 0.001). This study showed that the microbial community and short chain fatty acid concentration may be considered as significant determinants of the SCFI of the skin.

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Differences in Fecal Gut Microbiota, Short-Chain Fatty Acids and Bile Acids Link Colorectal Cancer Risk to Dietary Changes Associated with Urbanization Among Zimbabweans

Nutrition and Cancer ◽

10.1080/01635581.2019.1602659 ◽

2019 ◽

Vol 71 (8) ◽

pp. 1313-1324 ◽

Cited By ~ 4

Author(s):

L. Katsidzira ◽

S. Ocvirk ◽

A. Wilson ◽

J. Li ◽

C. B. Mahachi ◽

...

Keyword(s):

Colorectal Cancer ◽

Fatty Acids ◽

Cancer Risk ◽

Gut Microbiota ◽

Bile Acids ◽

Short Chain Fatty Acids ◽

Colorectal Cancer Risk ◽

Short Chain ◽

Dietary Changes ◽

Chain Fatty Acids

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866: Screening of Lactobacillus reuteri strains for their short chain fatty acids production, stability and potential in colorectal cancer: In-vitro analysis

European Journal of Cancer ◽

10.1016/s0959-8049(14)50769-1 ◽

2014 ◽

Vol 50 ◽

pp. S212

Author(s):

I. Kahouli ◽

M. Meenakshi ◽

C. Tomaro-Duchesneau ◽

S. Saha ◽

D. Marinescu ◽

...

Keyword(s):

Colorectal Cancer ◽

Fatty Acids ◽

Lactobacillus Reuteri ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Vitro Analysis ◽

In Vitro Analysis ◽

Chain Fatty Acids

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Synbiotics impact on dominant faecal microbiota and short-chain fatty acids production in sows

FEMS Microbiology Letters ◽

10.1093/femsle/fnz157 ◽

2019 ◽

Vol 366 (13) ◽

Cited By ~ 2

Author(s):

Katarzyna Śliżewska ◽

Agnieszka Chlebicz

Keyword(s):

Fatty Acids ◽

Intestinal Microbiota ◽

High Performance ◽

Anaerobic Bacteria ◽

Short Chain Fatty Acids ◽

Feed Additives ◽

Short Chain ◽

Control Group ◽

The Impact ◽

Chain Fatty Acids

ABSTRACT The aim of this study was to estimate the influence of synbiotics on intestinal microbiota and its metabolism in sows. Three different synbiotics were administered with feed to animals from three experimental groups. Two groups of sows were given commercially available probiotics (BioPlus 2B®, Cylactin® LBC) as forage additives for comparison. The control group of sows was given unmodified fodder. The study was conducted for 48 days (10 days before farrowing, and continued 38 days after) and faeces samples were collected four times. The scope of this work was to designate the dominant microbiota in sows’ faeces. Therefore, the total number of anaerobic bacteria, Bifidobacterium sp., Lactobacillus sp., Bacteroides sp., Clostridium sp., Enterococcus sp., Enterobacteriaceae, Escherichia coli and yeast was determined, using the plate method. Changes in the concentration of lactic acid, short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) were also determined in correlation with the feed additives administered to the sows using high-performance liquid chromatography analysis (HPLC). Our results allowed us to conclude that synbiotics have a beneficial effect on intestinal microbiota of sows and its metabolism. We observed that the impact of the synbiotics on the microbiota was more significant than the one induced by probiotics.

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Short Chain Fatty Acids Modulate the Growth and Virulence of Pathosymbiont Escherichia coli and Host Response

Antibiotics ◽

10.3390/antibiotics9080462 ◽

2020 ◽

Vol 9 (8) ◽

pp. 462

Author(s):

Shiying Zhang ◽

Belgin Dogan ◽

Cindy Guo ◽

Deepali Herlekar ◽

Katrina Stewart ◽

...

Keyword(s):

Fatty Acids ◽

Virulence Gene ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Host Responses ◽

Virulence Gene Expression ◽

E Coli ◽

The Impact ◽

Chain Fatty Acids

Short chain fatty acids (SCFA), principally acetate, propionate, and butyrate, are produced by fermentation of dietary fibers by the gut microbiota. SCFA regulate the growth and virulence of enteric pathogens, such as enterohemorrhagic E. coli (EHEC), Klebsiella and Salmonella. We sought to investigate the impact of SCFA on growth and virulence of pathosymbiont E. coli associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their role in regulating host responses to bacterial infection in vitro. We found that under ileal conditions (pH = 7.4; 12 mM total SCFA), SCFA significantly (p < 0.05) potentiate the growth and motility of pathosymbiont E. coli. However, under colonic conditions (pH = 6.5; 65 to 123 mM total SCFA), SCFA significantly (p < 0.05) inhibit growth in a pH dependent fashion (up to 60%), and down-regulate virulence gene expression (e.g., fliC, fimH, htrA, chuA, pks). Functional analysis reveals that colonic SCFA significantly (p < 0.05) inhibit E. coli motility (up to 95%), infectivity (up to 60%), and type 1 fimbria-mediated agglutination (up to 50%). In addition, SCFA significantly (p < 0.05) inhibit the activation of NF-kB, and IL-8 production by epithelial cells. Our findings provide novel insights on the role of the regional chemical microenvironment in regulating the growth and virulence of pathosymbiont E. coli and opportunities for therapeutic intervention.

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Diabetes Mellitus and Increased Tuberculosis Susceptibility: The Role of Short-Chain Fatty Acids

Journal of Diabetes Research ◽

10.1155/2016/6014631 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 31

Author(s):

Ekta Lachmandas ◽

Corina N. A. M. van den Heuvel ◽

Michelle S. M. A. Damen ◽

Maartje C. P. Cleophas ◽

Mihai G. Netea ◽

...

Keyword(s):

Diabetes Mellitus ◽

Fatty Acids ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Cytokine Responses ◽

Immunological Mechanisms ◽

Increased Risk ◽

Chain Fatty Acids

Type 2 diabetes mellitus confers a threefold increased risk for tuberculosis, but the underlying immunological mechanisms are still largely unknown. Possible mediators of this increased susceptibility are short-chain fatty acids, levels of which have been shown to be altered in individuals with diabetes. We examined the influence of physiological concentrations of butyrate on cytokine responses toMycobacterium tuberculosis(Mtb) in human peripheral blood mononuclear cells (PBMCs). Butyrate decreased Mtb-induced proinflammatory cytokine responses, while it increased production of IL-10. This anti-inflammatory effect was independent of butyrate’s well-characterised inhibition of HDAC activity and was not accompanied by changes in Toll-like receptor signalling pathways, the eicosanoid pathway, or cellular metabolism. In contrast blocking IL-10 activity reversed the effects of butyrate on Mtb-induced inflammation. Alteration of the gut microbiota, thereby increasing butyrate concentrations, can reduce insulin resistance and obesity, but further studies are needed to determine how this affects susceptibility to tuberculosis.

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