Despite the success of colonoscopy screening, colorectal cancer (CRC) remains one of the most common and deadly cancers, and CRC incidence is rising in some countries where screening is not routine ...and populations have recently switched from traditional diets to western diets. Diet and energy balance influence CRC by multiple mechanisms. They modulate the composition and function of gut microbiota, which have a prodigious metabolic capacity and can produce oncometabolites or tumor‐suppressive metabolites depending, in part, on which dietary factors and digestive components are present in the GI tract. Gut microbiota also have a profound effect on immune cells in the lamina propria, which influences inflammation and subsequently CRC. Nutrient availability, which is an outcome of diet and energy balance, determines the abundance of certain energy metabolites that are essential co‐factors for epigenetic enzymes and therefore impinges upon epigenetic regulation of gene expression. Aberrant epigenetic marks accumulate during CRC, and epimutations that are selected for drive tumorigenesis by causing transcriptome profiles to diverge from the cell of origin. In some instances, the above mechanisms are intertwined as exemplified by dietary fiber being metabolized by colonic bacteria into butyrate, which is both a short‐chain fatty acid (SCFA) and a histone deacetylase (HDAC) inhibitor that epigenetically upregulates tumor‐suppressor genes in CRC cells and anti‐inflammatory genes in immune cells.
Diet and gut microbiota influence epigenetic events and colorectal cancer by multiple mechanisms. Microbiota convert dietary factors and digestive components into metabolites that positively or negatively influence cancer. These metabolites exert their effects in multiple ways including epigenetic regulation of gene expression as exemplified by butyrate functioning as an HDAC inhibitor. Gut microbiota also have a profound effect on immune cells, which influences colorectal cancer incidence and progression through the immune response. This is important not only for cancer prevention but also for cancer treatment as exemplified by recent work suggesting that probiotics will be a successful adjuvant for cancer immunotherapy.
Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate ...that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source, so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences.
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► The Warburg effect mediates butyrate's action on cell proliferation ► Butyrate regulates histone acetylation and gene expression as an acetyl-CoA donor ► The dose of butyrate determines the utilization of epigenetic mechanisms ► Butyrate modulates different genes as a HAT cofactor compared to an HDAC inhibitor
It is becoming increasingly clear that microbiota inhabiting our bodies influence cancer predisposition and etiology. In addition to pathogens with oncogenic properties, commensal and symbiotic ...microbiota have tumor-suppressive properties. Diet and other environmental factors can modulate the abundance of certain members of microbial communities within the gastrointestinal tract and at other anatomical sites. Furthermore, some dietary factors are metabolized by commensal/symbiotic gut microbiota into bioactive food components believed to prevent cancer. For example, dietary fiber undergoes bacterial fermentation in the colon to yield butyrate, which is a short-chain fatty acid and histone deacetylase (HDAC) inhibitor that suppresses the viability and growth of colorectal cancer cell lines. A recent study using gnotobiotic mouse models demonstrates that fiber can protect against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner that involves the Warburg effect. This and other examples suggest that some of the inter-individual variation observed in epidemiology and intervention studies that have investigated associations between diet and cancer risk might be explained by differences in microbiota among the participants. Data from basic research studies also support the idea that probiotics and prebiotics could be plausible chemoprevention strategies that may be utilized to a greater extent in the future.
Gene-environment interactions underlie cancer susceptibility and progression. Yet, we still have limited knowledge of which environmental factors are important and how they function during ...tumorigenesis. In this respect, the microbial communities that inhabit our gastrointestinal tract and other body sites have been unappreciated until recently. However, our microbiota are environmental factors that we are exposed to continuously, and human microbiome studies have revealed significant differences in the relative abundance of certain microbes in cancer cases compared with controls. To characterize the function of microbiota in carcinogenesis, mouse models of cancer have been treated with antibiotics. They have also been maintained in a germfree state or have been colonized with specific bacteria in specialized (gnotobiotic) facilities. These studies demonstrate that microbiota can increase or decrease cancer susceptibility and progression by diverse mechanisms such as by modulating inflammation, influencing the genomic stability of host cells and producing metabolites that function as histone deacetylase inhibitors to epigenetically regulate host gene expression. One might consider microbiota as tractable environmental factors because they are highly quantifiable and relatively stable within an individual compared with our exposures to external agents. At the same time, however, diet can modulate the composition of microbial communities within our gut, and this supports the idea that probiotics and prebiotics can be effective chemoprevention strategies. The trajectory of where the current work is headed suggests that microbiota will continue to provide insight into the basic mechanisms of carcinogenesis and that microbiota will also become targets for therapeutic intervention.
Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may ...represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression.
Dietary factors, microbial composition, and metabolism are intimately intertwined into a complex network whose activities influence important intestinal functions. In a recent issue of Cell, Belcheva ...et al. (2014) show that microbial-derived butyrate promotes proliferation of cancer-initiated intestinal epithelial cells, suggesting that it can act as an oncometabolite.
The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial ...metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD
+, oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27
kip1 phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor.
► The microbiome is required to maintain energy homeostasis in colonocytes ► Germfree colonocytes are energy deprived and survive via autophagy ► Butyrate rescues the energetic perturbation and inhibits autophagy ► Butyrate rescues as energy source rather than HDAC inhibitor
A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is ...rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, (13)C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO(2) production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G(1)-to-S-phase transition that was rescued by a butyrate-fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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