Probiotic metabolites as epigenetic targets in the prevention of colon cancer.
ABSTRACT Dietary interventions for preventing colon cancer have recently attracted increased attention from researchers and clinicians. The probiotics have emerged as potential therapeutic agents but are also regarded as healthy dietary supplements for nutrition and health applications. The probiotic metabolome may interfere with various cellular and molecular processes, including the onset and progression of colon cancer. Probiotic metabolites may lead to the modulation of diverse cellular signal transduction and metabolic pathways. The gut microbial metabolites (organic acids, bacteriocins, peptides, etc.) have been noted to interact with multiple key targets in various metabolic pathways that regulate cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis, and metastasis. Progress in this field suggests that epigenetic alterations will be widely used in the near future to manage colon cancer. The present review provides insights into the molecular basis of the therapeutic applications and the chemopreventive activities of certain probiotic metabolites, with emphasis on the interaction between these metabolites and the molecular signaling cascades that are considered to be epigenetic targets in preventing colon cancer.
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ABSTRACT: Mice were fed low-fibre, or that supplemented with soluble fibre (konjac glucomannan, KGM; inulin), or insoluble fibre (cellulose) to determine how these three fibres modulated the acute colonic responses to an azoxymethane (AOM) treatment. Results indicated that KGM and inulin exerted greater anti-genotoxic effects compared to cellulose and up-regulated the gene expressions of glutathione S-transferase and antioxidant enzymes. The apoptotic index in the distal colon was the greatest and the expression of Bcl-2 was the lowest in the KGM group 24 h after the AOM treatment. On the other hand, the proliferative index and expression of Cyclin D1 were lower in all fibre groups. Furthermore, KGM increased cecal short-chain fatty acid contents, and both KGM and inulin increased fecal probiotic concentrations. This study suggested that soluble fibres were more effective than cellulose on ameliorating AOM-induced genotoxicity by up-regulating antioxidant enzyme genes, and enhancing epithelium apoptosis by down-regulating Bcl-2.Food Chemistry 07/2014; 155:304–310. · 3.26 Impact Factor
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ABSTRACT: During adaptive angiogenesis, a key process in the etiology and treatment of cancer and obesity, the vasculature changes to meet the metabolic needs of its target tissues. Although the cues governing vascular remodeling are not fully understood, target-derived signals are generally believed to underlie this process. Here, we identify an alternative mechanism by characterizing the previously unrecognized nutrient-dependent plasticity of the Drosophila tracheal system: a network of oxygen-delivering tubules developmentally akin to mammalian blood vessels. We find that this plasticity, particularly prominent in the intestine, drives-rather than responds to-metabolic change. Mechanistically, it is regulated by distinct populations of nutrient- and oxygen-responsive neurons that, through delivery of both local and systemic insulin- and VIP-like neuropeptides, sculpt the growth of specific tracheal subsets. Thus, we describe a novel mechanism by which nutritional cues modulate neuronal activity to give rise to organ-specific, long-lasting changes in vascular architecture.Cell 01/2014; 156(1-2):69-83. · 31.96 Impact Factor
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ABSTRACT: An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics. It is now 13 years since the definition of probiotics and 12 years after guidelines were published for regulators, scientists and industry by the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO). The FAO/WHO definition of a probiotic-"live microorganisms which when administered in adequate amounts confer a health benefit on the host"-was reinforced as relevant and sufficiently accommodating for current and anticipated applications. However, inconsistencies between the FAO/WHO Expert Consultation Report and the FAO/WHO Guidelines were clarified to take into account advances in science and applications. A more precise use of the term 'probiotic' will be useful to guide clinicians and consumers in differentiating the diverse products on the market. This document represents the conclusions of the ISAPP consensus meeting on the appropriate use and scope of the term probiotic.Nature Reviews Gastroenterology & Hepatology 06/2014; · 10.81 Impact Factor
Probiotic metabolites as epigenetic targets in the prevention of
Manoj Kumar, Ravinder Nagpal, Vinod Verma, Ashok Kumar, Navrinder Kaur, Rajkumar Hemalatha,
Sanjeev K. Gautam, and Birbal Singh
Dietary interventions for preventing colon cancer have recently attracted increased
attention from researchers and clinicians. The probiotics have emerged as poten-
tial therapeutic agents but are also regarded as healthy dietary supplements for
nutrition and health applications. The probiotic metabolome may interfere with
various cellular and molecular processes, including the onset and progression of
colon cancer. Probiotic metabolites may lead to the modulation of diverse cellular
signal transduction and metabolic pathways. The gut microbial metabolites
(organic acids, bacteriocins, peptides, etc.) have been noted to interact with
multiple key targets in various metabolic pathways that regulate cellular pro-
liferation, differentiation, apoptosis, inflammation, angiogenesis, and metastasis.
Progress in this field suggests that epigenetic alterations will be widely used in the
near future to manage colon cancer. The present review provides insights into the
molecular basis of the therapeutic applications and the chemopreventive activities
of certain probiotic metabolites, with emphasis on the interaction between these
metabolites and the molecular signaling cascades that are considered to be
epigenetic targets in preventing colon cancer.
© 2012 International Life Sciences Institute
Probiotics, the live microbial food supplements with the
been known to augment a variety of immunological and
metabolic parameters through diverse mechanisms.1The
following mechanisms are among those that are well
defined: altering composition of already existing normal
microbial ecosystem, maintaining gut lumen epithelial
barrier functions, and modulating mucosal and systemic
immune responses of the host (Figure 1).2–5The probiot-
ics recommended for human applications are primarily
the two classes of lactic-acid-producing microorganisms,
the bifidobacteria (e.g., Bifidobacterium longum, Bifido-
bacterium infantis, and Bifidobacterium adolescentis) and
the low-GC-content lactic acid bacteria such as Entero-
toc spp.,Pediococcus spp.,and Streptococcus spp.6–9Many
of these bacteria are also normal symbionts of mamma-
lian (human and animal) and other vertebrates’ intestine
and are already in use as probiotics or direct-fed micro-
bial agents and starter cultures. In particular, the Lacto-
bacillus spp.are ubiquitously present in fermented foods,
vegetation, the oral cavity, the gastrointestinal (GI)
Affiliations: M Kumar and R Hemalatha are with the Department of Microbiology and Immunology, National Institute of Nutrition,
Hyderabad, India. R Nagpal is with the Department of Biotechnology, SUS College of Research andTechnology, Mohali, India. V Verma is
with the Research and Development Centre, National Heart Centre, Singapore. A Kumar is with the Department of Zoology, MLK Post
Graduate College, Balrampur, India. N Kaur is with the Division of CancerTherapeutics, Institute of Cell and Molecular Biology, Singapore.
SK Gautam is with the Department of Biotechnology, Kurukshetra University, Kurukshetra, India. B Singh is with the IndianVeterinary
Research Institute, Regional Station Palampur, India.
Correspondence: M Kumar, Department of Microbiology & Immunology, National Institute of Nutrition, Hyderabad – 500007, India. E-mail:
firstname.lastname@example.org. B Singh, IndianVeterinary Research Institute, Regional Station Palampur – 176,061, India. E-mail:
email@example.com. Phone: +91-9418431715 (cell). Fax: +91-1894233063.
Key words: colon cancer, epigenetic alterations, probiotic metabolites
Nutrition Reviews® Vol. 71(1):23–34
ecosystem, and the urogenital tract and are found to
confer multiple health-promoting attributes.5,8,10
Traditionally, the natural ecological niches serve as
tries,but with the invention of novel structural classes in
decline, the need to search for alternative sources of bio-
catalysts, therapeutic agents, and chemical diversity is
increasing.11The distal gut in humans and monogastric
animals, in particular, is metabolically a highly active
organ and is regarded as a versatile digester, playing an
important role in the generation and utilization of meta-
bolic energy.12This largely unexplored area has attracted
microbial ecologists from around the globe who have
initiated culture-independent metagenomic studies tar-
geting the genome of the gut microbiota, collectively
called the “microbiome,” and exploring its association
with the host.13The gut microbial metabolome, which
consists primarily of biomolecules, such as antagonistic
proteins or peptides, organic acids, and hydrolytic
DIET, THE GUT MICROBIOME, AND
Cancer is an emerging and major common public health
problem in developing countries. Colorectal cancer
(CRC) is a complex disease associated with advancing
age,and evidence has shown that its risk can be managed
to a large extent by lifestyle and environmental fac-
tors.16,17Results of screening and surveillance for
primary prevention of CRC have shown this disease to
be a common cancer, with approximately 1,437,180 new
cancer cases and 565,650 deaths reported in the United
States in 2008.18,19Jass20has brought attention to several
contributing factors worthy of consideration while
Figure 1 Role of probiotics, prebiotics, and gut microbial short-chain fatty acids in gut health. Probiotics prevent
colonization of microbes that can possibly lead to genotoxicity in the colonocytes; in addition, they enhance mineral
absorption and prevent epigenetic alterations in colon cells. It has been noted that diet affects the composition of gut
microbiome2,3and that dysbiosis contributes to compromised epithelial integrity and impaired immune tolerance. Recent
studies have identified various metabolites and regulatory pathways that connect diet, the gut microbiome, the gut
metabolome, and immune responses.4
protein 2; NF-kB, nuclear factor kappa beta; SCFAs, short-chain fatty acids; TNF, tumor necrosis factor.
Nutrition Reviews® Vol. 71(1):23–34
evaluating colorectal adenomas as surrogate endpoints
for CRC, though the yearly conversion rates of the
adenomas to CRC may vary from 0.1% to 0.25%. Fur-
thermore, despite appreciable understanding of the
molecular basis of the pathogenesis of CRC, the reliable
and robust markers that would be used for screening,
surveillance, and primary preventive measures for CRC
are still lacking.21This is primarily because CRC is a
complex and multifactorial disease in which interaction
of host genetics with the environment is highly complex,
and environment plays a vital role in progression of the
disease.21Diet is a major factor that has multiple effects,
including alteration of both the transcriptome and the
metabolome of the host, and thus it may reduce CRC
incidence by as much as 80%.14,22,23Metabolites from
dietary sources may affect the intestinal mucosa directly
from the luminal side, or indirectly by affecting the
metabolism of the whole body.
Some dietary components that are toxic when
ingested in excess are also subject to microbial biotrans-
formation in the GI tract,and the metabolites (Figure 2)3
that are produced are assimilated into the circulatory
stream,where they may shift the cellular balance towards
undesirable situations such as susceptibility to, or induc-
tion of,genetic and epigenetic modifications in the host’s
cellular genome.3Mounting evidence suggests that some
of the gut microbes and their metabolites may, either
independently or in conjunction with each other, influ-
ence the risk of developing atopic disease.24
The impact of nutrients on epigenetic alterations in
the intestinal mucosa and colonocytes is of paramount
interest, as aberrantly methylated nucleotides may serve
as prognostic markers for CRC.Since epigenetic changes
are potentially reversible, they provide promising targets
for preventive as well as therapeutic interventions.Infor-
mation is increasing on eating habits, nutrients, and
dietary components and their impact on cellular mecha-
nisms and epigenetics in preventing CRC.Probiotics and
prebiotics alter metabolic processes within the lumen of
the gut and within the colonic epithelium, which may
prevent carcinogenesis.25,26Such processes include the
biotransformation of certain organic compounds to car-
cinogens, the subsequent hepatic detoxification of these
compounds, DNA damage and repair in the epithelium,
and apoptosis of damaged cells. Evidence from experi-
mental models shows that aberrant crypt foci are reduced
and apoptosis of damaged cells is increased after the
administration of probiotics.27–29Butyrivibrio fibrisolvens,
a hemicellulolytic butyrate-producing gut anaerobe, was
shown to reduce aberrant crypt foci in experimental
CRC. This organism is found widely in domestic rumi-
nants and wild animals and has also been detected in
human intestines in several populations in rural southern
India, where lower rates of CRC have been observed.30
Figure 2 Intake, gut and hepatic metabolism, and multiple epigenetic and anticarcinogenic effects of dietary
ingredients and their metabolites.3
Nutrition Reviews® Vol. 71(1):23–34
The anticarcinogenic attributes of probiotics may
lead to a resurgence of interest in the utilization of pro-
biotics or probiotic-containing foods.31,32The vital func-
tions that can minimize or prevent CRC include control
of epithelial cell proliferation and differentiation,produc-
tion of essential bioactive components, suppression of
pathogens,and stimulation of gut immunity.33Except for
a few studies (reviewed by Ishikawa et al.34), however,
information on clinical trials using probiotics for the pre-
vention and cure of colon cancer is scarce.
PROBIOTICS AS MULTIFACETED AGENTS
Probiotics,35,36prebiotics, and dietary phytometabolites
(such as polyphenols, phytoestrogens, nonprotein amino
lation and influence the incidence of CRC.37Among the
beneficial effects of probiotics observed in humans are
stimulation of gut immunity through various mecha-
nisms, prevention of intensity and duration of diarrhea,
and enhanced tolerance to ingested lactose.38In addition,
the lactobacilli have other pro-health attributes such as
synthesis of vitamin B, improvement of mineral and
nutrient absorption, and degradation and removal of
certain anti-nutritional phytometabolites.39,40However,
thecriteriaforselectionof probioticsof humangutorigin
and traditionally fermented foods are somewhat empiri-
cal.The selection is based on parameters such as enhanc-
ing the host endogenous defense mechanisms by
enhancing the humoral immunity, and thus promoting
the gut immunological barriers.41In addition, probiotics
have been found to stimulate nonspecific resistance to
host immunity to harmful antigens with a potential to
downregulate hypersensitivity reactions.43
GUT MICROBIAL SHORT-CHAIN FATTY ACIDS
The expression and regulation of genes is highly depen-
dent on, and coordinated by, nutrients, micronutrients,
and microbial metabolites.23,44,45The fiber and some fer-
mentable oligosaccharides are subjected to gut microbial
breakdown, resulting primarily in the production of
short-chain fatty acids (SCFAs), viz., acetate, propionate,
formate, valerate, caproate, and the branched-chain fatty
acids such as isobutyrate, 2-methylvalerate, and isovaler-
ate are also produced in low quantities from the catabo-
lism of some branched-chain amino acids.46The SCFAs
are bioactive molecules. They possess anti-inflammatory
functions at the intestinal mucosal cell surface1and are
postulated to be important effector molecules with mul-
tiple roles. Evidence shows that the ability of SCFAs to
activate the apoptosis cascade and reduce the growth of
certain tumors through histone hyperacetylation may
reduce the risk of cancer.47Studies have shown that poly-
unsaturated fatty acids and volatile fatty acids mutually
interact and can protect against colon cancer.48–50
The volatile fatty acids are the predominating
metabolites in most of the herbivorous ungulates. The
concentration of butyrate is highest in the cecum of
monogastric animals and humans, though it is progres-
sively reduced from the cecal to the distal colon,owing to
the rapid absorption of butyrate across mucosa and the
subsequent lack of fermentable carbohydrates in the
distal colon.51SCFAs have been found to induce apopto-
sis, presumably related to epigenetic modification, cell
cycle arrest,and activation of proapoptotic cellular genes.
Although the incorporation of fatty acids into CRC che-
motherapy regimens is still in its infancy, evidence is
accumulating to allow identification of the length of fatty
acid chains capable of exerting the most effective antine-
The data on the effect of butyrate on colon cancer is
extensive, but it cannot be considered conclusive. Based
on studies on the absorption and metabolism of SCFAs,it
is estimated that the daily production of butyrate in the
human large bowel is more than 200 mmol, which is
readily absorbed across the mucosa.52It was inferred,
based on observations in other species studied, that
humans had a larger capacity for absorption and metabo-
lism of SCFAs in the GI tract.52Three major pathways are
involved in the uptake of butyrate in the GI tract: diffu-
sion of the undissociated form through lipid membranes
of the distal colon, counter-transportation mediated by
form in the proximal colon.53It is believed that butyrate
can minimize the incidence of CRC.Clustering of SCFAs
which is vital for the effectiveness of numerous enzymes
and for inhibiting the metabolism of carcinogenic agents
in the gut.54
promoting actions,such as lowering intestinal pH,acting
as energy sources for colonocytes, stimulation of colonic
blood flow,contraction of smooth muscle cells,transepi-
thelial chloride secretion, and proliferation of colonic
epithelial cells through various proliferative stimuli.55
Evidence shows that dietary fibers and SCFAs lower the
incidence of inflammatory bowel disease (IBD) by
decreasing the expression of proinflammatory cytokines
lating absorption of sodium and water.56–58
Notably, the proportions of SCFAs in the intestine
are determined by the microbial consortia that ferment
dietary carbohydrates; the consortia, in turn, are influ-
Nutrition Reviews® Vol. 71(1):23–34
enced by the diet itself. For instance, certain prebiotics
augment the growth of bifidobacteria and thereby influ-
ence the proportion of SCFAs.58The studies on Jurkat
cells and on primary T cells demonstrate that T-cell acti-
vation in the presence of n-butyrate is characterized by
maintenance of the activity of a counter-regulatory sig-
naling cascade, which leads to impaired nuclear binding
of nuclear factor of activated T-cells.59The transcription
important role in the activation of various early immune
response genes. The study provides evidence that
n-butyrate interferes with NF-AT regulation, a mecha-
nism that might represent a bacterial strategy to subvert
host defense, which could be of clinical significance with
reference to the GI tract, which is a natural site of meta-
bolic synthesis and abundance of n-butyrate.59Luhrs
et al.60have inferred that butyrate reduced the expression
of proinflammatory cytokines by inhibiting activation of
NF-kB and degradation of IkBa.An increase in SCFAs in
the ceca of germ-free rats was observed, without a con-
comitant change in lactate concentration, after microor-
ganisms derived from human intestine were inoculated
into the ceca and the rats were fed fermented milks.61
Health-promoting effects of gut microbial butyrate
n-Butyrate is most widely studied as an energy source for
colonocytes and as a chemopreventive agent.25,62In addi-
tion, n-butyrate is also known to influence cell-specific
gene expression in intestinal cells, thereby influencing
stress.63–65Several lines of evidence indicate that SCFAs
may serve as epigenetic drugs or histone deacetylase
(HDAC) inhibitors that play an important role as anti-
cancer biomolecules with antiproliferative effects against
tumor cells.66,67Sodium butyrate, used as an HDAC
inhibitor, inhibits most HDAC enzymes except class III
and class II HDAC6 and HDAC10.68Fermented fecal
supernatants were found to be rich in butyrate and pro-
pionate and were found to exhibit strong anti-HDAC
activity in colon cancer cell lines.69The anti-HDAC activ-
ity was attributed to the disruption of processes involved
in the generation of dendritic cells from bone marrow
stem cells, primarily through associated sodium-coupled
monocarboxylate transporter (Slc5a8)-dependent inhibi-
tion of histone deacetylases.70Slc5a8 is responsible for
transportation of butyrate and propionate into cells, and
it is likely that these acids block the development of den-
dritic cells by interfering in the expression of some tran-
studies have been unable to detect significant effects, but
most case-control investigations advocate a protective
role of probiotics or fermented dairy foods against colon
cancer.71Interventional studies have also revealed a shift
of intermediate markers of CRC risk in human subjects
from a high-risk to a low-risk profile following intake or
consumption of probiotics and fermented dairy foods.71
Table 1 summarizes representative publications demon-
strating the anticarcinogenic attributes of probiotic
metabolites and some common dietary phytometabolites.
There is convincing evidence that optimal produc-
tion of SCFAs is an indicator of healthy gut microbial
fermentation, and that the pre- and probiotics have mul-
gut microorganisms in the production of SCFAs, probi-
for managing chronic IBD. Faecalibacterium prausnitzii
is one of the most abundant bacteria in human GI tract
and is an important producer of butyrate for utilization
by colonocytes. When the response to conventional
drug therapy is suboptimal in IBD, prebiotics and pro-
biotics such as lactic-acid-producing bacteria and
F. prausnitzii are recommended for treating IBD.73In
addition,butyrate-independent anti-inflammatory effects
of F. prausnitzii in IBD models have been observed.74
interleukin (IL)-12 levels and increased IL-10 levels, and
thus a reduced frequency of colitis, suggesting that
butyrate might be useful in protecting the host from
A probiotic bacterium identified in humans, Propi-
onibacterium freudenreichii,has been reported to destroy
colorectal adenocarcinoma cells through SCFA-mediated
apoptosis.76Lan et al.76demonstrated a major impact of a
shift in extracellular pH on the mechanisms of propioni-
bacterial SCFA-mediated HT-29 cell apoptosis,in the pH
range of 5.5 to 7.5, the milieu that also prevails in the
The majority of the anticarcinogenic effects of
butyrate have been observed in vitro by using cancer cell
lines. In these models, the addition of butyrate has been
found to inhibit cellular proliferation and to induce apo-
ptosis, necrosis, and differentiation of carcinoma cell
lines.76–80Butyrate has also been shown to stimulate a
physiological pattern of cellular proliferation in the basal
crypts in the colon as well as a reduction in the number
and size of aberrant cryptic foci, which serve as earliest
detectable neoplastic lesions in colon carcinoma.81Maier
et al.82haveshownthatbutyratereducesexpressionof the
genes cyclin D1 and c-myc, which are vital for the devel-
opment of CRC.
An optimal anticancer drug would be one that
destroys tumoral cells but not healthy somatic cells.
Butyrate is reported to induce cell cycle arrest, differen-
tiation, and/or apoptosis in certain colon carcinoma cell
lines, thus providing further evidence of the potential of
gut microbial butyrate to prevent colon cancer.83Another
important mechanism by which butyrate interferes with
Nutrition Reviews® Vol. 71(1):23–34
colon carcinoma cells is the inhibition of HDAC, which
leads to hyperacetylation of histone residues. The aber-
rant histone acetylation (Figure 3) leads to impaired tran-
scription and silencing of genes involved in the control of
cell cycle, differentiation, and apoptosis.84As an HDAC
inhibitor, the butyrate increases the expression of p21
(WAF1) by selectively regulating acetylation of the gene-
associated histones and by inducing the cell cycle arrest at
Table 1 Probiotic metabolites and bioactive dietary compounds and their therapeutic and epigenetic effects in
inhibiting colon cancer.
Lycopene (tomatoes) Demethylation of the GSTP1, RARb2, and HIN-1 genes in breast cancer cells (MDA-MB-231
(butyrate) and/or bioactive food components, prevention of overgrowth of pathogenic organisms,
and stimulation of intestinal immunity33
Inhibition of HDACs, histone hyperacetylation77
Induction of differentiation and apoptosis in neoplastic cells124
Transporter (Slc5a8)-dependent inhibition of HDACs70,125
Reduced risk of development of colon cancer and dyslipidemia126
Expression of c-jun, a proliferation-stimulating gene in immune cells; induction of apoptosis
in immortalized NIH 3T3 and malignant cancer cell lines129,130
Chemopreventive, antitumoral, radiosensibilizing, and chemosensibilizing activities against
various types of aggressive and recurrent cancers131
Allyl mercaptan (Allium
Capsaicin (chili peppers)Repression of transcriptional activity of b-catenin in human colorectal cancer cells; capsaicin
content (based on the Scoville scale)-mediated induction of significant growth arrest and
apoptosis in human breast and leukemia cancer cell lines, with no significant effect on
normal breast epithelial cells133,134
Caffeic acid phenethyl
ester or artepillin C
(beehives) component rich in caffeic acid phenethyl ester135,136
Resveratrol (red grapes;
genistein) (soy and
Induction of apoptosis in cancer cells147
ellagic acids (tea,
calorie restriction, oxidative stress, inflammation, cellular senescence, autophagy/
apoptosis, autoimmunity, metabolism, adipogenesis, circadian rhythm, skeletal muscle
function, mitochondrial biogenesis, and endothelial dysfunction153
SIRT1-mediated modulation of different pathways, such as NF-kB- and mitogen-activated
protein kinase-dependent signaling pathways153
Inhibition of azoxymethane-induced aberrant crypt foci through decreasing expression of
inducible nitric oxide synthase, cyclooxygenase-2, and cyclin D1 in rats and suppression of
b-catenin/GSK3b signaling and cyclin D and c-Myc expression in APC min/+mice162–164
Abbreviations: DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDACs, histone deacetylases; NF-kB, nuclear factor kappa
beta; SIRT1, sirtuin 1.
Epigenetic effect on carcinogenesis
Control of epithelial cell proliferation and differentiation, production of essential nutrients
HAT inhibition, histone hypoacetylation127,128
Inhibition of DNMT132
Suppression of malignant peripheral nerve sheath tumor by blocking of the oncogenic PAK1
signaling pathways, e.g., in neurofibromatosis type 2 tumors by Bio 30, a water-miscible
Inhibition of DNMT; activation of SIRT1137–140
Inhibition of DNMT activity; inhibition of aromatase, protein tyrosine kinase, and S6 activities;
inhibitory effects on angiogenesis; inhibition of DNA topoisomerase II; inhibition of HDAC,
activation of HAT141–146
Inhibition of DNMT132
Epigallocatechin-3-gallate (EGCG)-mediated antioxidant effects, e.g., delayed lipid
peroxidation, depletion of endogenous lipid-soluble antioxidants
Inhibition of DNMT and HAT148–152
Activation of SIRT1, which is beneficial for regulation of cell metabolism, stress resistance,
Inhibition of DNMT and HDACs154–159
Activation of SIRT1160
Inhibition of cell proliferation, which promotes cell-cycle arrest in human colon cancer cells161
Nutrition Reviews® Vol. 71(1):23–34
the G1 stage.85A novel contributory mechanism to the
chemopreventive effect of butyrate is the downregula-
tion of the key apoptotic and angiogenesis regulator
neuropilin-1, which promotes tumor cell migration and
survival in response to binding of vascular endothelial
mediates apoptosis include upregulation of the proapop-
totic protein BAK, caspase-3-mediated cleavage of poly-
(ADP-ribose) polymerase (PARP),and via mitochondrial
pathways.87,88A study by Thangaraju et al.89suggests a
novel mechanism of action of butyrate that involves
GPR109A, a G-protein-coupled receptor for nicotinate
that recognizes butyrate with low affinity.The receptor is
expressed in the lumen-facing apical membrane of
colonic and intestinal epithelial cells and recognizes
butyrate as a ligand. Its expression is silenced in human
colon cancer and murine models of CRC, in addition to
some other colon cancer cell lines.89The studies have
shown that GPR109A acts as suppressor of colon tumors
by mediating the tumor-suppressive effects of the bacte-
rial SCFAs in the colon.89–91
Hence, the biological and metabolic effects of
butyrate are relevant to various physiological and phar-
macological benefits. Although valuable information
about the uptake and metabolic effects of butyrate is
available, knowledge of the intracellular effects of
butyrate is lacking, and this need to be addressed.92
There is evidence that certain dietary ingredients
may favorably enhance the biotransformation of ingested
carcinogens,and the associated hypothesis is that the risk
of developing CRC could be reduced if the prevalence of
CRC is related to diet.93The mechanisms proposed
include upregulation of certain enzymes that metabolize
carcinogens, such as glutathione-S-transferases. This
modulationof expressionof glutathione-S-transferasesin
colon cells could contribute to a protective effect against
carcinogens, thus reducing the risk of cancer.84,93Dietary
fiber is another important factor that contributes to pro-
tection against CRC.94–97Mechanisms include reduction
exposure of mucosal cells to carcinogenic biomolecules,
along with absorption and utilization of bile salts, bio-
genic amines, and bacterial toxins. Findings on the
chemopreventive role of dietary fiber and its gut metabo-
lites, however, are still inconclusive.98
PROBIOTIC METABOLITES AND
Fermented dairy foods containing lactic acid bacteria are
the focus of attention as possible cancer-preventing
dietary supplements.31,32Manipulation of the gut ecosys-
tem through probiotics and prebiotics to reduce the risk
of coloncanceropensnewareasof scientificinvestigation
in gut disease.99,100Epigenetic modification, which refers
to the methylation of DNA through covalent addition of
a methyl moiety to the nucleotide cytosine,has an impor-
tant role in the regulation of gene expression. Virtually
every step of carcinogenesis or tumorigenesis is depen-
dent on epigenetic modifications in the cellular genome.
In the mammalian genome, the majority (90–98%) of
CpG sites are methylated, except for certain CpG-
enriched areas (CpG islands) that are not methylated. A
few genes, called imprinted genes, are regulated by
Figure 3 Probiotic-derivedshort-chainfattyacidsactashistonedeacetylaseinhibitorsandrestoregeneexpressionin
fatty acid; TF, transcription factor
Nutrition Reviews® Vol. 71(1):23–34
methylation of CpG islands in their promoter. These
genes are precisely replicated but are reversed during
inheritance.101Hypomethylation of promoters is associ-
ated with increased efficiency of gene transcription.
Epigenetic modifications, including histone modifi-
noncoding RNAs, have also been noted. In human
cancers, including CRC, the epigenetic events are of sig-
nificant concern.101Enhanced methylation of cytosine in
transcription and is used as a target to manipulate genes
involved in the progression of carcinogenesis. Interest-
potential to alter the transcriptome profile. Numerous
bioactive dietary components, namely, curcumin (tur-
meric),genistein (soybean and other leguminous plants),
polyphenols, and resveratrol (tea and fruits, etc.)
(Table 1), can interact with various epigenetic targets.
They alter the methylation and histone acetylation
required for the activation or silencing of genes in the
therapy or prevention of cancer.3,23The probiotics and
their metabolites can alter the population composition of
gut bacterial species that can, in turn, alter the fermenta-
tion metabolites, particularly the SCFAs. Miscellaneous
biological activities attributed to probiotics could be the
result of epigenetic alterations that may explain the wide
range of anticarcinogenic effects attributed to probiotics.
New findings about the effect of probiotics on the pro-
duction of SCFAs and about the epigenetic effects of
SFCAs will add to current understanding of the associa-
tions between gut symbionts and the management of
CRC through dietary interventions.
IMMUNOMODULATORY AND ANTI-CARCINOGENIC
ATTRIBUTES OF PROBIOTICS
Mounting evidence suggests that diet and the microbiota,
independently or in conjunction with each other, can
influence the risk of developing atopic diseases. Regula-
nism through which probiotics exert beneficial effects.102
The most widely studied and used probiotics with nutri-
and bifidobacteria.103The surge in allergic diseases in
infants is attributed to a relative lack of microbial stimu-
lation of their immune system, and probiotics might
provide such stimulation.104Cohort studies and clinical
trials have shown that a combination of prenatal or early
postnatal treatments could help in overcoming allergy
symptoms such as atopic eczema in high-risk neonates
and infants.104,105A study assessing the effect of Lactoba-
cillus GG administered at an early age in the treatment of
food allergies and allergic inflammation showed that
Lactobacillus GG was effective in the treatment of early
atopic diseases in infants at high risk and that the gut
microbiota might be a desirable source of probiotics or
immunomodulators for the prevention of such dis-
eases.106However, subsequent studies using the same or
different probiotics could not validate the above report,
indicating there might be additional intrinsic differences
between the probiotic strains employed and the popula-
Eukaryotic cells perceive and respond to prokary-
otes,both commensals and pathogens,by various stimuli
and signal cascades. Probiotics with immunomodulatory
cellular functions by enhancing the epithelial barrier via
interaction with Toll-like receptors, by augmenting the
epithelial signal transduction pathways that subsequently
lead to regulation of cytokine production to promote
anti-inflammatory responses,108–110by stimulating the
intestinal DCs, inhibiting the generation of interferon-g-
by degrading antigens, enhancing mucosal barrier func-
tions, promoting the onset of regulatory T cell activity
associated with enhanced secretion of tumor growth
factor b and IL-10 by peripheral blood mononuclear
cells,112,113by modulating immune responses differ-
ently,114by improving the immunogenicity of vac-
growth factor b, soluble CD14, and immunoglobulin
cillus casei, and Lactobacillus rhamnosus, each induced
response to consumption of L. acidophilus was associated
with 10 regulatory nodes that drive regulatory networks
associated with interleukins, interferon, and insulin
metabolism. Consumption of L. casei led to differential
metabolism together with genes involved in mitotic
transcriptional networks altered after consumption of
L. rhamnosus included key transcription factors such as
JUN, JAK2, STAT4, and IGF1, which affect cellular
growth, proliferation, and development.118
Proportions of SCFAs have been demonstrated to be
reduced in IBD,possibly due to alterations in the compo-
sition of normal microbiota. Gut epithelial cells of gno-
tobiotic mice were found to have reduced expression of
SCFA receptors,which returned to normal levels after the
normal bacterial composition in these animals was
restored.119In addition to having immunoregulatory
functions, the SCFAs also act as an energy source for
mucosal cells.120Moreover, HDAC inhibitors promote
cell maturation and differentiation, epithelial barrier
integrity through changes in gene expression,and expres-
sion of certain tight junction proteins like cingulin and
occludins as well as cytoplasmic proteins such as ZO-1
Nutrition Reviews® Vol. 71(1):23–34
and ZO-2.121,122Modulation of expression of specific tight
junction proteins plays a role in cellular differentiation.121
The increased intake of fermentable dietary oligo- and
polysaccharides or SCFAs seems to be clinically beneficial
in the treatment of colitis. The effect is attributed to res-
toration of the normal gut microbiome, concurrent with
an increase in the production of SCFAs, an increase in
gut lymphoid tissue.4Studies involving binding of SCFAs
with G-protein-coupled receptor 43 (GPR43) show that
SCFA-GPR43 interactions profoundly affect inflamma-
tory responses and that stimulation of GPR43 by gut
SCFAs is indispensable for the normal resolution of
certain models of colitis,arthritis,and asthma.4From the
above studies, it could be inferred that restoration of the
production of gut SCFAs by supplementation with pro-
and prebiotics could modulate the gut lumen milieu and
perhaps play a role in preventing IBD.
OPPORTUNITIES AND CHALLENGES
The fields of nutrition, microbiology, and genomics are
evolving tremendously and converging rapidly. Alter-
ations in histone acetylation and methylation are
common hallmarks of cancer.Aberrant epigenetic modi-
fications may prime the mucosal cells for progression of
cancer. However, epigenetic changes, unlike genetic
aberrations in cancer,are reversible.Hence,the impact of
food-derived ingredients and microbial metabolites on
reversing epigenetic changes in mucosal cells is of great
interest for preventing colon carcinogenesis. Identifica-
tion of methylation markers specific for colon carcino-
genesis would be highly useful for risk assessment,
especially in individuals who are genetically susceptible
to IBD or colon cancers. Probiotic metabolites and
certain dietary phytometabolites (Table 1) have been
shown to suppress carcinogenesis through various
mechanisms. Since the information gathered to date
seems incomplete,more studies are warranted to explore
the novel mechanisms and strategies to prevent CRC
The effectiveness of natural therapeutic and chemo-
preventive agents reflects the ability of such agents to
counteract certain upstream signals,such as NF-kB,acti-
vator protein 1, tumor necrosis factor, b-catenin, etc. In
addition,nonsteroidal and anti-inflammatory drugs with
similar modes of actions, alone or in combination with
probiotic supplementation, may prove to be safer than
become obvious that chemoprevention accompanied by
probiotic therapy could be an inexpensive and accept-
able approach in colon cancer. There is still, however,
much to be learned about the epigenetic mechanisms
that influence health and disease susceptibility, and how
these mechanisms are affected by lifestyle and environ-
mental factors. The studies described in this review
indicate a beneficial impact of probiotics, probiotic
metabolites, and certain dietary phytometabolites on
colon carcinogenesis.The most pressing need is to estab-
lish whether these alterations confer health benefits to
the host. Beyond this, an important challenge is to iden-
tify probiotic strain(s) that can safely elicit important
It is clear that gut microbial metabolites are of paramount
importance for communicating with intestinal epithelial
pathways that mediate initiation, progression, and dis-
semination of tumorigenesis have opened the door for
the development of therapeutic approaches that are
highly targeted and more efficient. Interest in the con-
has intensified in view of their safety and health benefits
in inflammatory and immunological disorders. Evidence
of the chemopreventive attributes of probiotics and their
metabolites is based on the findings of studies on the
activities of fecal enzymes and the detoxifications of
certain mutagens or carcinogen-induced preneoplastic
lesions and tumors. Advances in elucidating key epige-
netic mechanisms and epigenomic alterations in cancer
biology hold promise for developing novel approaches to
prevent colon cancer. Furthermore, in light of the costs
involved in healthcare,one of the most viable approaches
is to increase the awareness and intake of probiotics and
probiotic-fermented foods as cancer-preventive and
therapeutic strategies. Clear-cut criteria for the design as
well as the evaluation of the immunomodulatory and
anticarcinogenic attributes of probiotic metabolites that
can maintain healthy mucosal immune responses are
needed.An open dialogue between basic and clinical sci-
entists, regulatory authorities, food and nutrition indus-
try,and consumers could bridge the gap between science
and the marketing of probiotics with anticarcinogenic
Declaration of interest. The authors have no relevant
interests to declare.
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