Clinical Nutrition xxx (2016) 1e8

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Review

Surfacing role of probiotics in cancer prophylaxis and therapy: A

systematic review
Subramanyam Dasari a, Chandrasekhar Kathera b, Avilala Janardhan c,
Arthala Praveen Kumar d, Buddolla Viswanath e, *
a
Department of Biomedical Sciences, University of Illinois, College of Medicine at Rockford, Rockford, IL 61107, USA
b
College of Life Sciences, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210023, China
c
Department of Plant Biotechnology and Genomics, Centre for Biotechnology and Plant Genomics (CBGP), Polytechnic University of Madrid (UPM), Madrid
28040, Spain
d
Department of Virology, College of Sciences, Sri Venkateswara University, Tirupati 517502, India
e
Department of Bionanotechnology, Gachon University, San 65, Bokjeong dong, Sujeong gu, Seongnam si, Gyeonggi do 461 701, Republic of Korea

a r t i c l e i n f o s u m m a r y

Article history: Cancers figure among the most important causes of morbidity and mortality worldwide. Cancer and its
Received 8 August 2016 associated infections are always complicated even when specific cancer regimens are available. It is well
Accepted 21 November 2016 proved that Lactobacillus and other probiotic bacteria can modulate-ameliorate specific mechanisms
against various infections including cancers. The present systematic review is intended to focus on the
Keywords: ‘cellular and molecular mechanisms’ of probiotic bacteria in the prevention and treatment of various
Probiotics
cancers. The clinical and experimental findings of various studies explain the mechanisms such as
Molecular mechanism
apoptosis, antioxidant activity, immune response and epigenetics and illustrate the role of probiotics in
Cancer
Therapy
cancer management and prophylaxis. In addition, the present review also discusses the safety aspects of
Immune response probiotics when they are used in therapeutic and nutritional diet management. However, further in-
vestigations are required to reveal the effectiveness of probiotics in cancer treatment in clinical settings.
© 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction
Uncontrolled proliferation of cells and their resistance to
apoptosis are defining features of cancer cells. There is no single
specific therapy for cancer because the exact causes of most cancer
types are not understood; however, it is known that a range of
physiological and metabolic disturbances in the cell lead to the
development of cancer [1]. Each and every cancer has its unique
significant targets such as apoptotic signals, immune regulatory
signals, proteins and enzymes. Depending on these targets one can
evaluate the therapeutic drugs which might prove effective in
combatting any particular cancer. Once the treatment has been
given to the cancer cells, the efficacy of the cancer prophylaxis is
based on the restoration sensitivity of transforming cells to their
original state. Over prescription and misuse of chemotherapeutic
antibiotics has led to resistance to antibiotic and chemotherapy/
radiotherapy treatments and has become a problem in many cases
* Corresponding author.
E-mail address: buddolla@gmail.com (B. Viswanath).
[2]. The World Health Organization (WHO) has proposed that
alternative disease control strategies in the prevention and treat-
ment of certain infections may be required in the future [3]. The
Association of Modifiable Health has established that at least one-
half of all cancers may have dietary components, which indicates
that nutritional factors play a major role in cancer treatment.
Hence, many dietary components and natural health products have
attracted the attention of scientists for the development of natural
therapeutics. One such treatment is probiotics, non-pathogenic
microorganisms (living in host), which protect and benefit the
host against various infections including cancer [4].
According to the WHO nutritional guidelines, probiotics can be
defined as “live microorganisms when administered in adequate
quantities confer a health profit to the host cell” [5]. Probiotics have
become a typical ingredient in many traditional foods and formu-
lations hence the Food and Drug Administration (FDA) endorse
probiotics for their virtually null safety issues [6]. Several attributes
of probiotic bacteria have been used successfully in the treatment
of acute diarrhoea, inflammatory bowel disease (IBD) and other
intestinal disorders. In addition to the regulation of intestinal

http://dx.doi.org/10.1016/j.clnu.2016.11.017
0261-5614/© 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article in press as: Dasari S, et al., Surfacing role of probiotics in cancer prophylaxis and therapy: A systematic review, Clinical
Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.11.017
2 S. Dasari et al. / Clinical Nutrition xxx (2016) 1e8
epithelial homeostasis and immune responses, certain probiotics
have been reported to have anticancer activity through different
mechanisms [4].
The most common groups of probiotic bacteria belong to the
genera Lactobacillus (LAB) and Bifidobacterium (BFB), which are
common indigenous microbiota of the human gastrointestinal tract
[7]. The probiotic potentiality for management of intestinal and
other inflammatory disorders of these two bacteria is well known.
But there is a lack of well-documented mechanisms for these
probiotics in inhibiting the initiation and progression of carcino-
genesis. The present review will discuss emerging findings from
both experimental and clinical studies, describing the anticancer
activity of probiotics (Lactobacillus) through various mechanisms
such as immunomodulatory effects, antioxidant activity, apoptosis,
DNA damage prevention and epigenetic mechanisms (Fig. 1), thus
paving the way for potential therapeutic intervention against
various cancers [5,6].
1.1. An overview of probiotics in disease management
The probiotics LAB and BFB are an ecologically diverse group of
microorganisms specified by the formation of lactic acid as the
primary metabolite of sugar metabolism [8]. The beneficial activ-
ities of the probiotics were initially revealed by Metchnikoff
(1845e1919), who proposed and meticulously documented the
importance of fermented probiotic milk products in Balkan people
[9]. Both LAB and BFB survive in the intestine and promote the
recovery of normal gut microbiota [10]. Probiotic LAB could be
significantly used in the management of diarrhoea both in adults
and children [11]. Ozdemir [12], also reported that Lactobacillus GG
effectively manages milk allergy in infants with increased pro-
duction of IFN-ɣ. In another study, Del Carmen et al. [13] reported
the potential application of probiotics in the prevention and
treatment of inflammatory bowel disease. Recently it has been
suggested that oral bacteriotherapy with probiotics might be useful
Fig. 1. Probiotic bacterial strains and possible mechanisms against various cancers.
Please cite this article in press as: Dasari S, et al., Surfacing role of probiotics in cancer prophylaxis and therapy: A systematic review, Clinical
Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.11.017
in the management of atopic dermatitis (AD). A significant reduc-
tion of atopic eczema was demonstrated in children supplemented
with probiotics with respect to the placebo group [14].
1.2. Probiotics in cancer treatment and management
It is well known that the development of many cancer types can
be reduced by adopting certain lifestyle changes, for instance,
smoking cessation and consuming a balanced nutritional diet
which may counteract some causative factors, as suggested by the
adoption of a nutritious and complete diet [15]. Much attention has
been focused on decreasing cancer risk through diet variations,
mainly the consumption of prebiotics (special form of dietary fibre
that induces the growth of favourable bacteria) and probiotics.
Recent reports demonstrated that there is an inverse association
between cancer risk and cultured milk, yogurt and other fermented
milk [16]. There exists encouraging evidence that specific probiotics
(Lactobacillus) are valuable in the prevention and treatment of
cancer through the increased production of cytokines (IL-2 and IL-
12), antioxidants (SOD, CAT, GSH) and anti-angiogenic factors, in
addition to decreasing DNA damage, inflammation, tumour size,
cancer specific proteins, polyamine contents and pro carcinogenic
enzymes (Fig. 2). To summarize the above discussed confirmation,
probiotics aid in the suppression of cancer by multiple approaches
at various stages of cancer with various degrees of treatment effi-
cacy (Fig. 1).
Several experimental studies suggest the efficacy of probiotics in
cancer prevention and treatment in humans and murine models
[17e19]. Baldwin et al. [18] reported that Lactobacillus acidophilus
and Lactobacillus casei were able to increase apoptosis induction in
colorectal carcinoma cell line (LS 513), suggesting that these pro-
biotic bacteria may possess anticancer activity. Propionibacterium
freudenreichii was shown to induce the death of human colon and
gastric cancer cell lines through the secretion of short chain fatty
acids (SCFA) into the culture media. Both bacterial culture
 S. Dasari et al. / Clinical Nutrition xxx (2016) 1e8 3

Fig. 2. LAB induced biological modulations in cancer cells: In response to Lactobacillus some biological factors such as Cytokines, interleukins (IL-2, IL-12), Anti-oxidants (SOD, CAT,
GSH), indigenous microbial flora, interferons (IFN-g), immune cells (TH cells, NK cells) were increased, whereas other factors such as DNA damage, pathogens, inflammation, ulcers,
tumour size, cancer specific proteins, polyamine contents and procarcinogenic enzymes were decreased.

supernatants as well as pure SCFA induced emblematic signs of
apoptosis such as generation of reactive oxygen species, loss of
mitochondrial transmembrane potential, activation of caspase-3
and condensation of nuclear chromatin [19]. Probiotic Lactoba-
cillus spp. induced selective cytotoxic, pro-apoptotic effects on
leukemia and colon cancer cell lines, as well as anti-inflammatory
effects on macrophage cells at the molecular level. Shyu et al.
[20] reported that Lactobacillus spp. from dairy products secreted
metabolites with cytotoxic and anti-inflammatory effects and they
strongly suggest that the increased cytotoxicity for HT-29 and
HCT116 cells may be associated with an upregulation of the early
apoptosis gene markers cfos and cjun. Some probiotic strains have
been reported to influence haematological cancers such as Lacto-
bacillus reuteri, which enhanced TNF-induced apoptosis in human
chronic myeloid leukaemia derived cells [21]. Le et al. [22]
demonstrated that the symbiotic association between prebiotic
and probiotic considerably assists the apoptotic response to a
genotoxic carcinogen.
1.3. Probiotic induced immune response
The immune system plays a pivotal role in the prevention and
control of tumour initiation and progression [23]. The interaction of
numerous elements of the immune system such as antigen pre-
senting cells (APC), different subsets of T-cells, B-cells, natural killer
cells and dendritic cells are usually activated during invasion or
mutation [5,24]. Experimental studies demonstrated that pro-
biotics exert anticancer activity through immune-modulatory ef-
fects on cancer cells through macrophages, natural killer cells and
T-cells [10]. A population-based caseecontrol study showed an
inverse association between beverages containing L. casei Shirota
(LcS) consumption and breast cancer occurrence [25]. The ingestion
of LcS probiotics significantly prevents the recurrence of bladder
cancer. Another multi-centred, prospective study demonstrated
that the oral administration of LcS could enhance the efficacy of
intravesical chemotherapy in patients who underwent transure-
thral resection for superficial bladder cancer [26]. Kanazawa et al.
[27] demonstrated that the beneficiary activity of probiotics (LcS)
against post-operative infectious complications in patients with
biliary cancer.
Various mechanisms of the anticancer activity of probiotics such
as augmentation of natural killer cell activity, modulation of host
immune response through macrophages (induction of ILs) and re-
straint of the composition of indigenous microbiota and their
metabolic activity are important. Natural killer cells are crucial for
immune surveillance against cancer and infectious diseases, and
higher natural killer cell activity has been reported to be associated
with a lower risk of cancer development [10]. It has been demon-
strated that an intravenous injection of L. casei LC 9018 amplified
the NK cell activities of spleen cells in mice [28]. Previous studies
also showed that the oral administration of LcS enhanced NK cell
activity, leading to a delay of 3-methyl cholanthrene induced

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4 S. Dasari et al. / Clinical Nutrition xxx (2016) 1e8
carcinogenesis in mice [29]. In another study Gill et al. [30], also
reported that the dietary consumption of milk supplemented with
Lactobacillus rhamnosus and Bifidobacterium lactis enhanced the
activity of NK cells in elderly people. The enhanced activity of NK
cells was also observed in symbiotic association of probiotics with
prebiotics (indigestible dietary fibre/carbohydrate) [31]. It has also
been shown that oral administration of the probiotic bacteria in
association with prebiotic bacteria effectively enhances the hu-
moral immune response [31].
It was reported that a mechanism of increased NK cell activity by
some strains of Lactobacillus (Lactobacillus plantarum, L. rhamnosus
and Lactobacillus paracasei) activated peripheral blood mono-
nuclear cells (PBMC) to induce IL-12 [32,33]. The major biological
activities of IL-12 are directed towards T-cells and NK cells, which in
turn leads to the enhanced production of cytokines [34]. Ogawa
et al. [28] also reported that L. casei directly induced IL-12 pro-
duction by human PBMC. In addition, they demonstrated that
L. casei ssp. casei as well as other Lactobacillus sp. induced IL-15 in
the human intestinal epithelial cell line of colon cancer (Caco).
Previously Ogawa et al. [35] reported that symbiotic association
between probiotic Lcc, and its prebiotic dextran, exhibited immu-
noadjuvant activity in BALB/c mice. They also reported that IL-15
mediated the proliferation of Caco cells, while IL-15 induced by
intestinal epithelial cells mediated the activation of intestinal intra
epithelial NK cells [28]. Soltan Dallal et al. [36] suggest that the oral
administration of L. casei significantly increases the production of
IL-12, IFN-g and the natural killer cells (NK) in mice bearing inva-
sive ductal carcinoma. Together, these findings suggest that the
cytokines induced by L. casei are associated with the activation of
NK cells.
Phagocytosis is the means of removing microorganisms from
blood and tissue fluids and is mediated mainly by macrophages and
polymorpho nuclear neutrophils (PMN). It has been suggested that
live L. rhamnosus HN001 exhibits dose-dependent effects on the
phagocytic defense system of mice. LAB enhances natural and ac-
quired immunity in healthy mice by increasing phagocytic activity
of peripheral blood leukocytes and peritoneal macrophages as well
as by production of cytokines [37]. Various immuno modulators can
enhance the phagocytic activity in vitro, including probiotic bac-
teria. Dietary consumption of some strains of LAB has been shown
to stimulate and enhance the cellular immune responses, including
phagocytosis, proliferation of lymphocytes and cytokine produc-
tion [38]. Probiotic bacteria interact with dendritic cells (DCs)
through various surface molecules such as Lectin, TLR family
members and co-rectors (CR) [39]. It has been suggested that the
interactions between lipoteichoic acid (LTA)eToll-like receptor 2
(TLR2), lipopolysaccharide (LPS)eTLR4 and flagellin-TLR5 induce
the production of cytokines and co-stimulatory molecules for an-
tigen presentation that can modulate T cell polarization. These in-
teractions lead to phagocytosis and digestion in phagolysoomes, so
that the interacting microorganism-associated molecular patterns
(MAMPs) become available for recognition by pattern recognition
receptors (PRR) [39]. Apart from whole bacteria probiotics, various
components of LAB such as viable cells (VC), heat killed cells (HK),
cell wall (CW) and exopolysaccharides (EPS) of LAB have been
assayed for a macrophage-mediated immune response. Kim et al.
[40] reported that whole cells, and enzymatically digested, Bifido-
bacterium sp. induced the release of cytokine (TNF-a) and nitric
oxide (NO). Another study showed that viable cells of L. paracasei
spp. paracasei NTU 101, significantly increased innate immunity
and induced peyer's patch mediated gut mucosal immunity [41].
Liu et al. [42] also reported the ability of L. paracasei spp. paracasei
NTU 101 and 101EP, L. plantarum NTU 101EP and 102EP to induce
IL-6, IL-1b and TNF-a production. They also observed that phago-
cytosis was induced by 101EP and 102EP. Hence, LAB enhances
Please cite this article in press as: Dasari S, et al., Surfacing role of probiotics in cancer prophylaxis and therapy: A systematic review, Clinical
Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.11.017
immunity by increasing phagocytic activity of leukocytes and
macrophages.
Lactobacilli can draw out innate and adaptive immune responses
in host cells by binding to PRR expressed on immune cells. PRR
recognises conserved molecular structures known as pathogen
associated molecular patterns (PAMPs) or MAMPs which leads to
induction of cytokines, chemokines and other innate effectors [43].
These signal receptors can be divided into three families, namely
TLR, retinoic acid inducible gene I (RIG-I) like receptors that
recognise viral RNAs (RLRs) and nucleotide oligomarization domain
(NOD) like receptors (NLRs). Of these three receptor families, TLRs
are the best characterized, and approximately 10 types of TLRs have
been identified in humans, and 12 in mice [44]. TLRs are a family of
trans-membrane receptors that recognise repetitive patterns such
as PAMPs present in various Gram positive and Gram negative
bacteria [45]. TLRs are found in immune cells such as dendritic cells,
macrophages, endothelial and mucosal epithelial cells, as well as
cells from various organ systems [46].
Previously Meshkibaf et al. [47] documented the role of pro-
biotics in the production of anti-inflammatory cytokines (IL-10)
through TLR recognition both in murine and human models. In fact,
the cell surface component (LTA) of Lactobacillus acidophillus
stimulates innate immune cells to fabricate inflammatory and
regulatory cytokines [48,49]. The LTA can stimulate DCs through
TLR-2 resulting in the release of cytokines by the oral vaccine vector
Streptococcus gordonii [50]. Certain species of Lactobacillus can
stimulate DCs to produce IL-12 and the anti-inflammatory cytokine
(IL-10) [48,51]. However, disruption of LTA synthesis resulted in a
L. acidophilus derivative that acts on increased production of IL-10
in DCs, and down regulated IL-12 levels [52]. Matsuguchi et al.
[53] also reported that the purified LTA may be the better candidate
than the whole bacteria for clinical usage to induce an immune
response. Both peptidoglycan (PGN) and lipoteichoic acid have
been demonstrated to activate macrophages in a CD14-dependent
manner. Lipoteichoic acid from Gram positive bacteria (Bifidobac-
teria, Streptococci) also recognizes TLR-2, 6 and triggers the sig-
nalling cascade for the production of cytokines [54]. In light of the
above findings it can be concluded that the probiotic Lactobacillus
induces innate immunity in cancer cell lines.
1.4. Anti-oxidant activity of probiotics
Oxidative DNA damage induction is a preliminary step during
carcinogenesis of some drug induced cancers. It has been suggested
that probiotics could be efficacious in the reduction of oxidative
DNA damage caused by carcinogenic chemical agents in vitro and
in vivo [55]. However, this treatment had not been effective in
cancer prevention but the concept of antioxidant activity of pro-
biotics was developed since both milk and milk containing LAB
were shown to exert anticancer and antioxidant activity [56]. Data
from experimental studies indicate that oral administration of
certain types of LAB strains and their metabolic products reduced
the risk of ROS accumulation and also degraded superoxide anions
and hydrogen peroxides [42]. It was also reported that the exopo-
lysaccharides (EPS) from L. plantarum C88 had an antioxidant effect
which may involve scavenging of reactive oxygen species,
enhanced regulation of enzymatic and non-enzymatic antioxidant
activities and reduced lipid peroxidation. Recently, Zhang et al. [55]
reported that Lactobacillus Salivarious REN inhibited the oxidative
DNA damage in 4-nitroquinoline 1-oxide (4-NOO) induced oral
cancer. Ramesh et al. [57] also reported that antioxidant activity
was found to be strain specific and that these strains of Lactobacillus
may be useful in developing functional foods to fight oxidative
stress. Attention has been focused on extracellular polysaccharides
from LAB against antioxidant activities [58]. Various in vitro studies
 S. Dasari et al. / Clinical Nutrition xxx (2016) 1e8
showed that LAB strains possess antioxidant properties and inhibit
ROS through enzymatic mechanisms such as coupled NADH oxi-
dase/peroxidase systems and catalase [59]. Heat killed cells and
cytoplasmic fractions from the Lactobacillus strains L. paracasei NTU
101 and 102 also had inhibitory effects on cancer cell lines and
antioxidant activities in vitro [60]. Lin et al. [61] also reported that
the symbiotic association of Bifidobacterium longum and
L. acidophilus display antioxidant activity by inhibiting linoleic acid
peroxidation by 28e48%. Another study shows that the heat killed
L. acidophilus 606 along with soluble polysaccharide components
exhibited effective anti-oxidative activity [62]. In vitro studies
postulated that LAB possess antioxidant properties and inactivate
ROS through enzymatic (NADH oxidase/peroxidase system, super-
oxide dismutase and catalase) and non-enzymatic mechanisms
such as scavenging by Mn2þ [63].
1.5. Probiotics-induced apoptosis
Apoptosis is a process of programmed cell death, playing an
important role in the regulation of cell proliferation as well as cell
death [64]. An important event in many types of cancers is the
reduced ability to trigger apoptosis associated with alterations in
cell proliferation [65]. Most of the chemotherapeutic drugs against
cancer used today exert their effects by inducing apoptosis [66].
Several studies showed that probiotic bacteria play a key role in the
regulation of cell apoptosis through intrinsic and extrinsic path-
ways which are potentially critical mechanisms in the prevention of
cancer. Chen et al. [67] demonstrated that the oral administration
of L. acidophilus showed reduced severity of colorectal carcino-
genesis and improved apoptosis in mice. Little is known about the
mechanism of LAB-induced apoptosis via down regulation of the
nuclear factor-kappa B (NF-kB)- dependent gene products which
regulate cell proliferation (Cox-2, cycline D1) and survival (Bcl-2,
Bcl-xL) [21]. In addition, L. reuteri suppresses the TNF-induced NF-
kB activation, including the NF-kB dependent receptor gene, which
is expressed in a dose and time dependent manner to slow down
cancer cell growth [21]. Such characteristics of L. reuteri may be
involved in the extrinsic pathway of apoptosis. Le et al. [22]
demonstrated that a combination of probiotics (B. lactis) and pre-
biotics (starch) significantly facilitated the apoptotic response to a
genotoxic carcinogen. Several probiotic strains have been reported
to influence haematological cancers including L. reuteri-enhanced
TNF-induced apoptosis in chronic myeloid leukemia human-
derived cells by modulation of NF-kB and mitogen activated pro-
tein kinase signalling and condensed proteins that mediated cell
proliferation (cycline D1 and Cox-2) or inhibited apoptosis (Bcl-2,
Bcl-xL) [21]. Hwang et al. [68] also reported that LAB induced
apoptosis in gastric cancer cells (KATO3) by inhibiting NF-kB and
mTOR-mediated signalling. Cousin et al. [69] proposed another
mechanism for probiotic induced apoptosis in their report of the
pro-apoptotic potential of P. freudenreichii on HGT-1 gastric cancer
cell lines. These probiotic bacteria induce chromatin condensation,
apoptotic bodies, DNA fragmentation, accumulation of ROS, caspase
activation, inactivation of mitochondrial trans-membrane potential
and cell cycle arrest. Probiotic bacteria influence the intestinal
microbiota and stimulate the intestine-associated immune cells,
which is useful against intestinal inflammation and colon cancer.
Specifically, the oral administration of fermented (probiotic yogurt)
products induces cellular apoptosis by increasing cytokine (IL-10)
secreting cells in mice [70]. Baldwin et al. [18] evaluated the anti-
proliferative activity of L. acidophilus and L. casei against LS513
gastric cell lines through cellular apoptosis. The apoptotic potential
of these two probiotic bacteria was increased in the presence of 5-
fluorouracil (5-FU); this may be due to the faster activation of
caspase-3 protein and down regulation of p21 protein levels.
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5
HPV E6 and E7 proteins play a vital role in cervical carcino-
genesis through inactivation of p53 and pRb tumour suppressor
genes, which block apoptosis and reduce immune recognition [71].
Several attempts have been made to suppress these two genes by
therapeutic drugs. Li et al. [60] reported down regulation of onco-
genic genes which in turn increased the tumour suppressor genes
and finally induced apoptosis in cervical cancer cells. Bifidobacte-
rium adolescentis SPM1005-A showed antiviral activity through
suppression of HPV E6 and E7 oncogene expression which indi-
cated that the B. adolescentis SPM1005-A could potentially be used
for prevention of HPV-associated cervical cancer [72].
1.6. Probiotics-induced cytotoxicity in cancer cells
In-vitro experimental evidence suggests that probiotics used for
their anti-cancer activity operate via a process of cytotoxicity
against tumour cells [42]. Recently, Nami et al. [73] also reported
that the metabolites from L. acidophilus 36 YL exhibited the most
potent cytotoxic effect against human cervical cancer cell lines
(HeLa) and colorectal cancer cell lines (HT-29). Several other re-
ports demonstrated that the anti-proliferative activity of LAB on
growth of human cancer cell lines has its effects via cytotoxicity
[74,75]. Liu et al. [42] explored the effects of different modalities of
L. casei 01 cell free fractions (heat treated cells, crude cell wall, intra
cellular extracts and exopolysaccharides) on 4-nitroquinoline N-
oxide (4-NQO) induced genotoxicity and colon cancer cell line (HT-
29), finding that EPS induced higher anti-proliferative activity
against HT-29 cancer cell lines. Wang et al. [20] reported that whole
peptidoglycan (WPG) of Bifidobacteria bifidum promoted the non-
specific immunity through the secretion of IL-1, IL-6 and TNF-a
from the peritoneal macrophages of nude mice. Recently, Chiba
et al. [76] also reported that probiotic L. casei have the potential to
induce IL-12 production and promote TH1 cell development.
1.7. Other mechanisms induced by probiotics
In addition to the above discussed mechanisms, probiotic bac-
teria also induce other molecular mechanisms which lead to the
death of cancer cells. Epigenetics involves alteration of the
expression level of selected genes without any modifications in
DNA sequence, such as DNA methylation, chromatic remodelling,
and histone tail modifications [77]. Histone deacetylase inhibitors
(HDACi) are epigenetic drugs used for their anti-proliferative ac-
tivity against tumour cells [78]. Metabolites of probiotic bacteria,
such as butyrate, a short chain fatty acid (SCFA), are important
therapeutic compounds against cancer. Butyrate is one energy
source for the colonocytes and has been used in the regulation of
apoptotic cellular proliferation and differentiation [79]. Sodium
butyrate induces anti-proliferative activity on many cancer cell
types especially on colon cancer [80]. Archer & Hodin [81],
hypothesised that butyrate affects gene expression in a process
involving phosphorylation and acylation of histone proteins. In
another study, Lightfoot et al. [82] reported that a mutant strain of
L. acidophilus (LTA-deficient) induced epigenetic modifications and
found increased expression of tumour suppressor genes in oral NCK
2025 cell lines. L. reuteri exhibited potent inhibition of colon cancer
cell proliferation. The anti-proliferative activity of L. reuteri may be
related to the production of SCFA metabolites in the colon, which
may also decrease tumour growth and promote apoptosis [83].
Recent findings showed that LAB also induced anti-proliferative
activities of colon cancer cells through synergistic action between
cancer cells and SCFA metabolites [5]. Thirabunyanon et al. [84]
reported that cell free supernatants of L. casei and L. rhamnosus
decreased colon cancer cell invasion by inducing matrix metallo
protein-9 and zonaoccludens-1 thus acting to prevent colon cancer.
6 S. Dasari et al. / Clinical Nutrition xxx (2016) 1e8
1.8. Role of probiotics in post-treatment cancer complications
Although both chemotherapy and radiotherapy are the gold
standard for treatment of cancer, the severity of their associated
complications continues to negatively impact patients' quality of
life. The chemotherapy-induced complications include mucositis
(oral cavity and intestine) which is characterized by ulceration,
diarrhoea and inflammation [85]. Diarrhoea is a frequently
observed complication during pelvic radiotherapy in cervical,
lymphoma, colon cancer, and pancreatic cancer [86].
Chemotherapy-induced mucositis and radiotherapy-induced diar-
rhoea are both associated with cytotoxic agents which damage the
intestinal mucosal lining and alter water absorption capacity [87].
Regimen-induced complications are most widely treated by al-
terations in diet especially the introduction of probiotic food. Usage
of probiotic nutritional intervention pre and post treatment may
provide protection for healthy cells and tissues [86]. The protective
role of probiotic bacteria against diarrhoea and mucositis may be
due to the improved immune status of the gut [88]. Previous
studies also explain that these probiotic bacteria may compete with
pathogenic bacteria for binding on epithelial cells [86].
Saez-Lara et al. [89] reported that the probiotic compound VSL #
3 (VSL pharma, Italy) prepared from highly concentrated freeze-
dried living bacteria plays a major role in chemotherapy induced
diarrhoea and mucositis. The protective role of VSL # 3 is treatment
specific which exerts good effects on the host organisms by
improving the flora of indigenous micriobiota in the intestine and
reduces the growth of pathogens. Experimental and clinical studies
of VSL # 3 suggested the mechanism underlying the efficacy of
probiotic VSL # 3 to protect against diarrhoea. This mechanism is of
great importance because of the targeting of an unregulated pro-
cess of apoptosis which is the ultimate factor responsible for the
radiation-induced injury of the intestinal epithelial cells [90].
Recently, Yamashiro & Nagata [91], reported that probiotics are
used to ameliorate chemotherapy induced mucositis in paediatric
malignancies.
1.9. Safety aspects of probiotics in cancer treatment
Probiotics and their safety aspects have been important for
evaluation of the therapeutic role of probiotics against infections
and cancer. A properly assessed probiotic (diet) consumption/
treatment plays a key role in the management of disease [3].
Evaluation of safety aspects of probiotic consumption is a com-
plex but very important task when this is used as a therapeutic
agent. The safety aspects include viability in delivery vehicles
(diet), acid and bile resistance, adherence to gut epithelial tissue,
effect of antimicrobial substances, and stimulation of host im-
mune responses [92]. Experimental and clinical studies on the
therapeutic efficacy of probiotics depend on purity, dosage and
stability of those probiotic products [3]. Lactobacillus and Bifido-
bacteria are members of the indigenous microbiota of the human
oro-gastro intestinal tract and they occasionally cause opportu-
nistic infections. Both probiotics have been associated with
certain infections such as bacteremia, dental infections, food al-
lergies and endocarditis. These infections are associated with an
imbalance of intestinal microbiota and increased gut perme-
ability [92].
Well-established data are available for the safety assessment of
probiotics through several approaches, including intrinsic proper-
ties, and pharmacokinetics along with the hosteprobiotic in-
teractions [93]. The data explain the survival of the probiotics
within the gastrointestinal tract, their colonization, translocation
and the fate of active components which are important for evalu-
ation of probiotic ingestion. The pharmacokinetics of probiotics
Please cite this article in press as: Dasari S, et al., Surfacing role of probiotics in cancer prophylaxis and therapy: A systematic review, Clinical
Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.11.017
have been studied using perfusion and biopsy techniques [94].
In vitro studies of probiotic bacteria have reported the deconjuga-
tion of bile salts producing free bile acids, which are more inhibi-
tory to susceptible bacteria than the deconjugated form, and
degradation of mucus membranes [95,96]. Other in vitro parame-
ters being studied include platelet aggregation properties, binding
of human intestinal mucosa and the production of unwanted me-
tabolites [3]. Strains of Lactobacilli species that are intrinsically
resistant to antibiotic (vacomycin) have a good and a long history of
safety and these resistant strains could not transfer the resistance
to other bacteria. Probiotics and their products have been safely
consumed in large quantities for a long time in Europe and Japan.
However, the proven and presumptive findings indicate that spo-
radic localized infections may occur in immunocompromised pa-
tients and show that no zero risk has been attributed to
consumption of living probiotics [3].
Chemotherapy induced diarrhea is one of the most common
cancer associated toxicities which lead to the chemotherapy regime
being stopped or reduced [97]. Diarrhoea is unpleasant for the
cancer patient and may reduce the response to radiotherapy and
chemotherapy; they may also require further treatment to prevent
associated morbidity and mortality [98]. As infections are common
in immunocompromised patients, the microflora plays a role in
immunity [97], and probiotics should be evaluated both for efficacy
in preventing infection and for safety, and it is particularly impor-
tant to investigate whether probiotics may cause infection them-
selves [99]. Beckerson et al. [100] advise against the use of products
containing probiotics for neutropenic cancer patients. However,
Gibson et al. [101] suggest that consumption of probiotics (Lacto-
bacillus species) may help prevent diarrhoea during chemotherapy
or radiotherapy in patients with pelvic malignancies. A systematic
review demonstrated that the administration of probiotics reduces
the average frequency of daily bowel movements and may reduce
the need for anti-diarrhoeal medication but mentions that they
may be a rare cause of sepsis [97].
2. Conclusion
It is clear that in vitro, in vivo and clinical findings attest to the
fact that the probiotic-based therapeutics and diet play an impor-
tant role in suppressing various infections and dysplastic condi-
tions. Insights into cellular and molecular mechanisms such as
immune responses, apoptosis, anti-oxidant and epigenetic mech-
anisms bring novel approaches for the development of probiotic-
based therapeutics. Supplementation of dietary constituents is an
emerging and safe strategy in cancer prevention. Situated at the
interface of supplemented nutrition and health, probiotics play a
pivotal role in allaying many cancers. As stated earlier, many pre-
clinical and clinical studies of probiotics in the treatment and
prophylaxis of various cancers have illustrated their efficiency, the
benefits often being species and strain specific. In future, the pos-
sibility of genetically modified probiotic microorganisms may
provide new opportunities for their prophylactic and therapeutic
use. Therefore, constructive research on genetic manipulation is
required to improve the existing probiotic characteristics of
particular strains, as well as to prepare novel probiotic organisms
with specific properties for treatment and prophylaxis of various
cancers.
Conflicts of interests
The authors declare no relevant competing financial interests to
disclose.
 S. Dasari et al. / Clinical Nutrition xxx (2016) 1e8
Acknowledgements
The authors wish to thank Prof. Chris Anthony for his help in
drafting this manuscript. The authors are indebted to all the re-
searchers whom we cited in this review for their significant and
valuable research. No funding was received to perform this
review.
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