Content uploaded by Odinaka Mgbeke
Author content
All content in this area was uploaded by Odinaka Mgbeke on Jun 13, 2024
Content may be subject to copyright.
The Microbe 4 (2024) 100096
Available online 2 June 2024
2950-1946/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Gut microbiota alteration - Cancer relationships and synbiotic roles in
cancer therapies
Adekunle Rowaiye
a
,
b
,
*
, Gordon C. Ibeanu
b
, Doofan Bur
c
, Sandra Nnadi
d
, Odinaka E. Mgbeke
e
,
Ugonna Morikwe
f
,
g
a
Department of Agricultural Biotechnology, National Biotechnology Development Agency, Abuja, Nigeria
b
Department of Pharmaceutical Science, North Carolina Central University, Durham, NC, USA
c
Department of Medical Biotechnology, National Biotechnology Development Agency, Abuja, Nigeria
d
Plant Biology Department, University of Vermont, USA
e
Department of Clinical Skills, St. George’s University, Grenada
f
Department of Biology, North Carolina A&T State University, Greensboro, NC, USA
g
Department of Pharmaceutical Microbiology & Biotechnology, Nnamdi Azikiwe University, Awka, Nigeria
ARTICLE INFO
Keywords:
Cancer
synbiotics
therapies
microbiota
prebiotic
probiotic
ABSTRACT
Cancer poses a signicant global health challenge, with 10 million deaths and 19.3 million new cases reported
annually. This review aims to investigate the emerging eld of synbiotics and their potential to enhance the
effectiveness of cancer therapies. By conducting a thorough analysis of preclinical and clinical studies, this re-
view claries the various mechanisms through which synbiotics improve the efcacy of conventional cancer
treatments, such as chemotherapy, immunotherapy, surgery, and radiotherapy. A search of literature on the anti-
cancer efcacy of synbiotics was performed using the PubMed database and Google Scholar search engine to nd
important original research and review publications. A selection, analysis, and discussion of related English-
language papers were conducted. This review unravels the intricate connections between microbiota and can-
cer therapeutics, harnessing the power of synbiotics as a promising strategy to improve treatment outcomes and
elevate the standard of care in oncology. Further research is required to establish the efcacy and long-term
safety of synbiotics, the ideal prebiotic-probiotic combinations, and the distinct microbiota signatures of
different cancer types for the development of future synbiotics.
List of abbreviations: ABC, Adenosine triphosphate binding cassette; ACF, Aberrant crypt foci; ADSC, Adipose tissue-derived stem cells; AhR, Aryl hydrocarbon
receptors; ALL, Acute Lymphoblastic Leukemia; AMPK, AMP-activated protein kinase; AOM, Azoxymethane; APC, Adenomatous polyposis coli; BA, Bile Acid; BAX,
BCL2 associated X; BCL-2, B-cell lymphoma 2; BCLX, B-cell lymphoma-extra-large; BFT, Bacteroides fragilis Toxin; BYB, Baker’s yeast breads; CDT, Cytolethal dis-
tending toxin; CFE, Cell-free extracts; CFS, Cell-free supernatants; CFU, Colony forming unit; CoPEC, Colibactin-producing E. coli.; COX-2, Cyclooxygenase-2; CRC,
Colorectal cancer; CRP, C-reactive protein; CRT, Chemoradiotherapy; CSC, Cancer stem cells; CTL, Cytotoxic T lymphocytes; CTLA-4, Cytotoxic T-lymphocyte-
associated protein 4; DCA, Deoxycholic acid; DMH, 1,2-dimethylhydrazine; DNA, Deoxyribonucleic acid; DOX, Doxorubicin; DPPH, 1,1-diphenyl-2-picrylhydrazyl;
ERK, Extracellular signal-regulated kinase; ETBF, Enterotoxigenic B. fragilis; FAS, Fatty Acid Synthase; FOXM1, Forkhead Box M1; GF, Germ-free; HPBC, Hep-
atopancreatobiliary carcinoma; IL, Interleukin; ICB, Immune checkpoint blockade; INOS, Inducible nitric oxide synthase; IEC, Intestinal epithelial cells; IBS, Irritable
bowel syndrome; JNK, c-Jun N-terminal kinase; LCA, Lithocholic acid; LPS, Lipopolysaccharide; MDR, Multidrug resistance; MMP, Matrix metalloproteinase; MRNA,
Messenger Ribonucleic acid; MTT, 3–4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide; SRB, Sulforhodamine B; NADPH, Nicotinamide adenine dinucleo-
tide phosphate; NEW, Natto water extract; NFDE, Natto freeze-drying extract; NF-κB, Nuclear factor-kappa B; NK, Natural killer; NLR, NOD-like receptors; NLRP3,
NLR family pyrin domain containing 3; NSCLC, Non-small cell lung cancers; NTBF, Non-Toxic B. fragilis; PRR, Pattern recognition receptors; PBMC, Peripheral blood
mononuclear cells; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1; PTEN, Phosphatase and tensin homolog; PTP, Protein tyrosine
phosphatases; RCT, Randomized controlled trial; ROS, Reactive oxygen species; SCFA, Short chain fatty acids; SD, Sprague-Dawley; TLR, Toll-like receptors; TMA,
Trimethylamine; TMAO, Trimethylamine N-Oxide; TNF-
α
, Tumor necrosis factor-alpha; WET, Tempeh water extract; Wnt, Wingless and Int-1; ZO-1, Zonula
occludens −1.
* Corresponding author at: Department of Agricultural Biotechnology, National Biotechnology Development Agency, Abuja, Nigeria.
E-mail address: adekunlerowaiye@gmail.com (A. Rowaiye).
Contents lists available at ScienceDirect
The Microbe
journal homepage: www.sciencedirect.com/journal/the-microbe
https://doi.org/10.1016/j.microb.2024.100096
Received 11 March 2024; Received in revised form 14 May 2024; Accepted 29 May 2024
The Microbe 4 (2024) 100096
2
1. Introduction
Cancer is a complex set of diseases characterized by uncontrolled cell
replication, requiring the use of diverse therapeutic strategies (Merriel
et al., 2021). At present, cancer is the second leading cause of death in
the United States and a major global health issue, responsible for one in
six deaths worldwide (Siegel et al., 2022). Approximately 10 million
cancer-related deaths and 19.3 million new cases of cancer were re-
ported worldwide in 2020 (Sung et al., 2021). Traditional approaches
such as chemotherapy, radiotherapy, and surgery have been used to
manage cancer. Immunotherapies are a result of growing knowledge
about the immune system’s function in cancer (Roy et al., 2022). Among
all these changes, the gut microbiota has become a key component that
can affect how well cancer treatments work (Aggarwal et al., 2022).
The complex interplay between the human body and its resident
microbial communities, known as the microbiota, has been demon-
strated to have a profound impact on health and disease. Particularly
important to human health is the gut microbiome, which is primarily
made up of bacteria as well as other microbes like viruses, fungi,
archaea, and protozoa (Sasso et al., 2023). Recent ndings have un-
covered the impact of the gut microbiota on various host functions,
including immunity, inammation, metabolism, nutritional responses,
and responses to different therapeutic interventions (Lynch and Hsiao,
2019, Zheng et al., 2020, Hitch et al., 2022).
Probiotics are living microorganisms that, when ingested in suf-
cient quantities, confer health benets to the host. These microorgan-
isms, usually bacteria or yeast, are frequently present in fermented foods
or dietary supplements. Probiotics are recognized for their capacity to
promote and regulate a harmonious gut microbiota balance, crucial for
digestive health and overall wellness (Bodke et al., 2022). Prebiotics are
indigestible bers and substances that foster the proliferation and
function of probiotics. They act as nourishment for favorable gut bac-
teria (Raman et al., 2019).
Synbiotics combine probiotics and prebiotics to enhance gut health
and overall well-being through synergistic interaction. They come in
two main types: complementary and synergistic synbiotics, each with a
distinct approach to combining these components for greater health
benets (Gomez et al., 2022). Complementary synbiotics provide pro-
biotics and prebiotics separately, whether as different products or in-
gredients. This approach aims to leverage the complementary actions of
probiotics and prebiotics when consumed independently but in close
succession. On the other hand, synergistic synbiotics blend probiotics
and prebiotics into a single product, such as a capsule, tablet, or food
item. This unied approach creates a synergistic effect where probiotics
and prebiotics work together harmoniously, amplifying their individual
benets and improving gut health more effectively (Gomez et al., 2022).
Probiotics and synbiotics have demonstrated notable impacts beyond
gut health, extending their inuence on various diseases and conditions.
Clinical trials have revealed that synbiotic interventions can signi-
cantly lower systolic blood pressure (Hadi et al., 2022). Furthermore,
research has explored their role in metabolic disorders such as obesity
and diabetes, where they can modulate glucose metabolism, lipid pro-
les, and inammatory markers, contributing to improved metabolic
control (Hadi et al., 2020a; Hadi et al., 2020b; Hadi et al., 2021).
In a study by Purton et al. (2021), it was discovered that prebiotic
and probiotic supplementation impacts the tryptophan-kynurenine
pathway. This nding suggests potential benets of probiotics in
mental health, with certain strains showing promise in alleviating
symptoms of anxiety, depression, and stress. These diverse effects un-
derscore the multifaceted potential of probiotics and synbiotics in
enhancing overall health and managing a wide range of diseases beyond
gastrointestinal disorders.
Using the combined effects of probiotics and prebiotics to enhance
current cancer therapies is a novel approach in the eld of cancer
therapy. Several studies have shown how important synbiotics are for
controlling intestinal microecology and for both cancer prevention and
treatment. These results imply that synbiotics might develop into
possible microecological modulators for adjuvant cancer treatment
(Alam et al., 2022). Indeed, synbiotics may have an impact on long-term
cancer risk reduction by fostering a robust and health-promoting gut
microbiota that lowers the risk of cancer development and recurrence
(Scott et al., 2018).
This review examines the possible inuence of synbiotics on cancer
treatments, considering the reciprocal role that probiotics and prebiotics
play in fostering a healthy gut ora. The review explores the connections
between cancers and dysbiosis, emphasizing the impacts of oxidative
stress, inammation, and the carcinogenic metabolites produced by gut
microbiota. It delves into the roles of synbiotics in cancer therapies,
discussing a range of foods fermented by probiotics and formulated
synbiotics and their applications in cancer treatment. Additionally, the
study discusses future perspectives, outlining areas that require further
investigation, and draws conclusions regarding the promising potential
of synbiotic-based cancer therapy to enhance treatment outcomes,
minimize side effects of conventional therapies, and mitigate the need
for additional treatments that may induce dysbiosis, such as antibiotic
use.
2. Materials and methods
Key concepts relevant to the article’s subject were identied as the
foundation for constructing search strings in both the PubMed database
and Google Scholar search engine. These concepts encompassed cancer,
cancer therapies, synbiotics, gut microbiota, prebiotic, probiotic, among
others. Various search strings were devised to probe the database and
search engine, including combinations like "dysbiosis AND cancer,"
"probiotics AND cancer," "fermented foods AND cancer," and "synbiotics
AND cancer therapies." Inclusion criteria for articles included relevance,
quality, language, and publication date, with a focus on English-
language publications from 2018 to 2024. Relevant data were extrac-
ted from the selected articles, and their ndings were synthesized to
construct the review article. Ultimately, 190 English-language articles
were selected for inclusion.
3. Cancer and gut dysbiosis
3.1. Eubiosis to dysbiosis
The shift in the gut microbiota from eubiosis to dysbiosis and the
subsequent host immunological response profoundly alters the devel-
opment and progression of numerous cancer types (Shein et al., 2014).
The combined genomes of millions of bacteria present in the human gut
microbiota during dysbiosis have the potential to inuence carcino-
genesis (Sharma et al., 2021).
Research indicates that alterations in the gut microbiota composi-
tion, deviating from a healthy state, are associated with an increased risk
of developing various pathological conditions, including cancer, auto-
immune illnesses, and diabetes (Shui et al., 2020). In healthy in-
dividuals, the gut microbiota functions as a symbiont, preventing the
development of malignancies and offering defense against invasive
pathogens. The human gut microbiota is crucial to maintaining health
because of its effects on pathogen defense, nutritional absorption,
digestion, and immunomodulation (Shein et al., 2014). Nonetheless,
this commensal community upholds a delicate balance that, if disturbed,
results in dysbiosis and encourages host disease processes (Grenda and
Krawczyk, 2021).
Host-specic variables like heredity and disease state can cause
dysbiosis (Hrncir, 2022). Dysbiosis is exacerbated by lifestyle choices
such as low-ber, high-sugar diets, xenobiotic use, and poor hygiene
(Hrncir, 2022; Shein et al., 2014).
The hallmarks of dysbiosis include an unbalanced bacterial compo-
sition, changes to the metabolic activity of bacteria, or adjustments in
the location of bacteria inside the gut. The loss of benecial bacteria, the
A. Rowaiye et al.
The Microbe 4 (2024) 100096
3
increase in pro-inammatory bacterial species, and the reduction in
microbial diversity are among the various categories of dysbiosis. Usu-
ally, these several dysbioses show up at the same time (DeGruttola et al.,
2016; de Cedr´
on and de Molina, 2020).
However, the gut microbiota contains several unknown host-
microbe, microbe-microbe, and micro-environmental interactions,
which hinders the advancement of the comprehension of the relation-
ships between cancer and the microbiota. The development of tumors,
metabolism, immunology, genetic instability, and susceptibility to
immunotherapy and chemotherapy for cancer, are all indicators of these
relationships (Lee, 2021). Nonetheless, it has been demonstrated that
specic gut microbial communities can modulate immunological
response, inammation, and the metabolism of some foods and medi-
cations, all of which may raise the risk of certain types of cancers
(Matson et al., 2021; Vernocchi et al., 2020) (Fig. 1).
3.2. Oxidative stress and inammation
In dysbiosis, the exponential multiplication of pathogenic bacteria
has been linked with a higher risk of gut barrier dysfunction or "leaky
gut." Several microbiota subpopulations proliferate and generate large
amounts of virulence factors such as toxins (E. coli), invasins (Salmonella
Typhimurium), adhesins (Helicobacter pylori), and enzymes (Clostridium
difcile) which damage the cells of the gut epithelium subsequently
causing oxidative stress, inammation, and carcinogenesis (Vivarelli
et al., 2019).
In between intestinal cells exist tight junctions that prevent the entry
of harmful substances such as toxins, bacteria, and undigested food
particles. Upon microbiota dysbiosis-induced gut barrier dysfunction,
the integrity of these tight junctions is compromised (Violi et al., 2023).
With increased permeability, bacterial lipopolysaccharide (LPS) and
other substances translocate across the compromised gut barrier into the
bloodstream resulting in metabolic endotoxeamia (Mohammad and
Thiemermann, 2021).
LPS and other cellular debris are recognized by macrophages. Mac-
rophages express a variety of pattern recognition receptors (PRRs) on
their cell surfaces, which are crucial for recognizing microbial products
and endogenous danger signals. The PRR includes Toll-like receptors
(TLRs) and NOD-like receptors (NLR). It has been revealed from studies
that dysbiosis affects TLR signaling and NLR activation (Hou et al., 2022;
Sameer and Nissar, 2021). The binding of LPS to TLR4 triggers a
signaling pathway that leads to the activation of nuclear factor-kappa B
(NF-κB) and other transcription factors. This activation results in the
expression of pro-inammatory cytokines such as IL-1, IL-6, IL-17, and
tumor necrosis factor-alpha (TNF-
α
), consequently, causing inamma-
tion (Belanˇ
ci´
c, 2020; Mohammad and Thiemermann, 2021; Zheng et al.,
2020).
NLRs are a family of cytoplasmic receptors that can recognize various
microbial components, including bacterial peptidoglycans. NLRs are
particularly known for sensing intracellular pathogens or disturbances
in cellular homeostasis. Bacterial peptidoglycans bind to the NLR which
leads to the formation of inammasomes, caspase-1 activation and
consequently the expression of proinammatory cytokines IL-1β and IL-
18 (Chen et al., 2021a).
Certain marker genes, such as inducible nitric oxide synthase (iNOS)
and IL-12, are expressed in response to LPS activation and are linked to
the M1 phenotype (Orecchioni, et al., 2019). Studies reveal that in a
proinammatory state, dysbiosis is linked with the polarization of
macrophages towards an M1 phenotype (Wang et al., 2020; Hou et al.,
2022). The M1 phenotype in blood circulation suggests that there is a
direct host defense against pathogens, and this may gravitate towards
immune disorders and inammatory diseases (Inoue et al., 2019; Hou
et al., 2022). Macrophages engulf and digest LPS and other bacterial
debris. During phagocytosis, macrophages can undergo an oxidative
burst initiating a series of signaling events that cause the activation of
NADPH oxidase, which oversees generating reactive oxygen species
(ROS) (Canton et al., 2021).
ROS generated by macrophages also serve as activators of the
Wingless and Int-1 (WnT) and ERK signaling pathways which affect the
cell proliferation process (Jones et al., 2017; Zou et al., 2018; Moparthi
and Koch, 2019). Studies have revealed that as a mechanism of innate
immune subversion, WnT signaling can be manipulated by bacteria
which take advantage of the signal cascade to create infection (Rogan
et al., 2019). ROS can modulate Wnt signaling at various levels which
include the stabilization of β-Catenin and the activation of disheveled
(Staehlke, et al., 2020).
ROS can impact the extracellular signal-regulated kinase (ERK)
pathway, which is a critical signaling cascade involved in cell growth,
replication, differentiation, and survival (Guo et al., 2020). ROS may
oxidize and modulate specic components of the ERK pathway; oxidize
and inactivate protein tyrosine phosphatases (PTPs), which are negative
regulators of the ERK pathway; and modulate the redox state of growth
Fig. 1. Gut dysbiosis and cancers. Created with Biorender.com.
A. Rowaiye et al.
The Microbe 4 (2024) 100096
4
factor receptors, involved in the activation of the ERK pathway (Weng
et al., 2018). Furthermore, ROS may also modulate the Raf-1 and
redox-sensitive proteins in the ERK pathway (Rezatabar et al., 2019).
LPS can also promote the release of metal ions, such as iron, from host
cells. Free iron can participate in fenton reactions, generating highly
reactive hydroxyl radicals and contributing to oxidative stress (Carocci
et al., 2018).
Persistent oxidative stress leads to signicant DNA damage, cell
signaling disruption, inammation, mitochondrial dysfunction, and
cellular transformation. Through oxidative stress, dysbiosis has been
involved in the accumulation of DNA breaks which can consequently
result in cancer and genomic instability (Chen et al., 2021a,b). The in-
duction of DNA double strand breaks through bacterial virulence factors
has also been reported (Hsiao et al., 2023).
Overall, dysbiosis fosters an inammatory milieu, and persistent
inammation is linked to the emergence of several cancers (Shein
et al., 2014). Furthermore, inammaging has been shown to increase gut
dysbiosis. Age-related alterations in gut microbiota impair immuno-
logical tness, which aids in carcinogenesis. Increased gut dysbiosis and
microbial product leakage are factors in the chronic proinammatory
state, which continues to weaken the immune system and makes it more
difcult to eliminate senescent and mutant cells, promoting the estab-
lishment of tumors. Therefore, in older patients who are weak, therapies
that modify the gut microbiota’s composition may reduce inammation
and boost immunity to prevent cancer (Biragyn and Ferrucci, 2018).
3.3. Carcinogenic metabolites of gut bacteria
In addition to chronic inammation, carcinogenesis has been shown
to be caused by genotoxic metabolite production (Helmink et al., 2019).
A variety of pathologies can cause disturbances of the microbiota which
may lead to the generation of toxins, acute inammations, and the
production of carcinogenic metabolites (Artemev et al., 2022). Table 1
3.3.1. Skatole
Following the consumption of large quantities of animal protein, a
signicant number of human intestinal bacteria can convert aromatic
amino acids, some of which then decarboxylate to create aromatic
compounds like skatole. The metabolism of the amino acid tryptophan
can result in the production of an indole derivative (3-methylindole)
named skatole (Zgarbov´
a and Vrzal, 2023). Some of the
skatole-producing bacteria include Olsenella uli, Faecalicatena contorta,
Bacterioides thetaiotaomicron, Clostridium scatologenes, Clostridium nau-
seum, and Olsenella scatoligenes (Zgarbov´
a and Vrzal, 2023).
Increased fecal skatole concentrations modulate the biological ac-
tivity of intestinal epithelial cells (IEC), distorting the intestinal ho-
meostasis. IECs are susceptible to dose-dependent and time-dependent
induction of mortality and apoptosis by skatole. IEC death is triggered
when skatole activates aryl hydrocarbon receptors (AhR)-dependent
activation pathways which are the ERK pathway associated with cell
proliferation, survival, and differentiation; and the JNK pathway that is
involved in cellular stress responses and apoptosis (Kurata et al., 2019).
These skatole-induced pathways enhance increased TNF
α
expression,
genotoxicity to colon cells and hence play a major role in the colorectal
carcinogenesis (Kurata et al., 2023). Skatole is also involved in the
AhR-independent activation of p38 pathways including inammation,
immune response, cell differentiation, and apoptosis (Kurata et al.,
2019).
3.3.2. Secondary bile acids
The gut microbiota is involved in the metabolism of bile acids (BAs).
Bile acids, which are involved in fat digestion, can be transformed by gut
microbes into secondary bile acids. Elevated levels of certain secondary
bile acids, such as deoxycholic acid (DCA) and lithocholic acid (LCA),
have been linked to the development of colon cancer. This is because
these secondary bile acids promote oxidative stress, inammation, and
DNA damage (Nguyen et al., 2018). Bacteria form secondary BAs
through the 7-dehydroxylation of primary bile acids. DCA-forming
bacteria include Clostridium hiranonis and Clostridium scindens while
LCA-forming bacteria include Streptococcus gallolyticus, Clostridium
hylemonae, and Clostridium absonum (Ridlon, et al., 2020; Lucas et al.,
2021).
Several studies have shown that DCA and LCA can activate a wide
range of pathways as signaling molecules and they play critical roles in
cellular processes associated with several cancers (Lin et al., 2020).
Synthesized in hepatocytes, stored in the gallbladder, and utilized in
the gut, DCA and LCA can increase the capacity of cancer cells to invade
and metastasize, prevent cancer cells from undergoing apoptosis, stim-
ulate the development of cancer cell cycles, and encourage the conver-
sion of cells into cancer stem cells (CSCs). (Lin et al., 2020; Yang and
Qian, 2022). Furthermore, secondary BAs inuence immune cell activ-
ity, which further advances cancer (Yang and Qian, 2022). Studies
indicate that an imbalance in the ratio of primary to secondary bile acids
can inuence the composition of the gut microbiota and, consequently,
the immune response. Consequently, this imbalance may impact the
recruitment and function of immune cells, including natural killer (NK)
T cells, in the liver (Helmink et al., 2019).
Consequently, the controlled modulation of the gut and secondary
BAs could show promise in the prevention and treatment of different
malignancies (Yang and Qian, 2022). However, through
N6-methyladenosine-dependent microRNA maturation, DCA has been
demonstrated to modulate the gall bladder cancer progression (Lin et al.,
2020).
3.3.3. Nitrosamine
Certain gut bacteria can contribute to the formation of nitrosamines
from nitrite and amines in the diet such as processed meat when cooked
at hot temperatures. Some bacteria associated with nitrosamine
Table 1
shows the carcinogenic metabolites, the producing gut bacteria, and the type of
cancers induced.
Carcinogenic
Metabolite
Producing Bacteria Cancer induced (Reference)
Skatole Olsenella uli CRC (Kurata et al., 2023)
Faecalicatena contorta
Bacterioides
thetaiotaomicron
Deoxycholic acid Clostridium hiranonis CRC, Gall bladder, esophageal,
liver
Clostridium scindens & pancreatic cancers (Yang and
Qian, 2022).
Lithocholic acid Streptococcus
gallolyticus
CRC, Gall bladder, esophageal,
liver
Clostridium hylemonae & pancreatic cancers (Yang and
Qian, 2022).
Nitrosamine E. coli Stomach, esophagus, liver,
bladder,
Pseudomonas
aeruginosa
& lung cancers (Li and Hecht,
2022).
Salmonella spp
Trimethylamine N-
Oxide
E. coli Mouth & prostate cancers
Proteus spp (Jalandra et al., 2021; Chan
et al., 2019)
Citrobacter freundii
Colibactin E. coli pks+CRC (Lop`
es et al., 2020).
FadA Adhesin Fusobacterium
nucleatum
CRC (Guo et al., 2020).
Cytolethal distending
toxin
Helicobacter hepaticus CRC (He et al., 2018).
Campylobacter jejuni
CagA Toxin Helicobacter pylori Stomach cancer (Park et al.,
2018)
Bacteroides fragilis
Toxin
Bacteroides fragilis CRC (Cheng et al., 2020).
A. Rowaiye et al.
The Microbe 4 (2024) 100096
5
production include certain strains of E. coli, Salmonella spp, and Pseu-
domonas aeruginosa (Sorour et al., 2023).
Nitrosamines are metabolized by the liver when consumed through
processed meat, and these agents are then capable of adding alkyl
groups to DNA, which results in the production of DNA adducts. DNA
adducts could change the structure of the DNA molecule. The regular
sequence of the genetic code may be distorted as a result, causing DNA
damage and mutations. Additionally, nitrosamines could obstruct the
body’s processes for repairing DNA (Fahrer, and Christmann, 2023).
When damaged DNA is not adequately repaired, mutations may
persist and raise the risk of carcinogenesis. Nitrosamine-induced muta-
tions can both inactivate tumor suppressor genes, which prevent cell
development, and activate oncogenes, which encourage cell growth.
These molecular events culminate in unchecked cell division (Ejike and
Liman, 2022). Specically, nitrosamines have been linked to the growth
of malignancies in the stomach, esophagus, liver, bladder, and respira-
tory system, among other organs (Li and Hecht, 2022).
3.3.4. Trimethylamine N-Oxide (TMAO)
Certain gut microbiota can metabolize some specic natural com-
pounds, such as carnitine and choline, into trimethylamine (TMA),
which is further converted to trimethylamine N-oxide (TMAO) in the
hepatocytes. High TMAO levels have been linked with a higher risk of
cancer and cardiovascular diseases (Gatarek, and Kaluzna-Czaplinska,
2021). The bacteria associated with TMAO production include certain
strains of E. coli, Proteus spp., Citrobacter freundii. and Clostridium (Ramu
et al., 2022; Jameson et al., 2018).
TMAO has been associated with a potential role in the development
of colorectal cancer (CRC). In a clinical study, serum samples from 30
normal controls and 108 CRC patients were used to measure preopera-
tive TMAO levels. Patients with CRC showed signicantly higher serum
TMAO levels compared to normal, healthy control participants. Addi-
tionally, patients with higher serum TMAO levels had a poorer chance of
surviving than those with lower levels. These results indicate that serum
TMAO levels may be a useful prognostic indicator for CRC. This study
demonstrates that TMAO plays a part, either directly or indirectly in
CRC (Liu et al., 2017; Jalandra et al., 2021). Furthermore, several
studies suggest an association between TMAO and the development of
different kinds of malignancies such as oral squamous cell carcinoma
and prostate cancer (Jalandra et al., 2021; Chan et al., 2019).
TMAO has been a hypothetical link between the gut microbiota and
cancers. Recent data points to inammation as a possible molecular
mechanism. Other mechanisms, including oxidative stress, DNA dam-
age, and disruption in protein folding, may also be involved in
explaining the connection between TMAO and cancer (Chan et al.,
2019).
3.3.5. Colibactin
Colibactin is a DNA-damaging secondary metabolite produced by
specic strains of E. coli and Klebsiella pneumoniae which share a 100 %
sequence similarity of the pks gene cluster indicating a conserved
function and regulation (Strakova et al., 2021). The specic strains
associated with colibactin production have the pks+phenotype. These
strains carry a genomic island known as the pks (polyketide synthase)
island which contains genes (A and Q) responsible for the synthesis of
colibactin (Tariq et al., 2022). A study revealed that 43.47 % of the
E. coli isolates linked to cancer belonged to phylogroup B2, which is
more harmful than the other groups. Conversely, no isolate from B2 was
detected in the healthy control group (Tariq et al., 2022).
Findings suggest that Colibactin-producing E. coli (CoPEC) may
impair antitumor T-cell response, which could result in tumor resistance
to immunotherapy and promote a procarcinogenic immunological
environment. This is because there is growing evidence linking the
antitumor T-cells to colorectal carcinogenesis. Therefore, CoPEC could
serve as a new biomarker to predict the response to anti-PD-1 treatment
in CRC (Lop`
es et al., 2020). Most malignancies target the epithelium of
the intestinal mucosa, and pks+E. coli has been implicated in the
development of CRC by inducing a unique genotoxic signature in human
colorectal infections. Signicantly, the genomic contexts of DNA
double-strand breaks induced by colibactin show an enrichment of an
AT-rich hexameric sequence motif (Dziuba´
nska-Kusibab et al., 2020).
3.3.6. FadA adhesin
Numerous studies have suggested that Fusobacterium nucleatum is
closely associated with the development of CRC, and metagenomic
studies have demonstrated an enrichment of F. nucleatum in colorectal
carcinoma tissue. The underlying molecular mechanisms can likely offer
a viable method of therapeutic intervention for F. nucleatum-associated
CRC. Additionally, these ndings imply that an elevated presence of
F. nucleatum in tissues could function as a diagnostic or prognostic
biomarker (Sun et al., 2019).
FadA and Fap2 are two of the recognized adhesins of F. nucleatum
that facilitate attachment to intestinal epithelial cells (Sun et al., 2019).
This promotes inammation and tumor cell proliferation (Guo et al.,
2020). Fap2 can cause immunosuppression by binding to immune cells
(Sun et al., 2019). The mechanisms behind the contribution of
F. nucleatum infection to the development of CRC have been studied in a
mouse model. When F. nucleatum was administered to C57BL/6 J-Ade-
nomatous polyposis coli Min/J mice [APC (Min/+)] mice, it was
observed that the overexpression of Chk2 increased DNA damage and
tumor formation in CRC. Moreover, F. nucleatum increased the propor-
tion of CRC cells in the S phase of the cell cycle. However, with the
knockout of the FadA gene (FadA−/−), there was a decrease in the S
phase cells, DNA damage, cell division, and the expression of chk2 and
E-cadherin. FadA−/−show decreased tumor burden, size, and number.
In summary, this study demonstrated that F. nucleatum activated the
E-cadherin/β-catenin pathway in a FadA-dependent manner, resulting
in the upregulation of chk2, which in turn caused DNA damage and cell
proliferation in CRC (Guo et al., 2020).
In human colon cancer cell lines, the FadA adhesion can activate the
β-catenin–Wnt signaling pathway and cause oncogenic transcriptional
modulations (Helmink et al., 2019). One essential element by which
F. nucleatum delivers its stimulatory function is annexin A1, a regulator
of Wnt/β-catenin signaling. Annexin A1 plays a specialized role in
activating Cyclin D1 and is expressed only in CRC cells that are actively
growing. In colon cancer, its expression level is often associated with
poor prognosis. Through E-cadherin, the FadA adhesin from F. nucleatum
up-regulates the production of Annexin A1. There is a positive feedback
loop between Annexin A1 and FadA in malignant cells, but not in
non-cancerous ones (Rubinstein et al., 2019).
Moreover, F. nucleatum recruits tumor-inltrating immune cells,
creating a pro-inammatory environment that enhances colorectal
carcinogenesis. Through microRNA (miRNA)-21 expression and toll-like
receptor 2 (TLR2)/toll-like receptor 4 (TLR4) signaling, F. nucleatum was
also shown to enhance the development of CRC. Furthermore, by
modulating a molecular network comprising autophagy components,
miRNA-18a, and miRNA-4802, F. nucleatum enhances CRC recurrence in
addition to chemoresistance (Sun et al., 2019).
3.3.7. Cytolethal distending toxin
Helicobacter hepaticus and Campylobacter jejuni are two examples of
bacteria that produce the virulence factor known as Cytolethal dis-
tending toxin (CDT). It has the capacity to generate distension in
mammalian host cells and induce cell cycle arrest is well-known (Lai
et al., 2021). C. jejuni 81–176, a human clinical isolate, induces alter-
ations in microbial composition and transcriptome responses, as well as
promotes CRC. In comparison to uninfected mice, experimental mice
colonized with the human clinical isolate C. jejuni81–176 developed
signicantly more and larger tumors (He et al., 2018).
The complex toxin CDT comprises of CdtA, CdtB, and CdtC subunits.
The activity of the toxin is inuenced by each component. The catalytic
subunit of CDT, called CdtB, has activity like that of DNase I and it
A. Rowaiye et al.
The Microbe 4 (2024) 100096
6
causes DNA double-strand breaks (He et al., 2018). There was reduced
genotoxicity in cells and enteroids and mitigated C. jejuni-induced
carcinogenesis in vivo in mice infected with the mutant cdtB subunit.
Hundreds of colonic genes were activated for expression by the C. jejuni
infection; 22 of these genes required the presence of cdtB (He et al.,
2018).
Following internalization by the host cell, CdtB cleaves the DNA to
cause damage and causes cell cycle arrest in the G2 phase. By inducing
arrest at the G2/M checkpoint, CDT disrupts the host cell cycle. Cellular
distension, which is characterized by larger and swollen cells, might
result from this cell cycle arrest, which impairs regular cellular func-
tioning (Blandford, 2018). DNA damage response pathways, including
cell cycle checkpoint controls and DNA repair mechanisms, are activated
by the host cell in response to DNA damage caused by CDT (Martin and
Frisan, 2020).
Additionally, CDT has been linked to host immune response modu-
lation. It might have an impact on how pro-inammatory cytokines are
produced and how the bacteria interact with the host immune system.
Nonetheless, evidence indicates that CDT might inuence the
severity of the infection and the ability of bacteria to colonize the host
(Martin and Frisan, 2020).
3.3.8. CagA toxin
Research conducted on animal models suggests that Helicobacter
pylori has a major function in the onset of stomach cancer (Park et al.,
2018). The cytotoxin-associated gene A (CagA), which produces the
CagA protein in the cag pathogenicity island (cag PAI), is an important
virulence factor in H. pylori (Park et al., 2018). CagA is a translocated
oncoprotein that alters the morpho-functional properties of gastric
epithelial cells and triggers a persistent inammatory response that
raises the risk of pre-cancerous lesions. After undergoing translocation
and tyrosine phosphorylation, CagA relocates to the cell membrane
where it functions as a pathogenic scaffold protein. It concurrently en-
gages with many intracellular signaling pathways, impairing cell divi-
sion, proliferation, and death (de Melo et al., 2022).
CagA is overexpressed in human gastric cancer, and this signicantly
reduces the expression of PTEN, Tet1, APOBEC3A, APOBEC3C, and
APOBEC3F. Furthermore, Tet1 overexpression reversed the effects of
CagA’s increase in DNA methylation and decrease in PTEN expression.
Future therapeutic efforts aimed at treating gastric cancer in humans
may be facilitated by the current ndings (Zhang et al., 2019).
The NLRP3 inammasome is triggered by H.pylori to facilitate the
movement and invasion of gastric cancer cells. The virulence of H. pylori
is signicantly inuenced by the CagA protein. Infection with CagA-
positive H. pylori strain (Hp/CagA+) and transfection with the
pcDNA3.1/CagA vector result in the activation of the NLRP3 inam-
masome, intracellular ROS production, and increased invasion and
migration of gastric cancer cells. Furthermore, it has been discovered
that NLRP3 activation and pyroptosis are successfully blocked by ROS
inhibition via N-Acetylcysteine (NAC). CagA’s effects on the movement
and invasion of gastric cancer cells are lessened when NLRP3 is silenced.
CagA can stimulate the NLRP3 inammasome pathway, which in turn
can facilitate the invasion and movement of gastric cancer cells (Zhang
et al., 2022).
3.3.9. Bacteroides fragilis toxin
The Bacteroides genus includes ubiquitous commensals that make up
around 30 % of the human gut microbiota. Despite being one of the
rarest species of Bacteroides, Bacteroides fragilis is the most frequently
isolated anaerobe from human extraintestinal diseases (Valguarnera and
Wardenburg, 2020). Toxin-bearing strains of B. fragilis known as en-
terotoxigenic B. fragilis (ETBF) produce the Bacteroides fragilis Toxin
(BFT) which is a metalloprotease enterotoxin that is encoded by a ge-
netic element. BFT is known to cause acute and chronic intestinal illness
in both children and adults. It is highly likely that ETBF is a cause of CRC
given the discovery of ETBF-bearing biolms in colon biopsies from
people with loci that increase their risk of colon cancer (Valguarnera and
Wardenburg, 2020). The Non-Toxic B. fragilis (NTBF) does not produce
toxins (Cheng et al., 2020).
Although BFT was rst linked to diarrhea, more recent studies have
investigated its possible connection to CRC. BFT can cause inammation
and changes in colonic epithelial cells, which may aid in the develop-
ment of CRC (Cheng et al., 2020). ETBF forms biolms in the intestine
and produces BFT which triggers Cyclooxygenase (COX)-2, and conse-
quently PGE2 is released to cause inammation and regulate cell divi-
sion. This stimulates the release of signal transducers and activators of
transcription (STAT)3 which is involved in chronic intestinal inam-
mation to the initiation of cancer. Elevated STAT3 activity exerts an
immunosuppressive effect by inhibiting IL-2 production. As IL-2 levels
decline, IL-17 levels are raised promoting inammation and carcino-
genesis (Cheng et al., 2020).
Furthermore, BFT cleaves to the zonula adherens protein E-cadherin
and breaks it down compromising the colonic epithelial barrier. This
triggers a cell signaling response that causes spermine oxidase to be
elevated, which can cause inammation, irreversible damage to DNA,
and c-Myc-dependent pro-oncogenic hyperproliferation (Valguarnera
and Wardenburg, 2020; Chen et al., 2020). Germline mutations in the
adenomatous polyposis coli (APC) gene increases susceptibility of ETBF
adhesion to the intestinal mucosal layer thereby increasing the risk of
developing CRC (Cheng et al., 2020). Also, the development of CRC has
been associated with seropositivity to both ETBF and genotoxic E. coli,
indicating a potential role for co-infection of these bacterial species in
the pathogenesis of colorectal carcinogenesis (Butt et al., 2021).
4. Synbiotic roles in cancer therapies
The potential for improving gut health has made synbiotics that are
specically used by host an interesting area of research. Pre-clinical and
clinical studies reveal that synbiotics can be used in numerous ways in
the management of cancer patients (Scott et al., 2018). For example, the
fermented food ker is a type of synbiotic that has specic inhibitory
effects on the development of cancer and apoptosis in lung, breast,
colon, leukemia, and malignant T lymphocyte carcinoma. It also plays a
critical role in anti-mutagenic and anti-cancer activities. Ker can repair
damage to DNA damage and stop the growth of colon cancer Caco-2 and
HT29 cells, according to in vitro research. But ker consumption had no
discernible effect on the frequency of mucositis or serum levels of
proinammatory cytokines in colon cancer patients (Tasdemir and
Sanlier, 2020). The health benets of administering synbiotics include
the production of short-chain fatty acids such as acetate, butyrate, and
proprionate. Specically, butyrate possesses anti-inammatory and
anti-cancer properties. Synbiotics also promote the growth of benecial
bacteria and enhance immune system (Markowiak, and ´
Sli˙
zewska,
2018).
4.1. Foods fermented with probiotics
Anticancer treatments that are conventional are risky, costly, and
stressful. As a result, there is a growing market for cancer therapies,
preferably in the form of nutritional supplements or functional meals
(Ma’mon et al., 2018). Fermented foods are nutrient rich with a distinct
population of benecial microorganisms which can impact the gut
microbiome when consumed improving digestion, immunity, and
overall health (Leeuwendaal et al., 2022; Zhang et al., 2019) Table 2.
Fermented soy foods have been reported to possess anticancer properties
(Saeed et al., 2022), and the tumor inhibitory effects is due to the
presence of bioactive compounds including isoavones which protects
the integrity of the DNA by preventing oxidative stress and suppressing
cellular proliferation (Nurkolis et al., 2022).
Emerging evidence is consistent with the fact that certain fermented
foods are linked with a reduced risk of cancer. A meta-analysis of studies
concerning fermented foods and CRC, found that individuals that
A. Rowaiye et al.
The Microbe 4 (2024) 100096
7
consumed cheese had an 11 % decrease in colon cancer and 14 %
decrease rectal cancer, and in individuals with an elevated yogurt con-
sumption, there was a 25 % decrease in the incidence of rectal cancer
(Liang et al., 2022). Foods such as Sauerkraut, Kimchi, Kombucha, Miso,
Tempeh have been reported to increase the gut microbiome diversity,
and decrease pro-inammatory markers (Crowder et al., 2023).
4.1.1. Ker
Ker is a traditional fermented milk drink that contains a variety of
probiotic bacteria Lactobacillus keranofaciens, Lactobacillus delbrueckii
delbrueckii, Lactobacillus fermentum, Lactobacillus fructivorans, Aceto-
bacter aceti, Enterococcus faecium) and yeasts (Candida krusei, Candida
famata). It also contains lactose as a prebiotic. Ker, which possesses
strong antimutagenic and anticancer properties has been the subject of
numerous research studies (Ma’mon et al., 2018; Silva-Cutini et al.,
2019, Fatahi et al., 2021). Its consumption has been linked to a lower
risk of cancer (Jeong et al., 2021).
A recent study assessed the cytotoxic impact of ker on the growth
rate and proliferation of U87 glioblastoma cancer cells. The study
examined the relationship between cancer cells and varying quantities
of ker drink and supernatants over a period of 24 and 48 hours. When
compared to the control group, the MTT test result showed that the 48-
hour fermented drink treatment caused the highest amount of cell
cytotoxicity. The ndings demonstrated that the toxicity effect was
dose-dependent in all groups and that there was a signicant decrease in
cell survival with increasing dosage. The ndings showed that the fer-
mented ker drink supernatant, when used as a probiotic supplement, is
more toxic to glioblastoma cancer cells (Fatahi et al., 2021).
Another study investigated the theory that the condition of fermen-
tation affects the anticancer properties of ker. First, ker extracts made
according to the common procedure were tested using the MTT colori-
metric assay against seven cancer cell lines. Ker extracts were discov-
ered to have the greatest effect on cells from chronic myelogenous
leukemia and colon cancer. The effects of three fermentation times (24,
48, & 72 hours), three ker-to-milk ratios (2, 5, & 10 % wt/vol), and
three fermentation temperatures (4, 25, & 40◦C) on ker’s anticancer
properties were then evaluated using a factorial design. It is noteworthy
that by exploring the fermenting conditions, ker’s anticancer proper-
ties against sensitive cell lines were increased by a factor of 5–8. Given
the circumstances, these ndings point to the potential for enhancing
ker’s anticancer qualities as a functional diet in cancer treatment
(Ma’mon et al., 2018).
Cancer cells typically develop multidrug resistance (MDR) to
chemotherapeutic drugs, which results in the failure of cancer therapy.
To investigate the possible chemo-sensitizing properties of ker, or ker
supernatant, drug-resistant human colorectal cancer cells (HT-29) were
produced through a 12-week exposure to 34 nm of doxorubicin (DOX).
The ndings showed that in drug-resistant cells, ker treatment
enhanced DOX’s anticancer activity while attenuating MDR. Ker
caused drug-resistant cells to accumulate ROS and DOX intracellularly.
In drug-resistant cells, ker reduced the production of the drug efux
pump, and adenosine triphosphate binding cassette (ABC) transporters,
both in terms of gene and protein. Ker also affected the activity of ABC
transporter upstream regulators such as ERK 1/2, JNK, and NF-κB. Due
to its chemo-sensitizing properties, this study suggests that ker drink-
ing may be benecial for patients undergoing DOX chemotherapy
(Jeong et al., 2021).
4.1.2. Kimchi
Kimchi is a traditional Korean diet made of fermented vegetables,
usually cabbage and radishes, which provides both probiotics (Leuco-
nostoc spp, Lactobacillus spp, and Weissella spp) and prebiotics (Kim
et al., 2018; Cha et al., 2023). According to a recent study, Kimchi
prepared with Amtak Baechu cabbage and brine-treated showed
enhanced anticancer potential against human liver cancer cells (HepG2)
and pancreatic cancer cells (Capan-2). When compared to liver cancer
cells, the effects were more pronounced in pancreatic cancer cells (Song
et al., 2018).
In another study, rats injected with carcinogens and subsequently fed
with kimchi supplements for 120 days were examined to evaluate the
chemopreventive effect of Kimchi against CRC. At moderate and high
concentrations of kimchi supplementation, the study revealed a sup-
pression of precancerous lesions in the colon of rats fed red meat. The
Kimchi supplements also limited iron-mediated oxidation thereby
reducing lipid peroxidation in the rat feces. Also, Kimchi supplementa-
tion up-regulated the expression of tumor-suppressor genes and anti-
oxidant enzymes while down-regulating the expression of
proinammatory proteins thereby preventing colorectal carcinogenesis.
Acidication of the fecal matrix and an increase in fecal lactic acid
bacteria were linked to the chemopreventive effects of Kimchi (Surya
et al., 2023).
Ingredients and fermentation play a key role in boosting in vitro
Table 2
shows the different foods fermented with probiotics, their compositions and
their anti-cancer effects.
Fermented
food
Synbiotics Cancer (reference)
Probiotics Prebiotics
Ker Lactic Acid Bacteria Lactose U87 glioblastoma
cancer cells (Fatahi
et al., 2021).
Yeast (Candida krusei) Human CRC cells (Jeong
et al., 2021).
Chronic myelogenous
leukemia (Ma’mon
et al., 2018)
Colon cancer (Ma’mon
et al., 2018)
Kimchi Lactic Acid Bacteria Cabbage HepG2 human liver
cancer cells (Song et al.,
2018)
Capan-2 pancreatic
cancer cells (Song et al.,
2018)
CRC (Surya et al., 2023)
HT-29 human colon
carcinoma cells (Kim
et al., 2015)
AGS human stomach
cancer cells (Park and
Park, 1999)
Miso Zygosaccharomyces
sapae strain I-6
Soybeans Breast cancer (
Yamamoto et al., 2003)
Gastric cancer (
Hirayama, 1982)
Colon cancer (Ohara
et al., 2002)
Tempeh Limosilactobacillus
fermentum
Soybeans MCF-7 breast cancer
cells (Muzdalifah et al.,
2018)
Colon cancer (Divate
et al., 2023).
Pickles Bacillus licheniformis
KT921419
Cucumber HT-29 colon cancer cell
line (Ragul et al., 2020)
Pediococcus acidilactici
TMAB26 strain
HT-29 & Caco-2 cancer
cells (Barigela, and
Bhukya, 2021)
Natto Bacillus subtilis Soybeans Melanoma (Chou et al.,
2021)
murine breast cancer (
Zhang et al., 2019)
Sauerkraut Lactic Acid Bacteria Cabbage Breast cancer (Pathak
et al., 2021)
Sourdough
bread
Lactic Acid Bacteria Wheat ovarian carcinoma (
Tasdemir and Sanlier,
2020).
Yeast colon carcinoma (
Tasdemir and Sanlier,
2020).
A. Rowaiye et al.
The Microbe 4 (2024) 100096
8
anticancer activities. In HT-29 human colon carcinoma cells, the
bioactivity of Kimchi that had been fermented for varying lengths of
time and with other ingredients were investigated. The most potent
anticancer effect was demonstrated by optimally ripened Kimchi, which
also decreased proinammatory factor mRNA expression and increased
the production of Bax, caspase-9, and caspase-3 to induce apoptosis
(Kim et al., 2015).
The bioactivity of cabbages might vary depending on how they are
cultivated. Using AGS human stomach cancer cells, Park and Park
(1999), investigated the anticancer effects of methanol extracts from
both conventional Chinese cabbage Kimchi (CC Kimchi) and organically
grown Chinese cabbage Kimchi (OC Kimchi) on cell proliferation using
the MTT and SRB assays. Methanol extracts from fermented CC kimchi
and OC Kimchi, which were left for six days, decreased the growth of
tumors and increased the survival time of Balb.c mice injected with
sarcoma-180 cells. In comparison to the CC kimchi group and the control
group, the tumor weight was less in the OC Kimchi treatment group.
Furthermore, of the control and CC kimchi treated groups, the OC
Kimchi treated group had the greatest lifespan (Park and Park., 1999).
Furthermore, Kimchi prepared with organic components and LAB
starters (Leuconostoc mesenteroides and Lactiplantibacillus plantarum)
were tested on HT-29 human colon cancer cells. Evaluation was con-
ducted on four varieties of Kimchi: commercial (CK), organic (OAK),
anticancer (AK), and standard (SK). The ndings indicate that, of the
various Kimchi varieties examined, OAK has the highest total phenol
and avonoid content, as well as the highest DPPH free-radical scav-
enging activity. Additionally, the MTT assay demonstrates the highest
growth inhibition rate against HT-29 cancer cells (Lee et al., 2023).
4.1.3. Miso
Made from fermented soybeans with salt and koji (a kind of fungus),
miso is a traditional Japanese diet (Kusumoto et al., 2021). Miso has also
been discovered to contain a novel probiotic yeast Zygosaccharomyces
sapae strain I-6 which has anti-inammatory properties (Okada et al.,
2021). The consumption of Miso enhances immunological robustness.
To elucidate the effect of Miso on immune cells, Kotake et al. (2022)
evaluated its immunomodulatory potential in mice. It was discovered
that Miso boosted germinal center B cells, CD69+B cells, and regulatory
T cells but did not change the proportion of B and T cells in the spleen.
Consumption of miso led to an increase in levels of anti-DNA immuno-
globulin M antibodies, which help prevent autoimmune diseases.
Analysis of the transcriptome of mouse spleen cells cultured with miso
and its raw material revealed higher expression levels of genes such as
CD86, IL-10, and IL-22. Furthermore, Miso promoted Ca
2+
signaling in a
manner like probiotics, according to the intravital imaging of the small
intestine epithelium performed using a calcium biosensor mouse strain.
As a result, giving mice Miso increased their tolerance and immuno-
logical response (Kotake et al., 2022).
A population-based, prospective cohort study conducted in Japan
found that regular consumption of Miso soup was linked to a lower
incidence of breast cancer. In postmenopausal women, the inverse as-
sociation was stronger (Yamamoto et al., 2003). In another study in
Japan, the daily consumption of soybean paste soup was found to
signicantly lower standardized mortality rates for gastric cancer in 29
Health center districts, involving 122,261 males and 142,857 females
aged 40 and above, over a 12-year period (Hirayama, 1982). Miso may
also inuence colon carcinogenesis. In a study performed by Ohara
et al., (2002), male F344 rats were used to examine the impact of fer-
mented miso on the formation of aberrant crypt foci (ACF) by azoxy-
methane (AOM). The ndings suggest that consuming fully fermented
Miso in the diet may have chemopreventive effects on colon carcino-
genesis (Ohara et al., 2002).
4.1.4. Tempeh
Indonesia is the source of the fermented soybean product known as
Tempeh. Tempeh is a functional food made from soybeans fermented by
Rhizopus spp and probiotics such as Limosilactobacillus fermentum
(Muzdalifah et al., 2018; Handajani et al., 2022) The bioactive com-
pounds found in Tempeh can suppress cancer cell growth, inhibit
angiogenesis, induce cancer cell apoptosis, and have antioxidant prop-
erties (Nurkolis et al., 2022).
Fermentation of Tempeh signicantly increases the bioactivity of
soybeans (Divate et al., 2023). A study conducted by Muzdalifah et al.,
(2018) was aimed at determining whether Tempeh that had been fer-
mented for 0–156 hours and extracted with ethanol was cytotoxic. The
ndings revealed that there is a correlation between the cytotoxicity of
Tempeh and its equivalent antioxidant activity from 0 to 156 hours of
fermentation. A longer fermentation period (up to 108 hours), increased
Tempeh’s ability to inhibit the proliferation of MCF-7 breast cancer
cells. Antioxidant activity and cytotoxicity tended to decline with longer
fermentation times (up to 156 hours) (Muzdalifah et al., 2018).
In another study, the effect of Tempeh on colon precancerous lesions
(aberrant crypt foci, or ACF) in vivo and colorectal cancer cells in vitro
was evaluated. Tempeh water extract (WET) may prevent Caco-2 cell
growth in the in vitro experiment. Also, twelve weeks of daily Tempeh
consumption by Sprague-Dawley (SD) rats induced with 1,2-dimethyl-
hydrazine (DMH) was found to lower the amount of Clostridium per-
fringens in the cecum content and the number of big ACF in the colon
compared to the control. Because the bioactive peptides in Tempeh limit
the growth of Candida perfringens in the digestive tract, they may be able
to prevent colon cancer (Divate et al., 2023).
4.1.5. Pickles
Pickled cucumbers or other vegetables fermented in brine can pro-
vide probiotics and prebiotic ber from the vegetables (Pourjafar et al.,
2023). Fermented pickles contain bioactive compounds that may have
potential health benets, including anti-cancer properties. They are a
reliable source of probiotics, supporting the gut health and immune
function. The fermentation process of pickles boosts their
anti-proliferative activity, potentially inhibiting the growth of cancer
cells (Tan et al., 2023).
The anticancer potential of probiotic Bacillus isolates in fermented
brine mango pickles was assessed by Ragul et al. (2020). The intracel-
lular cell-free extracts (CFE) and cell-free supernatants (CFS) of Bacillus
strains were found to have possible inhibitory effects on
α
-amylase,
α
-glucosidase, and tyrosinase. Interestingly, when tested against the
HT-29 colon cancer cell line, CFS and crude ethyl acetate extracts of
PUFSTP35 (Bacillus licheniformis KT921419) showed signicant anti-
cancer activity (Ragul et al., 2020).
Another study examined the in vitro anti-inammatory and anti-
cancer properties of the Pediococcus acidilactici TMAB26 strain, iso-
lated from a traditional Indian tomato pickle. In comparison to periph-
eral blood mononuclear cells (PBMCs) alone, the probiotic isolate
TMAB26 culture supernatant (1:1 dilution) demonstrated signicant
cytotoxicity against HT-29 and Caco-2 cancer cells. Furthermore, in
lipopolysaccharide (LPS)-pretreated HT-29 cells and PBMCs, the su-
pernatant of the strain culture decreased the mRNA levels of the
proinammatory TNF-
α
by threefold and IL-6 by eightfold, while
increasing the mRNA levels of the anti-inammatory cytokine IL-10.
These ndings indicate that the TMAB26 isolate, Pediococcus acid-
ilactici MTCC 13014, may have a potential role in alleviating gut
inammation (Barigela, and Bhukya, 2021).
4.1.6. Natto
Natto is a Japanese diet made from fermented soybeans. It is rich in
probiotics and prebiotic bers (Afzaal, et al., 2022). In a study con-
ducted by Chou et al. (2021), the soybeans were fermented by Bacillus
subtilis to produce Natto. Natto was used to make natto water extract
(NWE) and natto freeze-drying extract (NFDE). NWE and NFDE were
assessed as potential anti-melanoma agents, and cell cytotoxicity tests
demonstrated that both exhibited potent, dose-dependent anti--
melanoma effects. Both extracts had mild effects on normal skin cells
A. Rowaiye et al.
The Microbe 4 (2024) 100096
9
such as HaCaT, Hs68, and adipose tissue-derived stem cells (ADSCs).
NFDE and NWE treatments inhibit AMP-activated protein kinase
(AMPK), which increases oxidative stress in cancer cells and leads to
apoptosis. Through the control of autophagy, stimulation of apoptosis,
and correction of reactive oxygen species, NFDE and NWE were thought
to be essential for cell death (Chou et al., 2021).
Zhang et al. (2019) studied the inhibitory effect of Bacillus sub-
tilis-produced nattokinase on murine breast cancer. The ndings showed
that cultured supernatant and bacterial suspension could prevent breast
carcinogenesis. Contrast-enhanced ultrasonography revealed that the
blood vessels within the tumor were distributed after being treated with
the supernatant and bacterial suspension. Also, the FOXM1 and MMP2
expressions of the tumor tissue were decreased by the suspension and
supernatant. This study demonstrated that nattokinase could have a
novel use in tumor therapy (Zhang et al., 2019).
4.1.7. Others
Sauerkraut, which is traditionally associated with German cuisine, is
a fermented cabbage containing high amounts of ascorbic acid, ascor-
bigen, and glucosinolates. It has been associated with reduced DNA
damage and lower cell mutation rates in cancer patients (Connolly et al.,
2021). Sauerkraut contains live probiotic bacteria, particularly lactic
acid bacteria, which can benet gut health and the immune system. In a
recent investigation into the benets of locally made Sauerkraut brine
for gut health, it was found that the brine boosted a strong inammatory
response to endotoxin by raising the production of TNF-
α
and IL-6 and
stimulating the synthesis of the anti-inammatory IL-10. This discovery
bolsters the idea that Sauerkraut brine may control gut immunological
activity (Gaudioso et al., 2022). The consumption of Sauerkraut has
been linked with the lower risk of breast cancer incidence (Pathak et al.,
2021).
Sourdough bread is a Mediterranean diet (Da Ros et al., 2021).
Sourdough bread contains bioactive compounds that may have potential
health benets, including anti-cancer properties, they are a good source
of probiotics (lactic acid bacteria and yeast strains), therefore support
gut health and immune function. The fermentation of Sourdough bread
produces peptides and phenolic compounds, which may have antioxi-
dant and anti-inammatory effects and potentially protect the cells from
damage and reduce the risk of cancer (Graça et al., 2021; Fekri et al.,
2020).
In another study, researchers explored the impact of sourdough lactic
acid bacterial fermentation on the release of 2,6-dimethoxybenzoqui-
none, a naturally glycosylated compound found in wheat germ that is
in a non-physiologically active form. The study focused on two isolated
strains, Lactobacillus plantarum LB1 and Lactobacillus rossiae LB5. Using
an ex vivo approach, both raw wheat germ and sourdough-fermented
wheat germ were tested for their antiproliferative effects against
ovarian carcinoma, and colon carcinoma cell lines. The results revealed
that raw wheat germ did not exhibit any signicant effect, whereas
sourdough-fermented wheat germ demonstrated antiproliferative ac-
tivity (Tasdemir and Sanlier, 2020).
4.2. Formulated synbiotics
4.2.1. Synbiotics of Lactobacillus spp
Lactobacillus rhamnosus GG (LGG) is a popular and well-researched
probiotic strain that has positive benets on gut health. Certain prop-
erties of LGG suggests its potential as part of anticancer synbiotics and
these include immunomodulation of both adaptive and innate immune
responses, the inhibition of tumor growth, reduction of chronic gut
inammation, the enhancement of chemotherapy, and the maintenance
of a healthy gut microbiome (Shi et al., 2020; Capurso, 2019; Salemi
et al., 2023).
Studies have been conducted on human colon and prostate cancer
cells to examine the possible synbiotic interaction between LGG and
salicylic acid. Salicylic acid, which is found in many herbs, has been
shown to have strong antioxidant effects and to signicantly boost the
co-aggregation of LGG with E. coli. Moreover, salicylic acid triggered
LGG’s cytotoxic activities on human colon cancer cells. These ndings
imply that the combination of salicylic acid and LGG may have addi-
tional probiotic effects (Celebioglu, 2021).
Furthermore, the therapeutic efcacy of cancer vaccine using whole
cancer cells (MC38 cells) in mice was signicantly increased by a
particular synbiotic preparation consisting of 100
μ
L of mixture of LGG
(2.0×10
9
CFU/mL) and jujube powder (800 mg/kg). This synbiotic’s
modication of the gut microbiota improved lipid metabolism, which
led to increased CD8+T cell inltration in the tumor microenvironment
and increased the effectiveness of the cancer vaccine. This promising
result would enhance future research aimed at improving the thera-
peutic effects of nutritional supplementation in cancer vaccines (Jing
et al., 2023).
4.2.2. Synbiotics of Bidobacteria spp
Recent research, utilizing preclinical mouse models and human
clinical trials, has illustrated the impact of gut commensals, such as
Bidobacterial spp on the effectiveness of tumor-targeting immuno-
therapy. In a preclinical study, increased Bidobacterium abundance in
the gut of mice led to decreased melanoma growth and enhanced im-
mune surveillance by antitumor cytotoxic T lymphocytes (CTLs). The
study also demonstrated a favorable correlation between the presence of
Bidobacterium and antitumor T cell responses. This suggests that spe-
cic species of the genus, namely Bidobacterium breve, Bidobacterium
adolescentis, and Bidobacterium longum, have benecial antitumor
immunological effects (Longhi et al., 2020). In clinical trials, Bido-
bacteria has also been shown to elicit positive effects against cancer
targeted by immunotherapies (Longhi et al., 2020).
Formulations of probiotics and synbiotics including Bidobacterium
lactis or Lactobacillus casei have been shown to boost NK cell function in
both rodent models and human studies. Furthermore, in mouse models,
probiotic-induced NK cell activation has been shown to hinder the onset
of cancer (Shashank et al., 2023). Bidobacteria spp can thrive and
multiply on soluble and insoluble bers because they have carbohy-
drases such as
α
-glucosidases, β-galactosidases, fructosyltransferases
which digest these carbohydrate molecules such as inulosucrase, xyla-
nases, amylases, and arabinofuranosidases (van den Broek et al., 2008;
Sharma et al., 2018).
4.2.3. Synbiotics of Bacteroides spp
Bacteroides species are among the most common bacteria found in
the human colon (Wang et al., 2021). Bacteroides species play important
roles in maintaining gut health and contributing to various physiological
functions (Zafar and Saier Jr, 2021). Bacteroides spp can play a critical
role in immunotherapy especially in Immune checkpoint blockade (ICB)
(Usyk et al., 2021). ICB has transformed the treatment strategy for
malignancies deemed non-immunogenic, such as
mismatch-repair-decient CRC or non-small cell lung cancers (NSCLC),
as well as immunogenic tumors like renal cell carcinoma and melanoma
(Feola et al., 2018).
Multiple studies have indicated that the composition of the micro-
biota inuences the efcacy of immune checkpoint blockade (ICB)
treatments. Longhi et al. (2020) found that mice treated with
broad-spectrum antibiotics or germ-free (GF) mice lacking certain bac-
terial species, such as Bacteroides, are resistant to CTLA-4 blocking
therapy. Oral dosing of Bacteroides fragilis has been shown to enhance
the response to CTLA-4 inhibition. Recolonization of the intestinal
microbiota by B. fragilis results in an upsurge of T-cell helper (Th1) re-
sponses in the lymph nodes closest to the tumor, thereby boosting the
efcacy of CTLA-4 inhibition (Longhi et al., 2020).
The interaction of an appropriate prebiotic will boost the anticancer
potential of Bacteroides spp. For example, yeast mannan has been
demonstrated to selectively increase the population of B. ovatus and
B. thetaiotaomicron (Oba et al., 2020)
A. Rowaiye et al.
The Microbe 4 (2024) 100096
10
4.2.4. Synbiotics of Akkermansia spp
Akkermansia muciniphila, a representative commensal bacterium,
has garnered signicant attention in the last decade and it has been
identied as a prospective next-generation probiotic (Zhao et al., 2023).
The gut bacteria have been shown to signicantly inhibit carcinogenesis
and enhance anti-tumor activities and can boost the efcacy of cancer
immunotherapy while lowering the risk of adverse effects (Fan et al.,
2023). The constituents and byproducts of A. muciniphila possess the
ability to impact tumorigenesis either directly or indirectly. Specically,
their activities on antitumor immunosurveillance, which involves acti-
vating pattern recognition receptors (PRRs), can improve outcomes in a
range of contexts, such as cancer prevention and treatment (Zhao et al.,
2023).
Patients with NSCLC or kidney cancer who have fecal A. muciniphila
have been shown to benet clinically from ICB. In a recent study uti-
lizing shotgun-metagenomics-based microbiome proling in a large
patient cohort treated with rst- or second-line immune checkpoint in-
hibitors, baseline A. muciniphila levels in stool were linked to higher
response rates and overall survival, independent of performance status,
antibiotic use, or PD-L1 expression. In a subgroup of patients, the
presence of intestinal A. muciniphila correlated with a more inamma-
tory tumor microenvironment and a diverse commensal community,
which included Bidobacterium adolescentis and Eubacterium hallii (Der-
osa et al., 2022).
Akkermansia can be sourced from supplements or certain foods that
promote its abundance, such as freeze-dried black raspberries or red
pitaya (Hylocereus polyrhizus) (Wang et al., 2020). Polysaccharides from
seaweed (Enteromorpha clathrata) and Bidobacterium and Lactobacillus
species also boosted the abundance of A. muciniphila. Moreover, in mice
on a high-fat diet, the presence of A. muciniphila can be boosted by
mannan-oligosaccharides derived from dietary bers (Hagi, and Belzer,
2021). The carbohydrate molecules that A. muciniphila utilizes are
galactose, fucose, and N-acetylgalactosamine (GalNAc), and N-acetyl-
glucosamine (GlcNAc) which are generated from mucin. In humanized
rats, the higher production of mucin that results in an enhanced fecal
abundance of A. muciniphila is inuenced by long-chain arabinoxylans
and inulin (Hagi, and Belzer, 2021). It is important that these
A. muciniphila-synbiotics be tested in NSCLC and renal cell carcinoma
patients (Wang et al., 2020).
4.3. Combination of synbiotics with cancer therapies
4.3.1. Immunotherapy and synbiotics
The diverse responses of patients to cancer immunotherapy are
signicantly inuenced by the gut microbiome (Bangolo et al., 2023).
For example, it has been discovered that through the modulation of the
tumor microenvironment in the treatment of pancreatic cancer, a range
of commensal bacteria can impact the effectiveness of traditional
immunotherapy (Bangolo, et al., 2023). Research has recently focused
on the impact of gut microbiota composition on the efcacy of novel
cancer treatments, such as immune checkpoint inhibitors and chimeric
antigen receptor T-cell therapy (Bangolo et al., 2023).
Certain gut bacteria can induce host responses to immune checkpoint
inhibitors, either by activating or repressing them, in addition to
generating mutations that alter gene expression. These bacteria and
their metabolites can also restore normal healthy microbiome during
cancer treatments (Shui et al., 2020; Grenda and Krawczyk, 2021).
Several bacteria have demonstrated advantageous potential in can-
cer patients treated with anti-CTLA-4, anti-PD-1, or anti-PD-L1 mono-
clonal antibodies. They include Faecalibacterium prausnitzii, Enterococcus
hirae, and Akkermansia mucinila. Patients’ guts enriched with these
bacterial species have demonstrated improved clinical outcomes from
therapy (Grenda and Krawczyk, 2021). Numerous human clinical trials
have also indicated that the presence or enrichment with other gut
bacteria may have an impact on how well cancer immunotherapy works.
In the use of Ipilimumab and other immune checkpoint inhibitors
against metastatic melanoma, Bacteroides caccae, Bacteroides thetaiota-
micron, Dorea formicogenerans, Collinsella aerofaciens, Enterococcus fae-
cium, Holdemania liformis, Bidobacterium longum, and Ruminococcus
spp have enhanced antitumor response and overall survival (Vivarelli
et al., 2019; Wang et al., 2020). Remarkably, Lactobacillus rhamnosus GG
(LGG), is the most researched probiotic model in cancer research.
Overall, new approaches combining probiotics, such LGG, with tradi-
tional anti-cancer treatments have been highly recommended (Vivarelli
et al., 2019).
Manipulating the gut microbiotas of cancer patients may enhance
their therapeutic responses, as there is compelling data from various
clinical trials that suggests the variety and composition of these micro-
bial populations at baseline may impact the patients’ response to cancer
immunotherapy. Having a comprehensive understanding of the factors
that inuence gut ora is crucial. Recent studies suggest that bioactive
compounds found in vegetables, fruits, and whole grains can enhance
the body’s response to cancer therapy by inuencing and diversifying
the gut microbiota (Wang et al., 2020).
4.3.2. Radiotherapy and synbiotics
Radiation therapy has achieved notable success in cancer treatment,
although the responsiveness of patient tumors to radiation and the fre-
quency and severity of side effects can vary considerably. Radiation-
induced gastrointestinal mucositis can be inuenced by the gut micro-
biota. As a result, it is possible to modify the gut microbiota to maximize
therapeutic responsiveness and minimize adverse consequences (Liu
et al., 2021). The intestinal microbiota of patients undergoing radiation
therapy is signicantly altered. Most commonly, there are increases in
Enterobacteriaceae and Bacteroides and decreases in Clostridium cluster
XIVa, Bidobacterium, and Faecalibacterium prausnitzii. These changes
could have a role in the development of the symptoms of mucositis,
specically bacteremia and diarrhea (Wang et al., 2020).
The intricate pathobiology of oral mucositis, especially in patients
diagnosed with oral cancer, makes its prevention and treatment during
radiation therapy for these patients a crucial and unmet therapeutic
need. A study comparing the benets of ordinary saline mouthwash with
synbiotic mouthwash was conducted to treat and prevent oral mucositis
induced by radiation in patients with oral cancer. A double-blind ran-
domized clinical trial (RCT) involving 64 patients with oral cancer who
underwent 6000 cGY of radiation in 34 segments and intensity-
modulated radiotherapy was conducted. The severity of oral mucositis
decreased statistically signicantly in the case group (synbiotic
mouthwash). Using a synbiotic mouthwash signicantly reduces and
prevents the severity of oral mucositis in individuals with radiation-
treated oral cancer (Manifar et al., 2023).
A clinical study was conducted on individuals who had acute proc-
titis caused by radiation to investigate the impact of a daily dose of
synbiotics on symptom relief and the reduction of systemic/rectal in-
ammatory response. Twenty patients undergoing three-dimensional
conformal radiation therapy for prostate cancer were randomly
assigned to receive either a placebo or a synbiotic powder comprising
10
8
CFU of L. reuteri and 4.3 g of soluble ber. The CRP/albumin ratio
did not alter, although the fecal calprotectin level increased more in the
placebo group. Synbiotics reduced rectal inammation after radiation
treatment for prostate cancer, improving quality of life and lowering
proctitis symptoms (Nascimento et al., 2020).
A thorough analysis of randomized controlled trials (RCTs) was
performed to assess the impact of probiotics and synbiotics on
chemoradiotherapy-related toxicity in CRC patients. The efcacy of
probiotics and synbiotics in mitigating the side effects of chemotherapy,
radiation therapy, and chemoradiotherapy in patients with CRC was
assessed. Probiotic supplementation reduced radiation-induced diar-
rhea, although its impact was minimal when anti-diarrheal drugs were
used concomitantly. In a separate trial, the consumption of synbiotic
supplements enhanced quality of life and decreased serum levels of high-
sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase (MMP-
A. Rowaiye et al.
The Microbe 4 (2024) 100096
11
2 and MMP-9), and diarrhea (Mahdavi et al., 2023).
A comprehensive study and meta-analysis were conducted to assess
the effectiveness of various dietary supplement regimens in preventing
or reducing symptoms of gastrointestinal toxicity in patients undergoing
radiation therapy for various pelvic cancers. The study analyzed twenty-
three RCT involving 191 people. In comparison to a placebo, probiotics,
synbiotics, and polyphenols were signicantly linked to a reduced
incidence of diarrhea. Moreover, biotic supplements reduced the like-
lihood of moderate-to-severe diarrhea and the requirement for antidi-
arrheal medication. However, amino acid supplementation did not
alleviate acute symptoms. There was a trend, although not statistically
signicant, for mean daily bowel movements and nausea to decrease
with the administration of nutritional supplements. In patients under-
going pelvic radiation therapy, probiotics and synbiotics decrease the
early symptoms (Bartsch et al., 2020).
In patients with rectal cancer undergoing neoadjuvant chemo-
radiotherapy (CRT), researchers also studied the impact of synbiotic
supplementation on matrix metalloproteinase (MMP) enzymes, hs-CRP
levels, quality of life, nutritional intake, and weight changes. In a six-
week research, 46 individuals with rectal cancer were involved (23
given synbiotics and 23 given a placebo). The synbiotic supplement
contained Bidobacterium breve PXN 25, Bidobacterium longum PXN 30,
Lactobacillus acidophilus PXN 35, 1 ×108 CFU/gr of Lactobacillus casei
PXN 37, Lactobacillus bulgaricus PXN 39, Lactobacillus rhamnosus PXN 54,
Streptococcus thermophilus PXN 66, Fructo-oligosaccharide, hydrox-
ypropyl methyl cellulose, and magnesium stearate. According to the
results, the use of synbiotic supplements enhanced the symptom scale
scores, functional scale scores, and global health status, according to the
results. hs-CRP, MMP-2, and MMP-9 levels were approximately four
times higher in the synbiotic group than in the placebo group. These
ndings imply that supplementing with synbiotics might be benecial
for cancer patients receiving CRT (Radvar et al., 2020).
4.3.3. Chemotherapy and synbiotics
Chemotherapy patients typically have an increased risk of infection,
which can lead to problems like colitis, mucositis, sepsis, and diarrhea.
Despite numerous dietary approaches being evaluated to alleviate
chemotherapy side effects in cancer patients, none have been approved
for routine clinical use thus far. Restoring the gut microbiota is one
strategy to lessen or prevent complications related to chemotherapy.
Chemotherapy causes the gut microbiota to disappear and erodes the
gastrointestinal tract’s mucosal layer. Studies have shown that taking
probiotics along with prebiotics, or synbiotics, may have greater health
advantages than taking probiotics alone (Singh et al., 2023).
Mucositis and gut dysbiosis are the two main gastrointestinal adverse
effects of chemotherapy. These show up as excruciating esophageal and
mouth ulcers, along with the onset of diarrhea and abdominal pain,
which causes patients with solid organ tumors to become malnourished
and dehydrated. Various dietary approaches, including the use of syn-
biotics, have been utilized to enhance gut microbiota and mitigate the
adverse effects of anticancer medications (Singh et al., 2023).
As previously mentioned, side effects from chemotherapy include
diarrhea, mucositis, and colonic infections. Taking synbiotics may help
reduce these symptoms in several ways. In a clinical study conducted in
2017, the effects of synbiotics were evaluated in 61 patients undergoing
neoadjuvant chemotherapy for esophageal cancer. The ndings revealed
that patients who received synbiotics experienced a signicant reduc-
tion in chemotherapy-induced diarrhea and lymphopenia. The syn-
biotics administered contained 15 g/day galacto-oligosaccharides and
3 g/day Yakult BL Seichoyaku (containing 1 ×10
8
living Lactobacillus
casei strain Shirota and 1 ×10
8
living Bidobacterium breve strain
Yakult). (Motoori et al., 2017).
Another clinical trial from 2020 showed how supplementing with
synbiotics positively affected 46 patients with CRC receiving chemo-
therapy. In comparison to the placebo group, the synbiotic group
showed a slight decrease in the mean symptom score for diarrhea,
whereas the placebo group experienced a signicant increase (Singh
et al., 2023).
Probiotics can combat dysbiosis in cancer patients undergoing
chemotherapy because of their ability to maintain gut homeostasis
(Vivarelli et al., 2019). Recent research indicates that the gut microbiota
can inuence the host’s response to chemotherapy by enhancing
medication efcacy, fostering chemoresistance, and mitigating chemo-
therapy toxicity and adverse effects through diverse mechanisms.
Several additional studies have also suggested that altering the micro-
biome could benet the treatment of colorectal cancer (Kalasabail et al.,
2021).
A study was undertaken to elucidate the role of synbiotics in bacte-
rial translocation and subsequent bacteremia following neoadjuvant
treatment for esophageal carcinoma. The study included twenty patients
in the synbiotics group and twenty in the control group. The synbiotics
group experienced a lower incidence of grade 3 gastrointestinal toxicity
following chemotherapy compared to the control group. Administering
synbiotics can decrease bacterial translocation and bacteremia poten-
tially induced by neoadjuvant chemotherapy for esophageal cancer
(Fukaya et al., 2021).
Thus, synbiotics seem to work better than probiotic or prebiotic
supplements taken separately. When compared to probiotics and pre-
biotics alone, synbiotics support improved intestinal integrity, immu-
nological control, higher fermentation of bers to release SCFAs, and an
increased modulation of metabolic activity. A recent study found that
the consumption of synbiotics led to an increase in the production of
certain biochemicals including methyl acetates, carbon disuldes, and
ketones while decreasing the buildup of undesirable metabolites, ni-
trosamines, and carcinogenic substances (Singh et al., 2023).
4.3.4. Cancer surgery and synbiotics
The anti-inammatory properties and microbiome-modifying abili-
ties of synbiotics, prebiotics, and probiotics suggest they might improve
surgical outcomes. They have the potential to combat anastomotic leaks,
the development of CRC, and surgical and hospital-acquired infections.
When administered during the perioperative phase, prebiotics, pro-
biotics, and especially synbiotics may prove to be highly advantageous.
Even a brief rehabilitation of the gut microbiota could have a substantial
impact on surgical outcomes (Trone et al., 2023).
A clinical study investigated the impact of preoperative synbiotic
administration on patients with CRC undergoing colorectal resection.
Patients were randomized to receive either synbiotics or placebo
(maltodextrin) seven days before surgery. The synbiotic employed in the
study was Simbioora (Farmoquimica, S˜
ao Paulo, Brazil), a dietary
supplement containing probiotics (Bidobacterium lactis HN019,
L. rhamnosus HN001, Lactobacillus acidophilus NCFM, and L. casei LPC-
37, each at a concentration of 10
9
CFU) and 6 g of fructooligo-
saccharide. Administering synbiotics for seven days before surgery in
CRC patients reduced the inammatory response and was linked to
decreased morbidity, as shown by signicant reductions in IL-6 and CRP
levels compared to the control group (Polakowski et al., 2019).
In a separate randomized, double-blind clinical trial, 91 participants
were divided into two groups: one receiving synbiotics and the other
receiving a placebo. The administration of the synbiotic preparation
containing 6 g of fructo-oligosaccharide and L. acidophilus (10
8–9
CFU),
L. casei (10
8–9
CFU), L. rhamnosus (10
8–9
CFU), and Bidobacterium
(10
8–9
CFU), reduced the incidence of surgical site of infection to 2 % as
compared with 21.4 % of participants administered with the placebo
(Ka´
zmierczak-Siedlecka et al., 2020). The synbiotics administered low-
ered the expression levels of β-catenin, COX-2, caspase 3, TRL4, and
whereas MUC2, occludin, TRL2, and ZO-1 were elevated. These ad-
justments prevented inammation and apoptosis, enhanced mucin
secretion, maintained tight connections, and reduced tumor growth
(Ka´
zmierczak-Siedlecka et al., 2020).
Administering probiotics and synbiotics perioperatively could
potentially decrease the incidence of adverse effects and improve
A. Rowaiye et al.
The Microbe 4 (2024) 100096
12
longevity and quality of life for CRC patients. Amitay et al. (2020)
analyzed sixteen randomized, placebo-controlled clinical trials
involving probiotics or synbiotics. All of them involved patients having
CRC surgery. The side effects related to surgery, the quality of life and
postoperative problems were studied. It was observed that a lower
incidence of infections and diarrhea, a quicker return to normal gut
function, a smaller need for postoperative antibiotics, a lower incidence
of septicemia, and a shorter duration of hospital stay were all linked to
the administration of probiotics and synbiotics during surgery. These
results support the idea that administering probiotics and synbiotics
perioperatively could reduce gastrointestinal symptoms and post-
operative complications in CRC patients. These treatments are
cost-effective compared to alternatives, simple to administer, and have
minimal side effects (Amitay et al., 2020).
A recent meta-analysis study found that synbiotics had an impact on
patients with gastrointestinal cancer’s early postoperative recovery of
gastrointestinal function. Included in this study were 21 RCTs with 1776
participants in total. The groups supplemented with synbiotics experi-
enced shorter durations for rst uid diet, rst solid diet, rst atus, rst
feces, and postoperative hospital stay compared to the control groups.
Additionally, synbiotic supplementation reduced the incidence of post-
operative ileus and abdominal distension. The rehabilitation of gastro-
intestinal function following gastrointestinal cancer surgery can be
effectively aided by perioperative synbiotic therapy (Tang et al., 2022).
Hepatopancreatobiliary carcinoma (HPBC) postoperative infection is
a leading cause of morbidity and death. Tang et al., (2022) studied eight
RCTs involving a total of 445 participants. In HPBC patients, probiotic or
synbiotic supplementation signicantly decreased the incidence of
postoperative infection, with synbiotics being particularly helpful in this
regard. Moreover, synbiotics can shorten hospital stays and the amount
of time patients need to take antibiotics. Synbiotics are useful tactics for
preventing postoperative infection in individuals with HPBC (Tang
et al., 2022).
In recent years, a series of clinical trials involving CRC patients has
demonstrated the efcacy of synbiotics in addressing post-surgical
pathological conditions. A 2016 clinical study specically highlighted
the benets of a particular multistrain/multiber synbiotic formulation.
This formulation included 2.5 grams each of prebiotics such as β-glucan,
pectin, inulin, and resistant starch, combined with 10 strains each of
probiotics including Pediococcus pentosaceus 5–33:3, Lactobacillus para-
casei ssp. paracasei 19, Leuconostoc mesenteroides 32–77:1, and Lactoba-
cillus plantarum 2362. This synbiotic formulation was found to reduce
the risk of postoperative complications, including irritable bowel syn-
drome (IBS), in colorectal cancer patients undergoing resection surgery
(Theodoropoulos et al., 2016; Singh et al., 2023).
In 2017, a follow-up randomized clinical trial involving 91 CRC
patients undergoing elective surgery was conducted. The trial admin-
istered synbiotics to 49 patients for ve days before the surgical pro-
cedure and continued for 14 days post-surgery, while 42 patients
received a placebo. The synbiotic formulation included probiotics such
as Bidobacterium lactis at 10
8–9
CFU, Lactobacillus acidophilus at 10
8–9
CFU, Lactobacillus paracasei at 10
8–9
CFU, and Lactobacillus rhamnosus at
10
8–9
CFU, along with 6 g of fructo-oligosaccharide as prebiotics. The
study’s ndings revealed a signicant reduction in post-operative
infection rates among CRC patients who received synbiotics compared
to those who received the placebo (Flesch et al., 2017 Singh et al., 2023).
Moreover, a randomized double-blind trial has examined the impact
of synbiotic administration in 73 individuals slated for colorectal sur-
gery (Krebs, 2016). Three patient groups were randomly assigned: one
received prebiotics alone, another received synbiotics alone, and a third
underwent preoperative mechanical colon cleansing. The symbiotic
formulation administered called Synbiotic 2000 FORTE consists 1011 of
each of four LAB: Pediacoccus pentosaceus 5–33:3, Leuconostoc mesen-
teroides 32–77:1, Lactobacillus paracasei subsp paracasei 19, and Lacto-
bacillus plantarum 2362. Also included in the formulation is 2.5 g of each
of the four fermentable bers – probiotics: beta-glucan, inulin, pectin,
and resistant starch. After colorectal surgery, there were no signicant
changes in the systemic inammatory response. However, the synbiotic
group showed higher levels of lactic acid-producing bacteria compared
to the other groups, indicating that the use of synbiotics may have
positively impacted the gut microbiota (Singh et al., 2023).
5. Limitations and future perspectives
While the study recognizes the potential benets of synbiotics in
cancer therapies, it may not thoroughly explore the potential adverse
effects or risks linked to their use in cancer treatment. Microbes possess
various mechanisms that can suppress or harm essential host processes
for their own benet. Risks associated with synbiotics may include
horizontal gene transfer of antibiotic-resistant genes or virulent mobile
genetic elements from probiotics to the gut commensal communities,
leading to antibiotic resistance; abdominal bloating due to small intes-
tinal bacterial overgrowth; probiotic-induced d-lactic acidosis; allergic
reactions to components of synbiotic formulations; and infection risk,
especially in immunocompromised individuals (Lerner et al., 2019;
Sotoudegan, 2019).
Furthermore, identifying the ideal prebiotic-probiotic combinations
for different cancer types may require more extensive research and
personalized approaches, which may not be fully addressed in the
review.
Several research tests and clinical trials are necessary to advance the
use of synbiotics in cancer therapy. Among the possible directions for
further research are: First, the proling of the microbiota in cancer pa-
tients. It is important to carry out thorough investigations that charac-
terize the gut microbiomes of cancer patients, considering differences
across cancer types, stages, and individual patients. Conducting thor-
ough research on the dynamic changes in the microbiome throughout
the onset, progression, and response to different cancer treatments is
crucial. Certain microbial metabolites are linked to various cancer types
could be identied by microbial proling and these would serve as
prognostic or diagnostic biomarkers. This would culminate in the
comprehensive understanding of relationships between microbial me-
tabolites and the immune responses they trigger.
Second, it’s important to identify the best synbiotic formulations.
Biomedical researchers should further investigate the probiotic-
prebiotic combinations that show maximal anticancer effects. More
preclinical research should be done to ascertain the best doses and
combinations of synbiotic therapies for various cancer types and stages.
To make sure that synbiotics do not present hazards or consequences
over longer periods of time, especially in cancer patients who may un-
dergo lengthy treatment regimens, these studies would involve long-
term safety assessments.
Thirdly, the advancement of methods for personalized medicine. It is
important to develop customized synbiotic therapies based on each
person’s distinct microbiome composition and cancer features. To assess
the effectiveness and safety of individualized synbiotic therapy, clinical
trials that take patient-specic aspects into account should be
conducted.
The creation of combination treatments comes in fourth. It would be
benecial to do a more thorough investigation in clinical settings to see
how synbiotics work in concert with traditional cancer therapies
including radiation, immunotherapy, and chemotherapy. This involves
investigating possible synergistic effects with newly developed cancer
treatments, like gene and targeted therapy. Informed consent, possible
dangers, and patient autonomy are ethical issues that should be
addressed in these clinical trials when using synbiotics to treat cancer.
Critical analysis should be done on patient-reported outcomes and
quality of life metrics in clinical studies to determine the overall effect of
synbiotic therapies. To efciently develop and carry out these trials,
cooperation between researchers, doctors, and industry partners will be
essential. Extensive clinical trials, encompassing diverse patient de-
mographics and varying sample sizes, are necessary to validate the
A. Rowaiye et al.
The Microbe 4 (2024) 100096
13
safety and efcacy of synbiotics in cancer therapy.
6. Conclusion
Prospects for personalized approaches that consider the unique fea-
tures of the tumor as well as the microbiome makeup of the patient exist
for synbiotic-based cancer therapy. With the potential to improve
therapeutic results and reduce side effects, these therapies may be used
in addition to conventional cancer treatments. Furthermore, synbiotics
may help avoid treatment-related side effects such antibiotic-induced
dysbiosis. The microbiota plays crucial roles in modulating many
physiological, biochemical, pathological, and pharmacological re-
sponses and metabolism. Therefore, there is potential to achieve syn-
ergistic therapeutic results and improve selective toxicity thereby
reducing side effects like antibiotic - induced dysbiosis when these
therapies are added to the conventional adjuvant and neoadjuvant
cancer management.
However, there are a few problems that still need to be xed.
Creating uniform synbiotic therapies is hampered by the variability of
individual microbiomes. A comprehensive understanding of the com-
plex interplay between the gut microbiota and cancer is essential for
identifying optimal synbiotic formulations for different types of cancer.
In addition, ethical deliberations and thorough clinical trials are
necessary to guarantee the security and efcacy of these treatments.
Future synbiotic integration into cancer treatment necessitates
continued investigation, teamwork, and a comprehensive comprehen-
sion of the complex interplay between the gut microbiota and cancer
biology.
Funding
No nancial support for this study.
CRediT authorship contribution statement
Doofan Bur: Writing – original draft, Investigation. Sandra Nnadi:
Writing – original draft, Investigation. Odinaka E. Mgbeke: Writing –
review & editing, Writing – original draft, Investigation. Ugonna Mor-
ikwe: Writing – original draft, Investigation. Adekunle Rowaiye:
Writing – review & editing, Writing – original draft, Visualization,
Project administration, Methodology, Conceptualization. Gordon
Chukwuma Ibeanu: Writing – review & editing, Writing – original
draft.
Declaration of Generative AI and AI-assisted technologies in the
writing process
The authors used generative AI for fact nding.
Declaration of Competing Interest
Authors declare no competing interests.
Data availability
No data was used for the research described in the article.
References
Afzaal, M., Saeed, F., Islam, F., Ateeq, H., Asghar, A., Shah, Y.A., Chacha, J.S., 2022.
Nutritional health perspective of natto: a critical review. Biochem. Res. Int. 2022.
Aggarwal, N., Kitano, S., Puah, G.R.Y., Kittelmann, S., Hwang, I.Y., Chang, M.W., 2022.
Microbiome and human health: current understanding, engineering, and enabling
technologies. Chem. Rev. 123 (1), 31–72.
Alam, Z., Shang, X., Effat, K., Kanwal, F., He, X., Li, Y., Zhang, Y., 2022. The potential
role of prebiotics, probiotics, and synbiotics in adjuvant cancer therapy especially
colorectal cancer. J. Food Biochem. 46 (10), e14302.
Amitay, E.L., Carr, P.R., Gies, A., Laetsch, D.C., Brenner, H., 2020. Probiotic/synbiotic
treatment and postoperative complications in colorectal cancer patients: systematic
review and meta-analysis of randomized controlled trials. Clin. Transl.
Gastroenterol. 11 (12).
Artemev, A., Naik, S., Pougno, A., Honnavar, P., Shanbhag, N.M., 2022. The association
of microbiome dysbiosis with colorectal cancer. Cureus 14 (2), e22156. https://doi.
org/10.7759/cureus.22156.
Bangolo, A.I., Trivedi, C., Jani, I., Pender, S., Khalid, H., Alqinai, B., Weissman, S., 2023.
Impact of gut microbiome in the development and treatment of pancreatic cancer:
newer insights. World J. Gastroenterol. 29 (25), 3984.
Barigela, A., Bhukya, B., 2021. Probiotic Pediococcus acidilactici strain from tomato pickle
displays anti-cancer activity and alleviates gut inammation in-vitro. 3 Biotech 11,
1–11.
Bartsch, B., Then, C.K., Harriss, E., Kartsonaki, C., & Kiltie, A.E. (2020). Systematic
review and meta-analysis of interventions with dietary supplements, including pre-,
pro-and synbiotics, to reduce acute and late gastrointestinal side effects in patients
undergoing pelvic radiotherapy. medRxiv, 2020-08.
Belanˇ
ci´
c, A., 2020. Gut microbiome dysbiosis and endotoxemia-Additional
pathophysiological explanation for increased COVID-19 severity in obesity. Obes.
Med. 20, 100302.
Biragyn, A., Ferrucci, L., 2018. Gut dysbiosis: a potential link between increased cancer
risk in ageing and inammaging. Lancet Oncol. 19 (6), e295–e304.
Fig. 2. Synbiotics (Prebiotics and Probiotics) and cancer therapies. Created with Biorender.com.
A. Rowaiye et al.
The Microbe 4 (2024) 100096
14
Blandford, L.E. (2018). Sequelae of Bacteroides fragilis infection and carriage (Doctoral
dissertation, King’s College London).
Bodke, H., Jogdand, S., Jogdand, S.D., 2022. Role of probiotics in human health. Cureus
14 (11).
Butt, J., Jenab, M., Werner, J., Fedirko, V., Weiderpass, E., Dahm, C.C., Hughes, D.J.,
2021. Association of pre-diagnostic antibody responses to Escherichia coli and
Bacteroides fragilis toxin proteins with colorectal cancer in a European cohort. Gut
Microbes 13 (1), 1903825.
Canton, M., S´
anchez-Rodríguez, R., Spera, I., Venegas, F.C., Favia, M., Viola, A.,
Castegna, A., 2021. Reactive oxygen species in macrophages: sources and targets.
Frontiers in immunology 12, 734229.
Capurso, L., 2019. Thirty years of Lactobacillus rhamnosus GG: a review. J. Clin.
Gastroenterol. 53, S1–S41.
Carocci, A., Catalano, A., Sinicropi, M.S., Genchi, G., 2018. Oxidative stress and
neurodegeneration: the involvement of iron. Biometals 31, 715–735.
de Cedr´
on, M.G., de Molina, A.R., 2020. Precision nutrition to target lipid metabolism
alterations in cancer. Precision Medicine for Investigators, Practitioners and
Providers. Academic Press, pp. 291–299.
Celebioglu, H.U., 2021. Effects of potential synbiotic interaction between Lactobacillus
rhamnosus GG and salicylic acid on human colon and prostate cancer cells. Arch.
Microbiol. 203 (3), 1221–1229.
Cha, J., Kim, Y.B., Park, S.E., Lee, S.H., Roh, S.W., Son, H.S., Whon, T.W., 2023. Does
kimchi deserve the status of a probiotic food? Crit. Rev. Food Sci. Nutr. 1–14.
Chan, C.W.H., Law, B.M.H., Waye, M.M.Y., Chan, J.Y.W., So, W.K.W., Chow, K.M., 2019.
Trimethylamine-N-oxide as one hypothetical link for the relationship between
intestinal microbiota and cancer-where we are and where shall we go? J. Cancer 10
(23), 5874.
Chen, L., Cao, Sq, Lin, Zm, et al., 2021a. NOD-like receptors in autoimmune diseases.
Acta Pharmacol. Sin. 42, 1742–1756. https://doi.org/10.1038/s41401-020-00603-
2.
Chen, L., Wang, D., Garmaeva, S., Kurilshikov, A., Vila, A.V., Gacesa, R., Fu, J., 2021b.
The long-term genetic stability and individual specicity of the human gut
microbiome. Cell 184 (9), 2302–2315.
Cheng, W.T., Kantilal, H.K., Davamani, F., 2020. The mechanism of Bacteroides fragilis
toxin contributes to colon cancer formation. Malays. J. Med. Sci.: MJMS 27 (4), 9.
Chou, H.Y., Liu, L.H., Chen, C.Y., Lin, I.F., Ali, D., Lee, A.Y.L., Wang, H.M.D., 2021.
Bifunctional mechanisms of autophagy and apoptosis regulations in melanoma from
Bacillus subtilis natto fermentation extract. Food Chem. Toxicol. 150, 112020.
Connolly, E.L., Sim, M., Travica, N., Marx, W., Beasy, G., Lynch, G.S., Bondonno, C.P.,
Lewis, J.R., Hodgson, J.M., Blekkenhorst, L.C., 2021. Glucosinolates from
cruciferous vegetables and their potential role in chronic disease: investigating the
preclinical and clinical evidence. Front. Pharmacol. 12. 〈https://www.frontiersin.
org/articles/10.3389/fphar.2021.767975〉.
Crowder, S.L., Jim, H.S.L., Hogue, S., Carson, T.L., Byrd, D.A., 2023. Gut microbiome and
cancer implications: potential opportunities for fermented foods. Biochim. Et.
Biophys. Acta (BBA) - Rev. Cancer 1878 (3), 188897. https://doi.org/10.1016/j.
bbcan.2023.188897.
Da Ros, A., Polo, A., Rizzello, C.G., Acin-Albiac, M., Montemurro, M., Di Cagno, R.,
Gobbetti, M., 2021. Feeding with sustainably sourdough bread has the potential to
promote the healthy microbiota metabolism at the colon level. Microbiol. Spectr. 9
(3), e00494–21.
DeGruttola, A.K., Low, D., Mizoguchi, A., Mizoguchi, E., 2016. Current understanding of
dysbiosis in disease in human and animal models. Inamm. bowel Dis. 22 (5),
1137–1150.
van den Broek, L.A., Hinz, S.W., Beldman, G., Vincken, J.P., Voragen, A.G., 2008.
Bidobacterium carbohydrases-their role in breakdown and synthesis of (potential)
prebiotics. Mol. Nutr. Food Res. 52 (1), 146–163.
Derosa, L., Routy, B., Thomas, A.M., Iebba, V., Zalcman, G., Friard, S., Besse, B., 2022.
Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in
patients with advanced non-small-cell lung cancer. Nat. Med. 28 (2), 315–324.
Divate, N.R., Ardanareswari, K., Yu, Y.P., Chen, Y.C., Liao, J.W., Chung, Y.C., 2023.
Effects of soybean and tempeh water extracts on regulation of intestinal ora and
prevention of colon precancerous lesions in rats. Processes 11 (1), 257.
Dziuba´
nska-Kusibab, P.J., Berger, H., Battistini, F., Bouwman, B.A., Iftekhar, A.,
Katainen, R., Meyer, T.F., 2020. Colibactin DNA-damage signature indicates
mutational impact in colorectal cancer. Nat. Med. 26 (7), 1063–1069.
Ejike, U.D.I., Liman, M.L., 2022. Role of Dietary antioxidants in chemoprevention of
nitrosamines-induced carcinogenesis. Handbook of Oxidative Stress in Cancer:
Therapeutic Aspects. Springer Singapore, Singapore, pp. 1–23.
Fahrer, J., Christmann, M., 2023. DNA alkylation damage by nitrosamines and relevant
DNA repair pathways. Int. J. Mol. Sci. 24 (5), 4684.
Fan, S., Jiang, Z., Zhang, Z., Xing, J., Wang, D., Tang, D., 2023. Akkermansia muciniphila:
a potential booster to improve the effectiveness of cancer immunotherapy. J. Cancer
Res. Clin. Oncol. 149 (14), 13477–13494.
Fatahi, A., Soleimani, N., Afrough, P., 2021. Anticancer activity of ker on glioblastoma
cancer cell as a new treatment. Int. J. Food Sci. 2021.
Fekri, A., Torbati, M., Khosrowshahi, A.Y., Shamloo, H.B., Azadmard-Damirchi, S., 2020.
Functional effects of phytate-degrading, probiotic lactic acid bacteria and yeast
strains isolated from Iranian traditional sourdough on the technological and
nutritional properties of whole wheat bread. Food Chem. 306, 125620.
Feola, S., Capasso, C., Fusciello, M., Martins, B., T¨
ahtinen, S., Medeot, M., Cerullo, V.,
2018. Oncolytic vaccines increase the response to PD-L1 blockade in immunogenic
and poorly immunogenic tumors. Oncoimmunology 7 (8), e1457596.
Flesch, A.T., Tonial, S.T., Contu, P.C., Damin, D.C., 2017. Perioperative synbiotics
administration decreases postoperative infections in patients with colorectal cancer:
a randomized, double-blind clinical trial. Rev. Col. Bras. Cir. 44, 567–573.
Fukaya, M., Yokoyama, Y., Usui, H., Fujieda, H., Sakatoku, Y., Takahashi, T., Ebata, T.,
2021. Impact of synbiotics treatment on bacteremia induced during neoadjuvant
chemotherapy for esophageal cancer: a randomised controlled trial. Clin. Nutr. 40
(12), 5781–5791.
Gatarek, P., Kaluzna-Czaplinska, J., 2021. Trimethylamine N-oxide (TMAO) in human
health. EXCLI J. 20, 301.
Gaudioso, G., Weil, T., Marzorati, G., Solovyev, P., Bontempo, L., Franciosi, E., Fava, F.,
2022. Microbial and metabolic characterization of organic artisanal sauerkraut
fermentation and study of gut health-promoting properties of sauerkraut brine.
Front. Microbiol. 13, 929738.
Gomez Quintero, D.F., Kok, C.R., Hutkins, R., 2022. The future of synbiotics: rational
formulation and design. Front. Microbiol. 13, 919725.
Graça, C., Lima, A., Raymundo, A., Sousa, I., 2021. Sourdough fermentation as a tool to
improve the nutritional and health-promoting properties of its derived-products.
Fermentation 7 (4). https://doi.org/10.3390/fermentation7040246.
Grenda, A., Krawczyk, P., 2021. Cancer trigger or remedy: two faces of the human
microbiome. Appl. Microbiol. Biotechnol. 105, 1395–1405.
Guo, Y.J., Pan, W.W., Liu, S.B., Shen, Z.F., Xu, Y., Hu, L.L., 2020. ERK/MAPK signalling
pathway and tumorigenesis. Exp. Ther. Med. 19 (3), 1997–2007.
Guo, P., Tian, Z., Kong, X., Yang, L., Shan, X., Dong, B., Yu, Y., 2020. FadA promotes DNA
damage and progression of Fusobacterium nucleatum-induced colorectal cancer
through up-regulation of chk2. J. Exp. Clin. Cancer Res. 39, 1–13.
Hadi, A., Arab, A., Khalesi, S., Rae, N., Kafeshani, M., Kazemi, M., 2021. Effects of
probiotic supplementation on anthropometric and metabolic characteristics in adults
with metabolic syndrome: a systematic review and meta-analysis of randomized
clinical trials. Clin. Nutr. 40 (7), 4662–4673.
Hadi, A., Ghaedi, E., Khalesi, S., Pourmasoumi, M., Arab, A., 2020a. Effects of synbiotic
consumption on lipid prole: A systematic review and meta-analysis of randomized
controlled clinical trials. Eur. J. Nutr. 59, 2857–2874.
Hadi, A., Moradi, S., Ghavami, A., Khalesi, S., Kafeshani, M., 2020b. Effect of probiotics
and synbiotics on selected anthropometric and biochemical measures in women with
polycystic ovary syndrome: a systematic review and meta-analysis. Eur. J. Clin. Nutr.
74 (4), 543–547.
Hadi, A., Pourmasoumi, M., Kazemi, M., Najafgholizadeh, A., Marx, W., 2022. Efcacy of
synbiotic interventions on blood pressure: a systematic review and meta-analysis of
clinical trials. Crit. Rev. Food Sci. Nutr. 62 (20), 5582–5591.
Hagi, T., Belzer, C., 2021. The interaction of Akkermansia muciniphila with host-derived
substances, bacteria and diets. Appl. Microbiol. Biotechnol. 105 (12), 4833–4841.
Handajani, Y.S., Turana, Y., Yogiara, Y., Sugiyono, S.P., Lamadong, V., Widjaja, N.T.,
Suwanto, A., 2022. Effects of tempeh probiotics on elderly with cognitive
impairment. Front. Aging Neurosci. 14, 891773.
He, Z., Gharaibeh, R.Z., Newsome, R.C., Pope, J.L., Dougherty, M.W., Tomkovich, S., …
& Jobin, C. (2018). Campylobacter jejuni promotes colorectal tumorigenesis through
the action of Cytolethal distending toxin. Gut, gutjnl-2018.
Helmink, B.A., Khan, M.W., Hermann, A., Gopalakrishnan, V., Wargo, J.A., 2019. The
microbiome, cancer, and cancer therapy. Nat. Med. 25 (3), 377–388.
Hirayama, T., 1982. Relationship of soybean paste soup intake to gastric cancer risk.
Nutr. Cancer 3, 223–233.
Hitch, T.C., Hall, L.J., Walsh, S.K., Leventhal, G.E., Slack, E., de Wouters, T., Clavel, T.,
2022. Microbiome-based interventions to modulate gut ecology and the immune
system. Mucosal Immunol. 15 (6), 1095–1113.
Hou, K., Wu, Z.X., Chen, X.Y., et al., 2022. Microbiota in health and diseases. Signal
Transduct. Target Ther. 7, 135. https://doi.org/10.1038/s41392-022-00974-4.
Hrncir, T., 2022. Gut microbiota dysbiosis: triggers, consequences, diagnostic and
therapeutic options. Microorganisms 10 (3), 578.
Hsiao, Y.-C., Liu, C.-W., Yang, Y., Feng, J., Zhao, H., Lu, K., 2023. DNA damage and the
gut microbiome: from mechanisms to disease outcomes. DNA 3 (1), 13–32. https://
doi.org/10.3390/dna3010002.
Inoue, Y., Fukui, H., Xu, X., Ran, Y., Tomita, T., Oshima, T., Miwa, H., 2019. Colonic M1
macrophage is associated with the prolongation of gastrointestinal motility and
obesity in mice treated with vancomycin. Mol. Med. Rep.
Jalandra, R., Dalal, N., Yadav, A.K., Verma, D., Sharma, M., Singh, R., Solanki, P.R.,
2021. Emerging role of trimethylamine-N-oxide (TMAO) in colorectal cancer. Appl.
Microbiol. Biotechnol. 1–10.
Jameson, E., Quareshy, M., Chen, Y., 2018. Methodological considerations for the
identication of choline and carnitine-degrading bacteria in the gut. Methods 149,
42–48.
Jeong, C.H., Cheng, W.N., Kwon, H.C., Kim, D.H., Seo, K.H., Choi, Y., Han, S.G., 2021.
Effects of ker on doxorubicin-induced multidrug resistance in human colorectal
cancer cells. J. Funct. Foods 78, 104371.
Jing, N., Wang, L., Zhuang, H., Jiang, G., Liu, Z., 2023. Enhancing therapeutic effects of
murine cancer vaccine by reshaping gut microbiota with Lactobacillus rhamnosus
GG and jujube powder. Front. Immunol. 14.
Jones, T.A., Hernandez, D.Z., Wong, Z.C., Wandler, A.M., Guillemin, K., 2017. The
bacterial virulence factor CagA induces microbial dysbiosis that contributes to
excessive epithelial cell proliferation in the Drosophila gut. PLOS Pathog. 13 (10),
e1006631.
Kalasabail, Sanjna, Engelman, Jared, Zhang, Linda Yun, El-Omar, Emad, Yim, Howard
Chi Ho, 2021. A perspective on the role of microbiome for colorectal cancer
treatment. Cancers 13 (18), 4623.
Ka´
zmierczak-Siedlecka, K., Daca, A., Fic, M., van de Wetering, T., Folwarski, M.,
Makarewicz, W., 2020. Therapeutic methods of gut microbiota modication in
colorectal cancer management–fecal microbiota transplantation, prebiotics,
probiotics, and synbiotics. Gut Microbes 11 (6), 1518–1530.
A. Rowaiye et al.
The Microbe 4 (2024) 100096
15
Kim, H.J., Noh, J.S., Song, Y.O., 2018. Benecial effects of kimchi, a korean fermented
vegetable food, on pathophysiological factors related to atherosclerosis. J. Med.
Food 21 (2), 127–135.
Kim, B., Song, J.L., Ju, J.H., Kang, S.A., Park, K.Y., 2015. Anticancer effects of kimchi
fermented for different times and with added ingredients in human HT-29 colon
cancer cells. Food Sci. Biotechnol. 24, 629–633.
Kotake, K., Kumazawa, T., Nakamura, K., Shimizu, Y., Ayabe, T., Adachi, T., 2022.
Ingestion of miso regulates immunological robustness in mice. PLOS One 17 (1),
e0261680.
Krebs, B., 2016. Prebiotic and synbiotic treatment before colorectal surgery-randomised
double blind trial. Coll. Antropol. 40, 35–40.
Kurata, K., Ishii, K., Koto, Y., Naito, K., Yuasa, K., Shimizu, H., 2023. Skatole-induced p38
and JNK activation coordinately upregulates, whereas AhR activation partially
attenuates TNF
α
expression in intestinal epithelial cells. Biosci., Biotechnol.,
Biochem. 87 (6), 611–619.
Kurata, K., Kawahara, H., Nishimura, K., Jisaka, M., Yokota, K., Shimizu, H., 2019.
Skatole regulates intestinal epithelial cellular functions through activating aryl
hydrocarbon receptors and p38. Biochem. Biophys. Res. Commun. 510 (4), 649–655.
Kusumoto, K.I., Yamagata, Y., Tazawa, R., Kitagawa, M., Kato, T., Isobe, K.,
Kashiwagi, Y., 2021. Japanese traditional Miso and Koji making. J. Fungi 7 (7), 579.
Lai, Y.R., Chang, Y.F., Ma, J., Chiu, C.H., Kuo, M.L., Lai, C.H., 2021. From DNA damage
to cancer progression: potential effects of cytolethal distending toxin. Front.
Immunol. 12, 760451.
Lee, M.H., 2021. Harness the functions of gut microbiome in tumorigenesis for cancer
treatment. Cancer Commun. 41 (10), 937–967.
Lee, Y.J., Pan, Y., Kwack, K.B., Chung, J.H., Park, K.Y., 2023. Increased anticancer
activity of organic kimchi with starters demonstrated in HT-29 cancer cells. Appl.
Sci. 13 (11), 6654.
Leeuwendaal, N.K., Stanton, C., O’Toole, P.W., Beresford, T.P., 2022. Fermented foods,
health and the gut microbiome. Nutrients 14 (7), 1527. https://doi.org/10.3390/
nu14071527.
Lerner, A., Shoenfeld, Y., Matthias, T., 2019. Probiotics: if it does not help it does not do
any harm. Really? Microorganisms 7 (4), 104.
Li, Y., Hecht, S.S., 2022. Metabolic activation and DNA interactions of carcinogenic N-
nitrosamines to which humans are commonly exposed. Int. J. Mol. Sci. 23 (9), 4559.
Liang, Z., Song, X., Hu, J., Wu, R., Li, P., Dong, Z., Liang, L., Wang, J., 2022. Fermented
dairy food intake and risk of colorectal cancer: a systematic review and meta-
analysis. Front. Oncol. 12, 812679 https://doi.org/10.3389/fonc.2022.812679.
Lin, R., Zhan, M., Yang, L., Wang, H., Shen, H., Huang, S., Wang, J., 2020. Deoxycholic
acid modulates the progression of gallbladder cancer through N6-methyladenosine-
dependent microRNA maturation. Oncogene 39 (26), 4983–5000.
Liu, J., Liu, C., Yue, J., 2021. Radiotherapy and the gut microbiome: facts and ction.
Radiat. Oncol. 16, 1–15.
Liu, X., Liu, H., Yuan, C., Zhang, Y., Wang, W., Hu, S., Liu, L., Wang, Y., 2017.
Preoperative serum TMAO level is a new prognostic marker for colorectal cancer.
Biomark. Med. 11, 443–447.
Longhi, G., Van Sinderen, D., Ventura, M., Turroni, F., 2020. Microbiota and cancer: the
emerging benecial role of bidobacteria in cancer immunotherapy. Front.
Microbiol. 11, 575072.
Lop`
es, A., Billard, E., Casse, A.H., Vill´
eger, R., Veziant, J., Roche, G., Bonnet, M., 2020.
Colibactin-positive Escherichia coli induce a procarcinogenic immune environment
leading to immunotherapy resistance in colorectal cancer. Int. J. Cancer 146 (11),
3147–3159.
Lucas, L.N., Barrett, K., Kerby, R.L., Zhang, Q., Cattaneo, L.E., Stevenson, D., Amador-
Noguez, D., 2021. Dominant bacterial phyla from the human gut show widespread
ability to transform and conjugate bile acids. MSystems 6 (4), 10–1128.
Lynch, J.B., Hsiao, E.Y., 2019. Microbiomes as sources of emergent host phenotypes.
Science 365 (6460), 1405–1409.
Mahdavi, R., Faramarzi, E., Nikniaz, Z., FarshiRadvar, F., 2023. Role of probiotics and
synbiotics in preventing chemoradiotherapy-associated toxicity in colorectal cancer
patients: a systematic review. Iran. J. Med. Sci. 48 (2), 110.
Ma’mon, M.H., Nuirat, A., Zihlif, M.A., Taha, M.O., 2018. Exploring the inuence of
culture conditions on ker’s anticancer properties. J. Dairy Sci. 101 (5), 3771–3777.
Manifar, S., Koopaie, M., Jahromi, Z.M., Kolahdooz, S., 2023. Effect of synbiotic
mouthwash on oral mucositis induced by radiotherapy in oral cancer patients: a
double-blind randomized clinical trial. Support. Care Cancer 31 (1), 31.
Markowiak, P., ´
Sli˙
zewska, K., 2018. The role of probiotics, prebiotics and synbiotics in
animal nutrition. Gut Pathog. 10 (1), 1–20.
Martin, O.C., Frisan, T., 2020. Bacterial genotoxin-induced DNA damage and modulation
of the host immune microenvironment. Toxins 12 (2), 63.
Matson, V., Chervin, C.S., Gajewski, T.F., 2021. Cancer and the microbiome—inuence
of the commensal microbiota on cancer, immune responses, and immunotherapy.
Gastroenterology 160 (2), 600–613.
de Melo, F.F., Marques, H.S., Pinheiro, S.L.R., Lemos, F.F.B., Luz, M.S., Teixeira, K.N.,
Oliveira, M.V., 2022. Inuence of Helicobacter pylori oncoprotein CagA in gastric
cancer: a critical-reective analysis. World J. Clin. Oncol. 13 (11), 866.
Merriel, S.W.D., Ingle, S.M., May, M.T., Martin, R.M., 2021. Retrospective cohort study
evaluating clinical, biochemical and pharmacological prognostic factors for prostate
cancer progression using primary care data. BMJ Open 11 (2), e044420.
Mohammad, S., Thiemermann, C., 2021. Role of metabolic endotoxemia in systemic
inammation and potential interventions. Front. Immunol. 11, 594150.
Moparthi, L., Koch, S., 2019. Wnt signaling in intestinal inammation. Differentiation
108, 24–32. https://doi.org/10.1016/j.diff.2019.01.002.
Motoori, M., Yano, M., Miyata, H., Sugimura, K., Saito, T., Omori, T., Sakon, M., 2017.
Randomized study of the effect of synbiotics during neoadjuvant chemotherapy on
adverse events in esophageal cancer patients. Clin. Nutr. 36 (1), 93–99.
Muzdalifah, D., Athaillah, Z.A., Devi, A.F., Udin, L.Z., 2018. Cytotoxicity of ethanol
overripe tempe extract against MCF-7 breast cancer cell and its antioxidant activity.
AIP Conf. Proc. 2024 (1).
Nascimento, M., Caporossi, C., Eduardo Aguilar-Nascimento, J., Michelon Castro-
Barcellos, H., Teixeira Motta, R., Reis Lima, S., 2020. Efcacy of synbiotics to reduce
symptoms and rectal inammatory response in acute radiation proctitis: a
randomized, double-blind, placebo-controlled pilot trial. Nutr. Cancer 72 (4),
602–609.
Nguyen, T.T., Ung, T.T., Kim, N.H., Do Jung, Y., 2018. Role of bile acids in colon
carcinogenesis. World J. Clin. Cases 6 (13), 577.
Nurkolis, F., Qhabibi, F.R., Yusuf, V.M., Bulain, S., Praditya, G.N., Lailossa, D.G.,
Permatasari, H.K., 2022. Anticancer properties of soy-based tempe: a proposed
opinion for future meal. Front. Oncol. 12, 1054399.
Oba, S., Sunagawa, T., Tanihiro, R., Awashima, K., Sugiyama, H., Odani, T., Sasaki, K.,
2020. Prebiotic effects of yeast mannan, which selectively promotes bacteroides
thetaiotaomicron and bacteroides ovatus in a human colonic microbiota model. Sci.
Rep. 10 (1), 17351.
Ohara, M., Lu, H., Shiraki, K., Ishimura, Y., Uesaka, T., et al., 2002. Prevention by long-
term fermented miso of induction of colonic aberrant crypt foci by azoxymethane in
F344 rats. Oncol. Rep. 9, 69–73.
Okada, Y., Tsuzuki, Y., Sugihara, N., Nishii, S., Shibuya, N., Mizoguchi, A., Hokari, R.,
2021. Novel probiotic yeast from Miso promotes regulatory dendritic cell IL-10
production and attenuates DSS-induced colitis in mice. J. Gastroenterol. 56 (9),
829–842.
Park, J.Y., Forman, D., Waskito, L.A., Yamaoka, Y., Crabtree, J.E., 2018. Epidemiology of
Helicobacter pylori and CagA-positive infections and global variations in gastric
cancer. Toxins 10 (4), 163.
Park, W.Y., Park, K.Y., 1999. Anticancer effects of organic Chinese cabbage kimchi. Prev.
Nutr. Food Sci. 4 (2), 113–116.
Pathak, D.R., Stein, A.D., He, J.P., Noel, M.M., Hembroff, L., Nelson, D.A., Willett, W.C.,
2021. Cabbage and sauerkraut consumption in adolescence and adulthood and
breast cancer risk among US-resident polish migrant women. Int. J. Environ. Res.
Public Health 18 (20), 10795.
Polakowski, C.B., Kato, M., Preti, V.B., Schieferdecker, M.E.M., Ligocki Campos, A.C.,
2019. Impact of the preoperative use of synbiotics in colorectal cancer patients: a
prospective, randomized, double-blind, placebo-controlled study. Nutrition 58,
40–46.
Pourjafar, H., Pimentel, T.C., Baú, T.R., 2023. Probiotic fermented vegetables. Probiotic
Foods and Beverages: Technologies and Protocols. Springer US, New York, NY,
pp. 119–132.
Purton, T., Staskova, L., Lane, M.M., Dawson, S.L., West, M., Firth, J., Marx, W., 2021.
Prebiotic and probiotic supplementation and the tryptophan-kynurenine pathway: a
systematic review and meta analysis. Neurosci. Biobehav. Rev. 123, 1–13.
Ragul, K., Kandasamy, S., Devi, P.B., Shetty, P.H., 2020. Evaluation of functional
properties of potential probiotic isolates from fermented brine pickle. Food Chem.
311, 126057.
Raman, M., Ambalam, P., Doble, M., 2019. Probiotics, prebiotics, and bers in nutritive
and functional beverages. Nutrients in Beverages. Academic Press, pp. 315–367.
Ramu, K., Rajagopal, A., Varyani, R., Kini, P., Kumar, P., Sabat, S., 2022. Inuence of
proteus sp. on trimethylamine n-oxide production via the choline metabolism
pathway and the formulation of a predictive model to assess the risk of coronary
artery disease in Indian patients. Iran. J. Med. Microbiol. 16 (3), 233–243.
Rezatabar, S., Karimian, A., Rameshknia, V., Parsian, H., Majidinia, M., Kopi, T.A.,
Youse, B., 2019. RAS/MAPK signaling functions in oxidative stress, DNA damage
response and cancer progression. J. Cell. Physiol. 234 (9), 14951–14965.
Ridlon, J.M., Devendran, S., Alves, J.M., Doden, H., Wolf, P.G., Pereira, G.V., Gaskins, H.
R., 2020. The ‘in vivo lifestyle’of bile acid 7
α
-dehydroxylating bacteria: comparative
genomics, metatranscriptomic, and bile acid metabolomics analysis of a dened
microbial community in gnotobiotic mice. Gut Microbes 11 (3), 381–404.
Rogan, M.R., Patterson, L.L., Wang, J.Y., McBride, J.W., 2019. Bacterial manipulation of
Wnt signaling: a host-pathogen tug-of-wnt. Front. Immunol. 10, 2390. https://doi.
org/10.3389/mmu.2019.02390its.
Roy, R., Singh, S.K., Misra, S., 2022. Advancements in cancer immunotherapies. Vaccines
11 (1), 59.
Rubinstein, M.R., Baik, J.E., Lagana, S.M., Han, R.P., Raab, W.J., Sahoo, D., Han, Y.W.,
2019. Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/
β-catenin modulator Annexin A1. EMBO Rep. 20 (4), e47638.
Saeed, F., Afzaal, M., Shah, Y.A., Khan, M.H., Hussain, M., Ikram, A., Ateeq, H.,
Noman, M., Saewan, S.A., Khashroum, A.O., 2022. Miso: a traditional nutritious &
health-endorsing fermented product. Food Sci. Nutr. 10 (12), 4103–4111. https://
doi.org/10.1002/fsn3.3029.
Salemi, R., Vivarelli, S., Ricci, D., Scillato, M., Santagati, M., Gattuso, G., Libra, M., 2023.
Lactobacillus rhamnosus GG cell-free supernatant as a novel anti-cancer adjuvant.
J. Transl. Med. 21 (1), 1–17.
Sameer, A.S., Nissar, S., 2021. Toll-Like Receptors (TLRs): structure, functions, signaling,
and role of their polymorphisms in colorectal cancer susceptibility. Biomed. Res. Int.
2021, 1157023 https://doi.org/10.1155/2021/1157023. PMID: 34552981; PMCID:
PMC8452412.
Sasso, J.M., Ammar, R.M., Tenchov, R., Lemmel, S., Kelber, O., Grieswelle, M., Zhou, Q.
A., 2023. Gut microbiome–brain alliance: a landscape view into mental and
gastrointestinal health and disorders. ACS Chem. Neurosci.
Scott, A.J., Merrield, C.A., Younes, J.A., Pekelharing, E.P., 2018. Pre-, pro-and
synbiotics in cancer prevention and treatment—a review of basic and clinical
research. Ecancermedicalscience 12.
A. Rowaiye et al.
The Microbe 4 (2024) 100096
16
Sharma, P., Bhandari, C., Kumar, S., Sharma, B., Bhadwal, P., Agnihotri, N., 2018.
Dietary bers: a way to a healthy microbiome. Diet, Microbiome and Health.
Academic Press, pp. 299–345.
Sharma, V.R., Singh, M., Kumar, V., Yadav, M., Sehrawat, N., Sharma, D.K., Sharma, A.
K., 2021. Microbiome dYsbiosis in Cancer: Exploring Therapeutic Strategies to
Counter the Disease. In: Seminars in Cancer biology, Vol. 70. Academic Press,
pp. 61–70 (May).
Shashank, V., Kiruthika, S.A., Harish, K.R., Pandey, P., 2023. Dietary Synbiotic as a
supplemental therapy to reduce cancer symptoms: a review. Bull. Environ.
Pharmacol. Life Sci. 12, 267–273.
Shein, A.M., Whitney, A.K., Weir, T.L., 2014. Cancer-promoting effects of microbial
dysbiosis. Curr. Oncol. Rep. 16, 1–9.
Shi, C.W., Cheng, M.Y., Yang, X., Lu, Y.Y., Yin, H.D., Zeng, Y., Wang, C.F., 2020.
Probiotic Lactobacillus rhamnosus GG promotes mouse gut microbiota diversity and
T cell differentiation. Front. Microbiol. 11, 607735.
Shui, L., Yang, X., Li, J., Yi, C., Sun, Q., Zhu, H., 2020. Gut microbiome as a potential
factor for modulating resistance to cancer immunotherapy. Front. Immunol. 10,
2989.
Siegel, R.L., Giaquinto, A.N., Jemal, A., 2022. Cancer statisticsa. Cancer J. Clin. 2024.
Silva-Cutini, M.A., Almeida, S.A., Nascimento, A.M., Abreu, G.R., Bissoli, N.S., Lenz, D.,
Andrade, T.U., 2019. Long-term treatment with ker probiotics ameliorates cardiac
function in spontaneously hypertensive rats. J. Nutr. Biochem. 66, 79–85.
Singh, N.K., Beckett, J.M., Kalpurath, K., Ishaq, M., Ahmad, T., Eri, R.D., 2023.
Synbiotics as supplemental therapy for the alleviation of chemotherapy-associated
symptoms in patients with solid tumours. Nutrients 15 (7), 1759.
Song, G.H., Park, E.S., Lee, S.M., Park, D.B., Park, K.Y., 2018. Benecial outcomes of
kimchi prepared with Amtak Baechu cabbage and salting in brine solution:
Anticancer effects in pancreatic and hepatic cancer cells. J. Environ. Pathol., Toxicol.
Oncol. 37 (2).
Sorour, M.A., Mehanni, A.H.E., Mahmoud, E.S.A., El-Hawashy, R.M., 2023. Nitrate,
nitrite and N-nitrosamine in meat products. J. Sohag Agric. (JSAS) 8 (1), 121–135.
Sotoudegan, F., Daniali, M., Hassani, S., Nikfar, S., Abdollahi, M., 2019. Reappraisal of
probiotics’ safety in human. Food Chem. Toxicol. 129, 22–29.
Staehlke, S., Haack, F., Waldner, A.C., Koczan, D., Moerke, C., Mueller, P., Nebe, J.B.,
2020. ROS dependent wnt/β-catenin pathway and its regulation on dened micro-
pillars—a combined in vitro and in silico study. Cells 9 (8), 1784.
Strakova, N., Korena, K., Karpiskova, R., 2021. Klebsiella pneumoniae producing
bacterial toxin colibactin as a risk of colorectal cancer development-a systematic
review. Toxicon 197, 126–135.
Sun, C.H., Li, B.B., Wang, B., Zhao, J., Zhang, X.Y., Li, T.T., Qian, Z.R., 2019. The role of
Fusobacterium nucleatum in colorectal cancer: from carcinogenesis to clinical
management. Chronic Dis. Transl. Med. 5 (03), 178–187.
Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F.,
2021. Global cancer statistics 2020: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries. CA: a Cancer J. Clin. 71 (3),
209–249.
Surya, R., Surya, E., Nugroho, D., Romulo, A., Kamal, N., Rahayu, W.P.,
Benchawattananon, R., Oh, J.-S., 2023. Chemopreventive potential of kimchi, an
ethnic food from Korea, against colorectal carcinogenesis associated with red meat
intake. J. Ethn. Foods 10 (1), 10. https://doi.org/10.1186/s42779-023-00176-5.
Tan, X., Cui, F., Wang, D., Lv, X., Li, X., Li, J., 2023. Fermented vegetables: health
benets, defects, and current technological solutions. Foods 13 (1), 38. https://doi.
org/10.3390/foods13010038.
Tang, G., Huang, W., Tao, J., Wei, Z., 2022. Prophylactic effects of probiotics or
synbiotics on postoperative ileus after gastrointestinal cancer surgery: a meta-
analysis of randomized controlled trials. PLOS One 17 (3), e0264759.
Tang, G., Zhang, L., Huang, W., Wei, Z., 2022. Probiotics or synbiotics for preventing
postoperative infection in hepatopancreatobiliary cancer patients: a meta-analysis of
randomized controlled trials. Nutr. Cancer 74 (10), 3468–3478.
Tariq, H., Noreen, Z., Ahmad, A., Khan, L., Ali, M., Malik, M., Bokhari, H., 2022.
Colibactin possessing E. coli isolates in association with colorectal cancer and their
genetic diversity among Pakistani population. PLOs One 17 (11), e0262662.
Tasdemir, S.S., Sanlier, N., 2020. An insight into the anticancer effects of fermented
foods: a review. J. Funct. Foods 75, 104281.
Theodoropoulos, G.E., Memos, N.A., Peitsidou, K., Karantanos, T., Spyropoulos, B.G.,
Zografos, G., 2016. Synbiotics and gastrointestinal function-related quality of life
after elective colorectal cancer resection. Ann. Gastroenterol. 29 (1), 56–62.
Trone, K., Rahman, S., Green, C.H., Venegas, C., Martindale, R., Stroud, A., 2023.
Synbiotics and surgery: can prebiotics and probiotics affect inammatory surgical
outcomes? Curr. Nutr. Rep. 12 (2), 238–246.
Usyk, M., Pandey, A., Hayes, R.B., Moran, U., Pavlick, A., Osman, I., Ahn, J., 2021.
Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in
immune checkpoint blockade treatment of metastatic melanoma. Genome Med. 13,
1–11.
Valguarnera, E., Wardenburg, J.B., 2020. Good gone bad: one toxin away from disease
for Bacteroides fragilis. J. Mol. Biol. 432 (4), 765–785.
Vernocchi, P., Del Chierico, F., Putignani, L., 2020. Gut microbiota metabolism and
interaction with food components. Int. J. Mol. Sci. 21 (10), 3688.
Violi, F., Pignatelli, P., Castellani, V., Carnevale, R., Cammisotto, V., 2023. Gut dysbiosis,
endotoxemia and clotting activation: a dangerous trio for portal vein thrombosis in
cirrhosis. Blood Rev. 57, 100998.
Vivarelli, S., Salemi, R., Candido, S., Falzone, L., Santagati, M., Stefani, S., Libra, M.,
2019. Gut microbiota and cancer: from pathogenesis to therapy. Cancers 11 (1), 38.
Wang, J., Chen, W.D., Wang, Y.D., 2020. The relationship between gut microbiota and
inammatory diseases: the role of macrophages. Front. Microbiol. 11, 1065. https://
doi.org/10.3389/fmicb.2020.01065.
Wang, L.S., Mo, Y.Y., Huang, Y.W., Echeveste, C.E., Wang, H.T., Chen, J., Bai, W., 2020.
Effects of dietary interventions on gut microbiota in humans and the possible
impacts of foods on patients’ responses to cancer immunotherapy. efood 1 (4),
279–287.
Wang, C., Zhao, J., Zhang, H., Lee, Y.K., Zhai, Q., Chen, W., 2021. Roles of intestinal
bacteroides in human health and diseases. Crit. Rev. Food Sci. Nutr. 61 (21),
3518–3536.
Weng, M.S., Chang, J.H., Hung, W.Y., Yang, Y.C., Chien, M.H., 2018. The interplay of
reactive oxygen species and the epidermal growth factor receptor in tumor
progression and drug resistance. J. Exp. Clin. Cancer Res. 37 (1), 1–11.
Yamamoto, S., Sobue, T., Kobayashi, M., Sasaki, S., Tsugane, S., 2003. Soy, isoavones,
and breast cancer risk in Japan. J. Natl. Cancer Inst. 95 (12), 906–913.
Yang, R., Qian, L., 2022. Research on gut microbiota-derived secondary bile acids in
cancer progression. Integr. Cancer Ther. 21, 15347354221114100.
Zafar, H., Saier Jr, M.H., 2021. Gut Bacteroides species in health and disease. Gut
Microbes 13 (1), 1848158.
Zgarbov´
a, E., Vrzal, R., 2023. Skatole: a thin red line between its benets and toxicity.
Biochimie 208, 1–12.
Zhang, B., Chai, J., He, L., Dusanbieke, M., Gong, A., 2019. Nattokinase produced by
natto fermentation with Bacillus subtilis inhibits breast cancer growth. Int. J. Clin.
Exp. Med. 12 (12), 13380–13387.
Zhang, K., Dai, H., Liang, W., Zhang, L., Deng, Z., 2019. Fermented dairy foods intake
and risk of cancer. Int. J. Cancer 144 (9), 2099–2108. https://doi.org/10.1002/
ijc.31959.
Zhang, X., Li, C., Chen, D., He, X., Zhao, Y., Bao, L., Xie, Y., 2022. H. pylori CagA
activates the NLRP3 inammasome to promote gastric cancer cell migration and
invasion. Inamm. Res. 1–15.
Zhang, B., Zhang, X., Jin, M., Hu, L., Zang, M., Qiu, W., Guo, D., 2019. CagA increases
DNA methylation and decreases PTEN expression in human gastric cancer. Mol.
Med. Rep. 19 (1), 309–319.
Zhao, L.Y., Mei, J.X., Yu, G., et al., 2023. Role of the gut microbiota in anticancer
therapy: from molecular mechanisms to clinical applications. Signal Transduct.
Target Ther. 8, 201.
Zhao, X., Zhao, J., Li, D., Yang, H., Chen, C., Qin, M., Xu, L., 2023. Akkermansia
muciniphila: A potential target and pending issues for oncotherapy. Pharmacol. Res.,
106916
Zheng, D., Liwinski, T., Elinav, E., 2020. Interaction between microbiota and immunity
in health and disease. Cell Res. 30 (6), 492–506.
Zou, S., Fang, L., Lee, M.H., 2018. Dysbiosis of gut microbiota in promoting the
development of colorectal cancer. Gastroenterol. Rep. 6 (1), 1–12.
A. Rowaiye et al.
