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FEMS Microbiology Reviews , 2023, 47 , 1–15
DOI: 10.1093/femsre/fuad036
Ad v ance access publication date: 5 July 2023
Re vie w Article
Crosstalk between gut microbiota and RNA
N6-methyladenosine modication in cancer
Hao Su
1 ,2
, Henley Cheung
1
, Harry Cheuk-Hay Lau
1
, Hongyan Chen
1 ,2
, Xiaoting Zhang
1 ,2
, Na Qin
1 ,2
, Yifei Wang
3
, Matthew Tak
Vai Chan
2
, William Ka Kei Wu
1 ,2
, Huarong Chen
1 ,2 ,*
1
Institute of Digestive Disease and Department of Medicine and Ther a peutics, State K ey labor atory of Digestiv e Disease , Li Ka Shing Institute of Health Sciences ,
CUHK Shenzhen Research Institute , T he Chinese University of Hong Kong , Hong Kon g 99077, China
2
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute , T he Chinese University of Hong Kong, Hong Ko ng 99077, China
3
School of Biomedical Sciences , T he Chinese University of Hong Kong, Hong Kong 99077, China
∗Corresponding author. Department of Anaesthesia and Intensive Care , T he Chinese University of Hong Kong, Shatin, N.T., Hong Kong 99077, China. E-mail:
hchen2@cuhk.edu.hk
Editor: [Dennis Nielsen]
Abstract
The gut microbiota plays a crucial role in regulating various host metabolic, immune, and neuroendocrine functions, and has a signif-
icant impact on human health. Several lines of evidence suggest that gut dysbiosis is associated with a variety of diseases, including
cancer. The gut microbiota can impact the development and pr ogr ession of cancer through a range of mechanisms, such as reg-
ulating cell proliferation and death, modulating the host imm une r esponse, and altering the host metabolic state. Gene regulatory
pr ograms ar e consider ed critical mediators between the gut microbiota and host phenotype, of which RNA N6-methyladenosine (m6A)
modications have attracted much attention recently. Aberrant m6A modications have been shown to play a crucial role in cancer
dev elopment. This r eview aims to provide an overview of the diverse roles of gut microbiota and RNA m6A modications in cancer
and highlight their potential interactions in cancer development.
Ke yw ords: cancer, microbiota, N6-methyladenosine, crosstalk
Introduction
Ongoing efforts are being made to enhance our understanding of
the etiology of cancer. Cancer de v elopment is now regarded as a
m ultifaceted pr ocess inuenced by v arious risk factors, suc h as
genetic (e.g. inherited mutations) and environmental factors (e.g.
diet and infections), which cooperatively contribute to the inci-
dence and pr ogr ession of cancer. In the past two decades, gut mi-
cr obiota has dr awn incr easing attention and is now recognized
as an additional environmental risk factor for cancer. In a 70-
kg adult man, it is estimated that there are 38 trillion microbial
cells, comprising a ppr oximatel y 0.3% of the total body weight,
with the majority residing within the colon (Sender et al . 2016 ). Pre-
clinical studies have provided compelling evidence that gut dys-
biosis signicantly impacts cancer development and progression
thr ough m ultiple mec hanisms, suc h as disturbing the balance be-
tween cell pr olifer ation and death, modifying the immune system,
and manipulating host metabolism (Garrett 2015 ). Conversely, the
presence of tumors can also alter the microbiome composition,
which, in turn, potentially contributes to tumorigenesis and can-
cer pr ogr ession (Zitvogel et al. 2017 , Goodman and Gardner 2018 ).
Preclinical studies conducted in cell lines or mouse models have
identied probiotic bacteria, such as Lacticaseibacillus casei , Strep-
tococcus thermophilus , and Bidobacterium longum , as having the po-
tential to pr e v ent cancer or suppr ess tumor gr owth (Konishi et al.
2016 , Singh et al . 1997 , Li et al. 2021c ). Conv ersel y, pathogenic mi-
cr obes suc h as Helicobacter pylori , P eptostreptococcus anaerobius , and
Fusobacterium nucleatum have been found to facilitate cancer de-
velopment (Moss 2017 , Long et al. 2019 , Wu et al. 2019a ).
Recent evidence suggests that dysregulated epitranscriptomic
mechanisms within cancer cells contribute to cancer develop-
ment. RNA modication is a crucial regulatory mechanism that
controls gene expression, with over 160 types of RNA mod-
ications identied to date. Among these modications, N6-
methyladenosine (m6A) is the most pr e v alent mRNA modica-
tion in eukaryotic cells (Boccaletto et al. 2018 ). The m6A epitran-
scriptomic system is dynamically regulated by a group of proteins
known as writers , erasers , and readers . T he m6A writers , which
include methyltr ansfer ase-like 3 (METTL3), METTL14, METTL16,
WT1-associated protein (WTAP), and other cofactors, catalyze the
m6A modications. In contrast, the m6A erasers, such as fat
mass and obesity-associated protein (FTO) and AlkB Homolog 5
(ALKBH5), r emov e m6A marks fr om RNA. Furthermor e, the m6A
readers, including YTH domain-containing proteins (YTHDF1-3
and YTHDC1-2) and insulin-like growth factor 2 mRNA binding
proteins 1–3 (IGF2BP1-3), specically recognize and bind to m6A
marks on target genes to trigger subsequent RNA metabolism
(Sun et al . 2019 , Satterwhite and Manseld 2022 ).
The microbiome has been shown to have the capacity to alter
host epigenetic modications, such as DNA methylation, histone
modication, and non-coding RNA expression (Tahara et al. 2014 ,
Liang et al. 2015 , Koh et al. 2016 , Woo and Alenghat 2017 ). While its
contribution to RNA m6A modication is still being investigated,
studies have shown that compared to the germ-free (GF) mice,
specic pathogen-free (SPF) mice exhibit different transcriptome-
wide m6A methylome proles in the brain, intestine, and liver
(Wang et al . 2019 ), suggesting that that the presence of microbiome
Recei v ed 22 August 2022; revised 23 June 2023; accepted 28 June 2023
©The Author(s) 2023. Published by Oxford Uni v ersity Pr ess on behalf of FEMS. All rights r eserv ed. For permissions, please e-mail:
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2 | FEMS Microbiology Reviews , 2023, Vo l. 47, No. 4
inuences host RNA m6A pr oles. Furthermor e, c hanges in gut
micr obiota hav e been associated with alter ed RNA m6A modica-
tions in the cecum and liver tissues in mice carrying conventional,
modied, or no microbiota (Jabs et al. 2020 ). Commensal bacteria
such as Akkermansia muciniphila and Lactiplantibacillus plantarum
have also been shown to inuence m6A modications of genes
involved in cell growth and death (Jabs et al . 2020 ). These ndings
suggest that the gut microbiota could potentially alter host RNA
m6A modications , which ma y ha ve implications for cancer de-
v elopment. This r e vie w details the r ole of gut micr obiota and m6A
modication in cancer and summarizes k e y ndings establishing
their potential connections.
Gut microbiota and cancer
The gut microbiota can exert its effects on host cells through
v arious mec hanisms, including dir ectl y binding thr ough surface
receptors and secretion of metabolites such as short-chain fatty
acids (SCFAs) like butyrate , acetate , and propionate , bacterial vir-
ulence factors such as cytotoxin-associated gene A (CagA) pro-
tein and colibactin, and proteins such as beta-Galactosidase (Dal-
masso et al. 2014 , Li et al. 2021c ). These factors can cooper ativ el y
regulate tumor growth and metastasis. In the following section,
we will discuss the dual roles of the gut microbiota in cancer
(Table 1 ).
Gut microbiota as tumor promoters
P athogens ar e micr oor ganisms that can cause disease, and in
some cases , they ha v e been implicated as driv ers of carcinogen-
esis. Recent studies suggest that pathogenic bacteria may be re-
sponsible for de v eloping cancer in an estimated 15%–20% of hu-
man cases (Bhatt et al . 2017 ). This highlights the importance of
understanding the potential role that these microorganisms may
play in cancer pathogenesis. Helicobacter pylori is a well-studied
and widely known pathogen, classied as a class 1 carcinogen
by the Wor ld Health Organization (WHO). It is responsible for
a ppr oximatel y 90% of noncardiac gastric cancer (GC) cases in
humans (Moss 2017 ). The Ca gA pr otein expr essed by Helicobac-
ter pylori can interact with the apoptosis-stimulating of p53 pro-
tein 2 (ASPP2) in host cells, leading to enhanced degradation of
p53 protein and thereby abrogating its tumor-suppressive func-
tion, whic h may incr ease cancer susceptibility (Buti et al . 2011 ). In
addition, Helicobacter pylori secrete tumor necrosis factor- α(TNF-
α)-inducing proteins (TNFAIPs) to promote TNF- αexpression in
host cells, which is known to be involved gastric carcinogene-
sis in humans (Suganuma et al . 2021 ). Compared to healthy mu-
cosa, tumor biopsies taken from patients with colorectal cancer
(CRC) show a higher abundance of Esc heric hia coli , with the ma-
jority of these being polyketide synthase (pks) + Esc heric hia coli
(Dalmasso et al. 2014 ). The pks + Esc heric hia coli str ain r eleases
colibactin, a genotoxic compound that promotes tumor growth
in a xenograft mouse model (Dalmasso et al. 2014 ). Propionibac-
terium acnes has been identied in human prostate cancer tissues
using cultur e methods, uor escence micr oscopy methods, and
DNA analysis. Cutibacterium acnes can induce cyclooxygenase-2
signaling, which enhances cancer cell pr olifer ation (Goodman and
Gardner 2018 ). Fusobacterium nucleatum is an oral bacterium that
is enriched in CRC. Based on studies using CRC cell lines or mouse
models, it has been shown that Fusobacterium nucleatum promotes
color ectal carcinogenesis thr ough a unique adhesin called FadA,
which binds to E-cadherin and activates β-catenin signaling in
the host cells (Rubinstein et al . 2013 ). Furthermore, Fusobacterium
nucleatum -expr essing Fa p2 can dir ectl y inter act with TIGIT, a coin-
hibitory r eceptor expr essed on natur al killer (NK) cells, to inhibit
the cytotoxicity of primary human NK cells (Gur et al . 2015 ). En-
terotoxigenic Bacteroides fragilis ( ETBF ) also promotes β-catenin
signaling in CRC cells by secreting a metalloprotease toxin, which
facilitates CRC cell growth (Wu et al . 2007 ). Moreover, ETBF can
induce colon tumorigenesis in mice by activating Th17 cell re-
sponses (Wu et al. 2009 ). Toxigenic Clostridioides difcile is another
potential driver of CRC. A recent study sho w ed that gavage of a hu-
man colon cancer-derived Clostridioides difcile strain that secretes
the cytotoxin TcdB into germ-free APC
min / +
mice facilitated CRC
tumorigenesis (Dr e wes et al . 2022 ). Collectiv el y, pathogenic bacte-
ria can promote the de v elopment of cancer through both direct
and indirect interactions with the host.
Gut microbiota as tumor suppressors
Pr obiotics ar e liv e micr oor ganisms that pr ovide health benets to
the host through various mechanisms . T he Lactobacillaceae fam-
ily of lactic acid bacteria is generally considered non-pathogenic
(Zheng et al . 2020 ). Ho w e v er, some species within this famil y,
such as Lacticaseibacillus rhamnosus, may cause r ar e infections in
critically ill patients (Hazards et al. 2017 ). Lacticaseibacillus and
Lactobacillus ar e gener a of bacteria commonl y found in the hu-
man digestive and urinary tracts. Several species and strains
of these bacteria may benet human health, such as reducing
the risk of certain illnesses. For example, Lacticaseibacillus casei is
commonly used in probiotic supplements to impr ov e gastr oin-
testinal function. Recent r esearc h has also found that Lactica-
seibacillus casei may induce cancer cell death by secreting fer-
ric hr ome metabolite, whic h activ ates the JNK pathway in cell
lines and mouse models (Konishi et al. 2016 ). Similarl y, pr eclin-
ical studies using cell lines and mouse models have suggested
that supernatants of Lacticaseibacillus rhamnosus , Lactobacillus aci-
dophilus , and Lactobacillus gallinarum can inhibit the pr olifer ation
of CRC cells and induce apoptosis (Dehghani et al. 2021 , Sug-
im ur a et al . 2021 , Yue et al . 2021 ). Specically, Lactobacillus galli-
narum has been found to secrete indole-3-lactic, which inhibits
the growth of CRC cells and patient-derived CRC organoids, as
well as suppresses intestinal tumorigenesis in Apc
Min / +
mice (Sug-
im ur a et al . 2021 ). Aside from these, Lacticaseibacillus casei has been
shown to induce an anti-tumor immune response in mice, as ev-
idenced by the activated dendritic cells (DCs) and CD8
+ T cells
(Takagi et al. 2008 ).
Bidobacteria is another group of probiotics that has been stud-
ied for its potential health benets. In mice, the administration of
Bidobacterium bidum was found to suppress AOM/DSS-induced
colorectal tumorigenesis by modifying the gut microbial compo-
sition and metabolome (Wang et al. 2020 ). In addition, oral gav-
age of Bidobacterium breve in mice was shown to increase the ac-
cumulation of dendritic cells (DCs) in the intestinal villi, which
may enhance anti-tumor immunity (Li et al. 2021b ). Akkerman-
sia muciniphila , a gr am-negativ e bacterium natur all y found in the
human gut, has been the subject of recent research as a poten-
tial next-generation probiotic with anti-tumor effects. A preclini-
cal study in mice found that Akkermansia muciniphila suppressed
prostate cancer cell proliferation and invasion by modulating the
immune system (Luo et al. 2021 ). In addition, studies have demon-
strated that the probiotic bacteria Propionibacterium acidipropionici
and Propionibacterium freudenreichii generate SCFAs, namely ac-
etate and propionate, that are effective in inducing apoptosis in
CRC cells (Jan et al . 2002 ). Together, these ndings suggest that
probiotics may have anti-tumor properties . Nevertheless , it is
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Su et al. | 3
Tab l e 1. The role of gut microbiota in cancer
Bacteria Cancer type Abundance Mechanism Reference
Gut microbiota as tumor promoters
Peptostreptococcus anaerobius CRC enriched Inhibiting cancer growth (Long et al. 2019 : 2319–30)
Helicobacter pylori GC - Attaching to host cells and
deliv ering Ca gA into host
cells
(Buti et al. 2011 : 9238–43,
Suganuma et al. 2021 )
Esc heric hia coli CRC enriched Secretion of colibactin (Dalmasso et al. 2014 : 675–80)
Enterotoxigenic Bacteroides fragilis CRC - Secretion of BFT (Dejea et al. 2018: 592–7, Wu
et al. 2007 : 1944–52)
Clostridioides difcile CRC enriched Secretion of TcdB (Dr e wes et al. 2022 )
Fusobacterium nucleatum CRC enriched Suppressing anti-tumor
immunity
(Gao et al. 2021: 398, Gur
et al. 2015 : 344–55, Liu et al.
2022 : e2105222, Rubinstein et
al. 2013 : 195–206, Wu et al.
2022 : 1981–95)
Cutibacterium acnes PCa enriched unknown (Cohen et al. 2005: 1969–74)
Salmonella enterica GBC - Inducing MAPK/ERK,
PI3K/AKT/mTOR, CREB/SP-1,
BSG signaling
(Samonis et al. 2003: 5820–2)
P orph yromonas sp. CRC enriched Secretion of butyrate (Okum ur a et al. 2021: 5674)
Cutibacterium acnes EOC - Activating hedgehog pathway (Huang et al. 2022)
Gut microbiota as tumor suppressors
Streptococcus thermophilus CRC depleted Secretion of
beta-Galactosidase
(Li et al. 2021 : 1179–93 e14)
Lacticaseibacillus casei CRC depleted Secretion of ferrichrome
Regulating immune response
(Konishi et al. 2016 : 12 365,
Lee et al. 2004 : 41–8)
Bidobacterium longum CRC - Regulating immune response (Lee et al. 2004 : 41–8, Singh et
al. 1997 : 833–41)
Lactiplantibacillus plantarum CRC - Enhance butyrate uptake (Kim et al. 2022: 100–17)
Lactobacillus gallinarum CRC depleted Secretion of ILA (Sugim ur a et al. 2021 )
Bidobacterium bidum CRC - Regulating gut microbiota
and metabolic prole
(Wang et al. 2020 : 5915–28)
Bidobacterium breve CRC - Regulating immune response (Li et al. 2021 : 1 868 122)
Akkermansia muciniphila PCa - Regulating immune response (Luo et al. 2021 : 2949–63)
Propionibacterium acidipropionici and
Propionibacterium freudenreichii
CRC - Secretion of propionate and
acetate
(Jan et al. 2002 : 179–88)
Bidobacterium pseudolongum CRC - Secretion of inosine to
enhance anti-tumor
immunity
(Mager et al. 2020 : 1481–9)
Lacticaseibacillus rhamnosus CRC - Inducing cell apoptosis by
metabolites
Regulating immune response
(Dehghani et al. 2021 : 245–52,
Rahimpour et al. 2022 :
2622–31, Si et al. 2022 :
521–33)
Lactobacillus delbrueckii CRC - Inducing cell apoptosis (Wan et al. 2014: 1738–42)
Limosilactobacillus fermentum CRC - Inhibiting tumor metastasis (Liu et al. 2021 : 7281–93)
Lactobacillus acidophilus CRC - Inhibiting cell apoptosis
Regulating redox status
(Deepak et al. 2021: 225, Yu e
et al. 2021 : 788 040)
Lactobacillus brevis BRCA - Secretion of Lb-PPSPs (Pourbaferani et al. 2021:
982–92)
Bidobacterium breve HNC - Inducing cell cycle arrest and
cell apoptosis
(Wang et al. 2019 : 1044)
Clostridium sporogenes LC/CRC - Secretion of methionine
gamma-lyase
(Bhave et al. 2015: 15 681,
P okro vsky et al. 2019 : 201–9)
Faecalibaculum rodentium and
Holdemanella biformis
CRC depleted Secretion of SCFA (Zagato et al. 2020: 511–24)
Abbre via tion: BRC A, breast cancer; CRC, colorectal cancer; GBC, gallbladder cancer; GC, gastric cancer; HNC, head and neck cancer; LC, lung cancer; PCa, prostate
cancer; EOC, epithelial ova rian cancer.
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4 | FEMS Microbiology Reviews , 2023, Vo l. 47, No. 4
Figur e 1. T he function of m6A on RNA metabolism. RNA m6A modication is dynamically regulated by three types of proteins: writers , erasers , and
r eaders. Writers catal yze the addition of m6A marks, er asers r emov e m6A marks, and r eaders specicall y r ecognize and bind to m6A sites to impact
the RNA metabolism. m6A modications control RNA metabolism, including RNA splicing, nuclear export, translation, and RNA degradation.
Figur e 2.
T he role of m6A in cancers. m6A regulators play a critical role in regulating various aspects of cancer biology, including cancer stemness,
cancer gr owth, differ entiation, and metastasis, as well as tumor immunity and chemoresistance, by regulating the expression of cancer-related genes.
important to note that the benets and safety of probiotics in
humans are not yet fully understood, as many studies investigat-
ing their effects have been preclinical and conducted in animal
or cell culture models . T herefore , further research, particularly
well-designed clinical studies in humans, is necessary to deter-
mine the potential benets, optimal dosing, and safety of these
probiotics.
RNA m6A modication and cancer
The m6A modication is pr edominantl y found near stop codons
and in 3’-untranslated regions (3’-UTRs) of mRNA molecules, with
a consensus motif of RR(m6)ACH (R = G or A, H = A, C, or U) (Sun
et al. 2019 ). T he m6A modication pla ys a vital r ole in r egulat-
ing various aspects of RN A metabolism, including RN A splicing,
miRNA pr ocessing, nuclear export, tr anslation, and RNA decay
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Su et al. | 5
(Fig. 1 ) (Sun et al . 2019 ). Aberrant m6A modications have been
implicated in the regulation of multiple aspects of cancer biol-
ogy, including cancer stem cell pluripotency (Liu et al . 2021 ), cell
differentiation (Weng et al . 2018 ), cell pr olifer ation (H. Chen et al.
2021a ), cell metastasis (Zhou et al . 2021 ), anti-tumor immunity
(Bai et al . 2022 , Chen et al . 2022a ), and c hemor esistance (Jin et al.
2019 ). Her e we pr esent a thor ough ov ervie w of the m ultifaceted
roles that m6A modications play in different aspects of cancer
de v elopment (Fig. 2 and Table 2 ).
M6a writers
The m6A writer complex, composed of METTL3, an m6A methyl-
tr ansfer ase, and other ada ptor pr oteins, including METTL14,
WT AP, Vir -like m6A methyltr ansfer ase associated pr otein
(VIRMA), zinc nger CCCH-type containing 13 (ZC3H13), HAKAI,
RNA-binding motif protein 15 (RBM15), and RNA-binding motif
pr otein 15B (RBM15B), pr edominantl y catal yzes m6A methylation
on mRNA molecules (Zaccara et al . 2019 ). In addition to METTL3,
two new m6A methyltransferases have recently been identied,
namely METTL16 and Zinc Finger CCHC-Type Containing 4 (ZC-
CHC4). METTL16 methylates U6 spliceosomal small nuclear RNA,
MALAT long non-coding RNA, and the MAT2A mRN A (Bro wn
et al . 2016 , Pendleton et al. 2017 , Satterwhite and Manseld 2022 ),
while ZCCHC4 adds m6A to 28S rRNA (Ma et al . 2019 ). METTL3 is
fr equentl y ov er expr essed in v arious types of cancers, including
CRC , GC , hepatocellular carcinoma (HCC), lung cancer (LC), and
prostate cancer (PCa). Studies have shown that METTL3 upregu-
lates m6A le v els of GLUT1, miR-1246, and Sec62 in different CRC
cell lines and mouse models of CRC. This upregulation leads to
the activation of various oncogenic signaling pathwa ys , which
can further promote the pathogenesis of CRC (Chen et al . 2021a ,
Peng et al . 2019 , Liu et al . 2021 ). Furthermore, METTL3 facilitates
the formation of circHPS5 in an m6A-dependent manner, which
subsequently enhances HMGA2 expression and promotes HCC
pr ogr ession, as demonstr ated in both in vitro cell lines and in vivo
mouse models (Rong et al . 2021 ). According to Wang et al . ( 2022b ),
METTL14 is upregulated in primary PCa tissues and is associated
with poor prognosis of PCa patients. Functionally, METTL14
plays an oncogenic role by inhibiting THBS1 expression in an
m6A-dependent manner (Wang et al . 2022b ). Ho w e v er, in HCC
cells, METTL14 has been reported to have a tumor-suppressive
role (Du et al. 2021a ), suggesting that the role of METTL14 in
cancer may be context-dependent. Although it has no catalytic
activity, WTAP stabilizes the m6A methyltr ansfer ase complex
for m6A deposition. Similar to METTL3, WTAP is upregulated in
different types of human cancer, including HCC, bladder cancer
(BLCA), and breast cancer (BRCA). Studies have shown that WTAP
can promote cancer progression and metastasis by regulating
the expression of ENO1 in BRCA cells and TNFAIP3 in BLCA cells
(Ou et al. 2021 , Wei et al. 2021 ). Additionall y, studies hav e shown
that METTL16 dri ves leuk emogenesis in mice by regulating the
expression of BC AT1/BC AT2 (Han et al . 2023 ).
M6a erasers
FTO and ALKBH5 are tw o w ell-kno wn m6A erasers . FT O is the rst
m6A demethylase to be identied and is responsible for reducing
total RNA m6A le v els in cells (Jia et al . 2011 ). FTO has been found to
have both oncogenic and tumor-suppressive roles. In BLCA, CRC,
and GC cells, high FTO expression promotes cancer cell growth
and metastasis via promoting MALAT and MYC expression, and
inducing cav eolin-1 degr adation, r espectiv el y (Tao et al. 2021 , Yu e
et al . 2020 , Zhou et al . 2022 ). Mor eov er, a specic FTO inhibitor has
been shown to suppress the growth and lung colonization of BRCA
cells in mice (Xie et al . 2022 ). Ho w e v er, hypoxia-induced downr eg-
ulation of FTO has been reported to facilitate CRC growth and
metastatic potential (Ruan et al . 2021 ). In this study, protein ex-
pression of FTO, but not mRN A, w as reduced in CRC tissues, and
low FTO protein expression could predict a high recurrence rate
and poor prognosis in CRC patients (Ruan et al . 2021 ). Addition-
ally, SIRT1 has been reported to play an oncogenic role in HCC
by r epr essing FTO expr ession (Liu et al . 2020b ), suggesting that
the function of FTO in cancer is context-dependent. Similar to
FTO, abnormal expression of ALKBH5 has been observed in differ-
ent types of human cancer. ALKBH5 is ov er expr essed in multiple
myeloma (MM) and predicts a poor prognosis of MM patients (Qu
et al. 2022 ). Functionall y, ALKBH5 r educes the m6A le v el of TRAF1
mRNA to increase TRAF1 mRNA stability, leading to the activation
of NF- κB and MAPK pathways that contribute to MM tumorigen-
esis (Qu et al . 2022 ). Ho w e v er, low expr ession of ALKBH5 has been
identied in osteosarcoma, which is associated with poor survival
of osteosarcoma patients. ALKBH5-mediated m6A demethylation
inhibits the decay of SOCS3 mRNA, leading to the inactivation of
the ST A T3 pathway and consequent inhibition of cell pr olifer a-
tion, induction of cell apoptosis, and cell cycle arrest (Yang et al.
2022 ).
M6a readers
T he m6A readers , such as YTHDF1-3, YTHDC1-2, and IGF2BP1-3,
specicall y r ecognize and bind to m6A-modied RNAs and regu-
late their biological functions. Each m6A reader plays a distinct
role in RNA metabolism, contributing to the intricate nature of
the m6A epitranscriptome. YTHDF1 has been shown to function
as an oncogene in various cancers by accelerating the transla-
tion of m6A-modied mRNAs (Chen et al. 2021b ; Liu et al. 2020a ,
Wan g et al. 2015 , 2021 a). In contrast, YTHDF2 reduces the stability
of m6A-modied targeted mRNAs, making it the primary decay-
inducing m6A r eader. Additionall y, YTHDF3 pr omotes YTHDF2-
mediated mRNA decay by increasing the accessibility of RNA to
YTHDF2 (Shi et al . 2017 ). YTHDF2 has been found to play a role in
tumorigenesis and cancer pr ogr ession. In liv er cancer cells, Zhang
et al. reported that YTHDF2 promotes cancer stemness and
metastasis by increasing OCT4 expression in an m6A-dependent
manner (Zhang et al. 2020a ). Additionally, Li et al . sho w ed that
YTHDF2 promotes CRC cell proliferation by targeting m6A-
modied GSK3- βmRNA for degr adation, whic h leads to the ac-
tivation of Wnt/beta-catenin/Cyclin D1 signaling pathway (Li et
al . 2021a ). In contrast, Zhong et al. demonstrated that YTHDF2
suppressed HCC cell growth by destabilizing m6A-modied EGFR
mRNA (Zhong et al. 2019 ). The discrepancies in these ndings
could be due to the differing m6A-modied RNAs targeted by
YTHDF2 across various cancer types and cell lines. YTHDC1
is known to regulate the alternative splicing of m6A-modied
RNAs, while YTHDC2 inuences the translation efciency of tar-
get genes in an m6A-dependent manner (Yang and Chen 2021 ).
Both YTHDC1 and YTHDC2 play a pivotal role in various cancer
types by targeting different m6A-modied mRNAs (Hou et al. 2021 ,
Tanabe et al. 2016 , Ma et al . 2021 , Sheng et al. 2021 , Wu et al. 2021 ).
The family of IGF2BP proteins has recently been recognized as
m6A readers. Unlike YTHDF2-induced RNA decay, IGF2BP1-3 can
stabilize m6A-containing RN A b y binding to the m6A sites (Huang
et al. 2018 ). Furthermor e, the tr anscriptome-wide binding sites of
YTHDF2 and IGF2BP1-3 are distinct (Huang et al. 2018 ). The role of
IGF2BP proteins in tumorigenesis and cancer pr ogr ession has been
documented in different cancer types, including gastrointestinal
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6 | FEMS Microbiology Reviews , 2023, Vo l. 47, No. 4
Tab l e 2. The role of m6A regulators in cancer.
Regulator Cancer type Role Targets Function Reference
METTL3 CRC oncogene SOX2 ↑ , GLUT1 ↑ ,
YPEL5 ↓ , miR-1246 ↑ ,
CRB3 ↓ , Sec62 ↑
Tumorigenesis and
metastasis ↑
(Chen et al. 2021 : 1284–300
e16, Liu et al. 2021 : 132, Pan
et al. 2022 : 19, Peng et al.
2019 : 393, Zhou et al. 2021 :
2172–84)
METTL3 HCC oncogene SOCS2 ↓ , LINC00958 ↑ ,
Has_circ_0 058 493 ↑ ,
CircHPS5, HMGA2 ↑ ,
RDM1 ↓
Tumor pr ogr ession ↑ (Chen et al. 2018 : 2254–70,
Chen et al. 2020 : 373–86,
Rong et al. 2021 : 637–48, Wu
et al. 2021 : 762588, Zuo et al.
2020 : 5)
METTL3 GC oncogene HDGF ↑ , ZMYM1 ↑ ,
SPHK2 ↑ , THAP7-AS1 ↑ ,
PBX1/GCH1 ↑
Tumor angiogenesis,
tumor gr owth, and liv er
metastasis ↑
(Huo et al. 2021 : 2968–81, Liu
et al. 2022 : 627–41, Wang et
al. 2020 , Liu et al. 2022 :
1193–205, Yue et al. 2019 : 142)
METTL3 PCa oncogene USP4/ELAVL1 ↓ , PCAT6 ↑ Migration and
invasion ↑
(Chen et al. 2021: 7640–57,
Lang et al. 2021 : e426)
METTL3 LC oncogene ABHD11-AS1 ↑ , ZBTB4 ↓ ,
YAP ↑
Pr olifer ation,
metastasis, and drug
resistance ↑
(Cheng et al. 2021: 487–500,
Jin et al. 2019 : 135, Xue et al.
2021 : 2649–58)
METTL14 PC oncogene THBS1 ↓ Pr olifer ation ↑ (Wang et al. 2022 : 143)
METTL14 CRC TSG MiR-375 ↑ Tumorigenicity and
metastasis ↓
(Chen et al. 2020: 599–612)
METTL14 HCC TSG USP48 ↑ , HNF3 γ↑ Gl ycol ysis, malignancy,
and anti-cancer
c hemother a py ↑
(Du et al. 2021 : 3822–34, Zhou
et al. 2020 : 296)
METTL16 AML oncogene BC AT1/ B C AT2 ↑ Leukemogenesis ↑ (Han et al. 2023 : 52–68 e13)
WTAP HCC oncogene ETS1 ↓ Tu m o r pr ogr ession ↑ (Chen et al. 2019: 127)
WTAP OS oncogene HMBOX1 ↓ Growth and
metastasis ↑
(Chen et al. 2020: 659)
WTAP BRCA oncogene ENO1 ↑ Gl ycol ysis and growth ↑ (Ou et al. 2021 : 737)
WTAP DLBCL oncogene HK2 ↑ Tu m o r pr ogr ession ↑ (Han et al. 2021: 1603–14)
FTO BLCA oncogene MALAT ↑ /miR-
384/MAL2
Tumorigenesis ↑ (Tao et al. 2021 : e310)
FTO CRC oncogene MYC ↑ Tu m o r pr ogr ession ↑ (Yue et al. 2020 : 240)
FTO GC oncogene Caveolin-1 ↓ Growth and
metastasis ↑
(Zhou et al. 2022 : 72)
FTO CRC TSG MTA1 ↓ Metastasis ↓ (Ruan et al. 2021 : 5168–81)
FTO HCC TSG GNAO1 ↑ Tu m o r pr ogr ession ↓ (Liu et al. 2020 : 2029–50)
FTO HCC oncogene SOX2, KLF4, NANOG ↑ Cancer stemness ↑ (Bian et al. 2021: e352)
ALKBH5 MM oncogene TRAF1 ↑ Tumorigenesis ↑ (Qu et al. 2022 : 400–13)
ALKBH5 OS TSG SOCS3 ↑ Pr olifer ation and
tumorigenicity ↓
(Yang et al. 2022 : 104 019)
YTHDF1 GC oncogene USP14 ↑ Tumorigenesis and
metastasis ↑
(Bai et al. 2022 , Chen et al.
2021: 647702)
YTHDF1 CRC oncogene ARHGEF2 ↑ Tu m o r growth and
metastasis ↑
(Wang et al. 2021 )
YTHDF1 HCC oncogene A TG2A ↑ , A TG14 ↑ ,
FZD5 ↑ , EGFR ↑
Autophagy and
autopha gy-r elated
malignancy ↑
(Liu et al. 2020 : 750–65,
Ouyang et al. 2021 : 1217, Su
et al. 2021 : 1339–56)
YTHDF2 HCC oncogene OCT4 ↑ Cancer stemness and
metastasis ↑
(Zhang et al. 2020 : 4507–18)
YTHDF2 CRC oncogene GSK3 β↓ Pr olifer ation ↑ (Li et al. 2021 : e602)
YTHDF2 HCC TSG IL11 ↓ , SERPINE2 ↓ ,
EGFR ↓
Inammation, vascular
reconstruction, and
metastasis ↓
(Hou et al. 2019: 163, Zhong
et al. 2019 : 252–61)
YTHDF3 CRC oncogene LncRNA GAS5 ↓ Tum o r pr ogr ession ↑ (Ni et al. 2019: 143)
YTHDC1 HCC oncogene Has_circ_0 058 493 Growth and
metastasis ↑
(Wu et al. 2021 : 762588)
YTHDC1 AML oncogene MCM4 Tumor de v elopment ↑ (Sheng et al. 2021 : 2838–52)
YTHDC1 PC TSG MiR-30d ↑ Tumorigenesis ↓ (Hou et al. 2021 : 3105–24)
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Su et al. | 7
Tab l e 2. Continued
Regulator Cancer type Role Targets Function Reference
YTHDC2 CRC oncogene HIF-1 α↑ Tu m o r metastasis ↑ (Tanabe et al. 2016 : 34–42)
YTHDC2 LC TSG SLC7A11 ↓ Tumorigenesis ↓ (Ma et al. 2021 : 101801)
IGF2BP1 HCC oncogene c-MYC ↑ , MKI67 ↑ Tumorigenesis ↑ (Gutschner et al. 2014 :
1900–11)
IGF2BP1 CRC oncogene LDHA Anticancer ther a py ↓ (Zhang et al. 2021: 835–46)
IGF2BP1 LC oncogene Kras ↑ Growth and migration ↑ (Wallis et al. 2022: 26–43)
Abbre via tion: AML, acute myeloid leukemia; BLCA, bladder carcinoma; BRCA, breast cancer; CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular carci-
noma; LC, lung cancer; MM, multiple myeloma; OS, osteosarcoma; PC, pancreatic cancer; PCa, prostate cancer; TSG, tumor suppressor gene.
cancer , breast cancer , and lung cancer (Du et al. 2021b ). For ex-
ample, IGF2BP1 has been found to promote HCC cell pr olifer ation
while inhibiting apoptosis by stabilizing c-MYC and MKI67 mRNAs
(Gutschner et al. 2014 ). Overall, the functions of m6A regulators in
cancer are context dependent.
Crosstalk between gut microbiota and m6A
modication
Both gut microbiota and m6A modication have been shown to
play a signicant role in cancer development. Understanding their
individual and combined effects could pro vide no vel insights into
cancer biology and lead to the de v elopment of ne w ther a peutic
strategies for cancer patients.
The inuence of gut microbiota on host RNA m6a
modication
Studies have demonstrated that gut microbiota composition al-
ter ations can signicantl y c hange host epitr anscriptomic pr o-
les (Fig. 3 ). In a recent publication, signicant differences were
found in the m6A proles of the cecum and liver tissues between
conv entional and germ-fr ee mice, whic h could be attributed
to altered expression of m6A methyltransferase METTL16 (Jabs
et al. 2020 ). These differential m6A peaks were enriched in the
metabolic , inammatory response , and antimicr obial r ecognition
and signaling pathways (Jabs et al. 2020 ). In support of this, an-
other study using m6A-MeRIP sequencing of various tissues from
germ-free and SPF mice revealed higher m6A content of the brain,
intestine, and kidney tissues of germ-free mice compared to SPF
mice (Wang et al. 2019 ). Intriguingly, this study found that m6A
writers, METTL3 and METTL14, as well as m6A erasers, ALKBH5
and FTO, were upregulated in brain tissues of GF mice compared
to SPF mice. At the same time, higher expression of METTL14 was
observed in the intestine of SPF mice compared to GF mice (Wang
et al . 2019 ). Additionally, a study sho w ed that a high-fat diet de-
cr eased global m6A le v els in pig jejunal, whic h could be r estor ed
by fecal microbiota transplant (FMT) of wild boar fecal suspen-
sion (Zhu et al. 2022 ). These ndings suggest that gut microbiota
can signicantly impact the host RNA m6A prole.
We next ask whether a specic micr oor ganism can impact the
m6A patterns of its host. Gr owing e vidence suggests that certain
bacteria have the ability to increase RNA m6A modications in
the host cells. Enterotoxigenic Escherichia coli has been shown to
promote global RNA m6A level mediated by METTL3 in intesti-
nal epithelial cells, leading to increased expression of β-defensin
(Zong et al . 2021 ). Additionally, heat-killed Salmonella typhimurium
infection has been shown to increase WTAP-mediated global RNA
m6A le v els in THP-1 cells (Wu et al . 2020a ). Lactobacilli and Bi-
dobacterium species have also been found to incr ease m6A le v els
in the total RNA of gut tissues, which favors intestinal de v elop-
ment (Wu et al. 2020b ). On the other hand, certain bacterial in-
fections have been shown to suppress m6A enrichment in host
cells . For example , a r ecent publication demonstr ated that Fu-
sobacterium nucleatum could decrease the RNA m6A le v el in CRC
cells and patient-deriv ed xenogr aft tissues by activating YA P sig-
naling and inhibiting FOXD3 expr ession, whic h leads to reduced
METTL3 transcription and decreased m6A levels of kinesin fam-
ily member 268 (KIF268) (Chen et al . 2022 c). T his , in turn, abro-
gates YTHDF2-dependent degradation of KIF268 mRNA, result-
ing in upregulated KIF268 expression that contributes to Fusobac-
terium nucleatum -induced CRC metastasis (Chen et al . 2022 c). More-
over, ETBF has been found to inhibit METTL14 expression and dis-
rupts the splicing process of pri-miR-149 in an m6A-dependent
manner, leading to reduced miR-149–3p expression and increased
CRC cell pr olifer ation (Cao et al . 2021 ). All these ndings suggest
that certain bacteria have the potential to alter the RNA m6A pro-
le of their host, which may, in turn, inuence the de v elopment
of cancer. Ne v ertheless, it is essential to note that onl y a limited
number of studies have investigated the potential role of host RNA
m6A modication as an intermediary between microbial dysbio-
sis and cancer de v elopment. Ther efor e, further r esearc h is needed
to examine the potential interplays between gut microbiota and
host RNA m6A modication to better understand their contribu-
tions to cancer de v elopment.
What mechanisms underlie the regulatory role of microbiota
on the host m6A pr ogr am? Lactiplantibacillus plantarum and Lati-
lactobacillus sakei have been found to upregulate the AMPK/SIRT1
pathway in mice (Jang et al . 2019 , Wang et al . 2021 b). Importantly,
SIRT1 has been demonstrated to play a crucial role in various
types of human cancers, including leukemia, BRCA, and CRC (Her-
ranz et al. 2013 , Chen et al. 2014 , Yuan et al. 2012 , Jin et al . 2018 ).
SIRT1 can promote the degradation of FTO through RANBP2-
mediated SUMOylation of FTO, which results in the alteration of
the m6A methylome and the tuning of downstr eam tar get expr es-
sion (Liu et al . 2020b ). Ther efor e, the AMPK/SIR T1 pathw ay r epr e-
sents a possible mediator between bacterial infections and alter-
ations in host m6A le v els . T he IL-6/ST A T3 pathway is another pos-
sible intermediate link. IL-6 is an inammatory factor that plays
a vital role in various biological processes (Heinrich et al . 2003 ,
Waldner et al . 2012 ), and the IL-6/ST A T3 pathway is crucial for
cancer growth and development. Bacteria, such as Escherichia coli ,
Staph ylococcus hominis , and Staph ylococcus lentus , can promote the
production of IL-6 (Larsson et al. 1999 ). Additionally, the admin-
istr ation of lipopol ysacc haride (LPS), an essential component of
Gr am-negativ e bacteria, consistentl y activ ates IL-6 and ST A T3 sig-
naling in the mouse br ain (Beur el and J ope 2009 ). Furthermore ,
bacteria-deriv ed extr acellular v esicles hav e been demonstr ated
to r elease LPS, whic h can stim ulate the secr etion of IL-6 in pe-
ripheral blood mononuclear cells (Tulkens et al. 2020 ). T hus , the
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8 | FEMS Microbiology Reviews , 2023, Vo l. 47, No. 4
Figur e 3.
T he inuences of gut microbiota on host m6A prole. Different bacterial species may modulate m6A modication through various
mechanisms . For example , Lactiplantibacillus plantarum and Latilactobacillus sakei upregulate AMPK/SIRT1 signaling to promote FTO degradation, while
Esc heric hia coli , Staphylococcus hominis , and Staphylococcus lentus activate IL-6/ST A T3 signaling to enhance the expression of m6A methyltransferase
complex (METTL3/METTL14/WTAP) and ele v ate RNA m6A le v els. Akkermansia muciniphila and Lactiplantibacillus plantarum have also been shown to alter
host m6A le v els. Additionall y, enter otoxigenic Esc heric hia coli pr omotes global RNA m6A le v els mediated by METTL3, while Salmonella typhimurium
induces global RNA m6A le v els thr ough WTAP. Fusobacterium nucleatum , on the other hand, decr eases RNA m6A le v els by r epr essing METTL3
expr ession, and enter otoxigenic Bacteroides fragilis inhibits METTL14 to suppr ess miR-149–3p expr ession.
gut microbiota can manipulate the IL-6/ST A T3 pathway . Notably ,
the activation of IL-6/ST A T3 has been reported to increase RNA
m6A le v el by enhancing the expression of the m6A methyltrans-
fer ase complex (METTL3/METTL14/WTAP), r esulting in an alter ed
m6A methylome that promotes cancer stemness (Ye et al . 2021 ).
Together, the microbiome can potentially trigger intracellular cas-
cades within host cells that inuence RNA m6A pr ole, ultimatel y
impacting cancer de v elopment.
The inuence of host RNA m6a modication on
the microbiome
The gut microbiota is not only affected by external factors but
also by host gene expr ession pr ogr ams . T hr ough the anal y-
sis of metagenomic data from the Human Microbiome Project,
Blekhman et al. discov er ed signicant corr elations between se v-
eral host signaling pathwa ys , such as Leptin signaling, JAK/ST A T
signaling, and IL12-mediated signaling, and gut microbiota com-
position (Blekhman et al . 2015 ). Furthermore, in a study that
analyzed the 16S ribosomal RNA gene sequences of intestinal
biopsies and genotypes of 474 individuals, Knights et al. found a
signicant correlation between the host NOD2 risk allele dosage
and increased Enterobacteriaceae abundance (Knights et al . 2014 ).
T hese ndings , in conjunction with those of Blekhman et al., sug-
gest a connection between host gene expression and gut micro-
biota composition. Furthermore, Nod2 -decient mice exhibit gut
dysbiosis, leading to more severe colitis and a higher incidence of
colitis-associated carcinogenesis (Couturier-Maillard et al . 2013 ).
ALKBH5 has been shown to control bacterial infections in trans-
genic mouse models (Liu et al . 2022 ). In a mouse model of sep-
sis, mice with Alkbh5 knoc k out exhibit a higher bacterial burden
in the peritoneal cavity and blood, leading to increased sepsis-
related mortality (Liu et al . 2022 ). Collectively, alterations in host
gene expr ession thr ough genetic , epigenetic , or epitranscriptomic
r epr ogr amming can potentially modify the gut microbiota.
The host RNA m6A pr ogr am may impact micr obiome compo-
sition by regulating the expression of genes closely related to the
gut micr obiota, suc h as the famil y of suppr essors of cytokine sig-
naling (SOCS), vitamin D receptor (VDR), and mucin. The family
of SOCS pr oteins serv es as inhibitors of cytokine signaling, in-
cluding JAK/ST A T (Croker et al . 2008 ). Importantl y, SOCS famil y
genes, including SOCS1, SOCS2, SOCS3, and CISH, exhibit enriched
m6A peaks and are subject to m6A-dependent mRNA degradation
(Chen et al . 2018 , Li et al . 2017 ). In naive T cells decient in METTL3,
the loss of m6A marks on SOCS1, SOCS3, and CISH mRN A slo ws
do wn their mRN A decay, r esulting in incr eased mRNA and pr otein
expr ession le v els (Li et al . 2017 ). As a consequence, the inactiva-
tion of IL-7-mediated ST A T5 signaling occurs upon the silencing
of METTL3 (Li et al . 2017 ). This nding is consistent with the ob-
servation that the knockdown of METTL3 reduces the m6A level
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Su et al. | 9
of SOCS2 mRNA, leading to increased SOCS2 expression in HCC
cells (Chen et al . 2018 ). The JAK/ST A T pathway is critical for main-
taining intestinal and microbial homeostasis. Upon nematode in-
fection, activation of ST A T6 in mouse epithelium inhibits ion ab-
sorption while increasing mucous secretion and release of antimi-
crobial compounds to facilitate infection clearance (Spencer et al.
2001 ). Similarl y, activ ated ST A T3 in the epithelium promotes the
r elease of antimicr obial compounds, suc h as β-defensins (Wolk
et al . 2004 ). Ther efor e, the host m6A pr ogr am has the potential to
inuence gut microbiota composition by regulating the JAK/ST A T
pathway.
Deletion of VDR in the mouse intestine has been demonstrated
to induce gut dysbiosis through the modulation of the JAK/ST A T
pathway (Zhang et al . 2020b ). VDR is expressed at high le v els in
the intestine and is recognized to have a protective role in can-
cer (Carlberg and Munoz 2020 ). A genome-wide association study
comprising 1812 individuals r e v eals a signicant association
between VDR genotypes and ov er all gut micr obial v ariation (Wang
et al . 2016 ), suggesting that host VDR activation may alter the gut
microbiota composition. Consistent with this, constitutive knock-
out of Vdr in mice has been shown to result in a signicant shift
in gut microbiota composition (Wang et al . 2016 ). Specically, a
higher abundance of Parabacteroides is observed in mice when Vdr
is deleted (Wang et al. 2016 ). VDR not only affects bacteria but
also regulates the gut virome. In an intestinal Vdr knockout mouse
model, silencing of Vdr has been found to increase the abundance
of Vibrio phage JSF5 and bovine viral diarrhea virus-1 in the stool
(Zhang et al . 2021b ). In contrast, Lactobacillus prophage Lj771 , Lac-
tobacillus prophage phiadh , Lactobacillus prophage KC5a , Macacine al-
phaherpesvirus 1 , and Catovirus CTV1 are depleted in female mice
with Vdr deletion (Zhang et al . 2021b ). Mec hanisticall y, VDR r egu-
lates the expression and signaling of target genes that contribute
to gut dysbiosis. When Vdr is knocked out in the intestinal, it leads
to impair ed P aneth cell function and r educed pr oduction of an-
timicrobial peptides (Wu et al . 2015 ). Collectiv el y, VDR plays a cru-
cial role in maintaining the balance of the intestinal microbiome.
Inter estingl y, emer ging e vidence has shown that the expr ession
of VDR is regulated by various m6A regulators. For instance, the
knockdown of YTHDF1 has been found to increase the translation
efcienc y of VDR b y anal yzing ribosome pr oling data (Wang et al .
2015 ). Ad ditionally, de pletion of METTL14 has been shown to re-
duce VDR mRNA expression by analyzing RNA-seq data in both
HepG2 and NB4 cells (Weng et al . 2018 , Huang et al . 2019a ). How-
e v er, none of these studies have conrmed the presence of m6A
marks on VDR mRNA. Ther efor e, whether VDR is a direct down-
str eam tar get of the m6A pr ogr am r emains to be determined.
Like VDR, mucin also plays a protective role in humans and has
a close relationship with the gut microbiota (Bergstrom et al. 2020 ,
Hansson 2020 , Paone and Cani 2020 ). Dysregulated mucin expres-
sion is str ongl y linked to various diseases, including CRC (Pothu-
raju et al . 2020 ). There are two types of mucins: transmembrane
mucins (MUC1, MUC3, MUC4, MU12, MUC13, MUC15, MUC17,
MUC20, MUC21, and MUC22) and secreted mucins (MUC2, MUC5B,
and MUC6) (Paone and Cani 2020 ). Tr ansmembr ane m ucins ar e
present on the apical surfaces of epithelial cells and are involved
in host-microbe interactions. MUC1 has been found to prevent
the binding of Helicobacter pylori to enterocytes in mice (McGuckin
et al. 2007 ). Furthermore , o verexpression of MUC17 can protect ep-
ithelial cells by blocking the attachment of enteropathogenic Es-
c heric hia coli (Schneider et al. 2019 ). In contrast, secreted mucins,
mainl y pr oduced by goblet cells, pr ovide nutrients and attach-
ment sites for gut microbiota (Hansson 2020 ). MUC2 is the pri-
maril y secr eted m ucin in the intestine, forming the m ucus skele-
ton (Paone and Cani 2020 ). MUC2 maintains a healthy gut mi-
cr obiota, and dysr egulated MUC2 expr ession can lead to micro-
biome dysbiosis (Ber gstr om et al . 2020 ). Supporting this observ a-
tion, distinct microbiome compositions have been identied be-
tween Muc2
−/ −mice and their control littermates (Leon-Coria et
al . 2021 ). As a result, Muc2
−/ −mice are susceptible to chemical,
bacterial, and parasite-induced colitis (Leon-Coria et al . 2021 ). Sev-
eral members of the MUC family genes are m6A-modied, in-
cluding MUC3A (Zhao and Xie 2021 ), MUC5B (Ruan et al . 2022 ),
and MUC15 (Gan et al. 2021 ). Their expressions can be modulated
by differ ent m6A r egulators. In addition, se v er al m6A-modied
genes, such as Galectin-3 and KLF4, have been shown to regu-
late m ucin expr ession. Galectin-3 has been identied as a tar-
get of the m6A eraser ALKBH5 (Zhang et al. 2022 ). In CRC cells,
Galectin-3 has been shown to regulate MUC2 transcription (Song
et al . 2005 ). In addition, KLF4, a zinc-nger transcription factor, is
suppressed by METTL3 (Chien et al. 2021 , Wu et al. 2019b ). Deletion
of KLF4 has been found to increase MUC2 expression in GC cells
(Yu et al . 2016 ).
All of these studies suggest that disruptions to the host RNA
m6A pr ogr am hav e the potential to alter microbiome composition
by altering host gene expression.
Use of probiotics and small molecules
targeting m6A regulators for cancer
treatment
Pr obiotics ar e belie v ed to offer potential health benets, including
reducing certain side effects of cancer treatment. Some preclinical
studies have even suggested that probiotics may help prevent cer-
tain types of cancer (Luo et al . 2021 , An and Ha 2022 ). Meanwhile,
dysregulation of m6A modication has been linked to the de v el-
opment and pr ogr ession of v arious cancers, making it a pr omising
target for cancer treatment. By targeting m6A regulators, it may
modulate the le v els of m6A modication in cancer cells and al-
ter their behavior (Chen et al. 2012 , Dolbois et al. 2021 , Su et al.
2018 , 2020 , Huang et al. 2019b , Moroz-Omori et al . 2021 , Yank ov a
et al . 2021 , Zheng et al. 2014 ). Although these studies are still pre-
clinical, probiotics or targeting m6A regulators may be considered
potential adjuvants to cancer therapy.
Probiotics for cancer treatment
Pr obiotics hav e gained signicant attention in recent years due to
their potential health benets . T her e ar e ov er 1 900 clinical studies
r egister ed at ClinicalTrials .go v ( https://clinicaltrials.go v/) in vesti-
gating the ther a peutic potential of probiotics, and an increasing
number of these studies are specically focusing on using probi-
otics as food supplements to support cancer patients during an-
ticancer tr eatments. Se v er al published clinical trials hav e shown
pr omising r esults for using pr obiotics in cancer patients. For ex-
ample, Enterococcus faecium M-74 has been administered to prevent
febrile neutropenia, a severe side effect of anti-cancer chemother-
ap y, and w as found to be effective for cancer patients (Mego et al.
2005 ). In another study, supplementation of Lacticaseibacillus rham-
nosus GG alle viated c hemother a py-induced diarrhea in cancer pa-
tients r eceiving 5-Fluor our acil (5-FU) tr eatment (Osterlund et al .
2007 ). Additionally, Lacticaseibacillus rhamnosus GKLC1 has been re-
ported to reduce cisplatin-induced chronic ne phroto xicity in pa-
tients (Tsai et al. 2022 ). These encour a ging r esults fr om the clini-
cal trials suggest that probiotics may have potential benets as a
supportiv e ther a py for cancer patients.
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10 | FEMS Microbiology Reviews , 2023, Vo l. 47, No. 4
Preclinical studies conducted in cell lines or mouse models also
suggest that probiotics may enhance tumor response to treat-
ment. For instance, Lactiplantibacillus plantarum -derived extracel-
lular vesicles have been shown to restore the chemosensitivity of
5-FU-resistant CRC cells (An and Ha 2022 ). Additionally, Akkerman-
sia muciniphila has shown promising results in enhancing the anti-
tumor efcacy of c hemother a py and imm unother a py in immune-
competent mice and is considered a next-generation probiotic
(Luo et al . 2021 ). T hus , probiotics ma y serve as adjuv ant ther a py
for cancer by reducing intestinal toxicity and improving the host’s
anti-tumor r esponses. Notabl y, Nazli et al. r ecentl y conducted
an open-label and single-center pr ospectiv e study (NCT03829111)
demonstrating the potential benets of supplementing the diet of
adv anced r enal cell carcinoma patients receiving dual immune
c hec kpoint bloc kade (Nivolumab plus ipilim umab) with liv e bac-
terial product CBM588 containing Clostridium butyricum (Dizman et
al. 2022 ). Despite the small sample size of this study, patients with
metastatic renal cell carcinoma who received CBM588 achieved
higher objective response rates and prolonged progression-free
survival (Dizman et al . 2022 ). While these ndings are promising, it
is crucial to consider the potential health risks of using probiotics
in imm unocompr omised cancer patients individuall y. Lar ge-scale
clinical trials are needed to evaluate the safety and efcacy of ad-
ministering probiotics during anticancer therapy.
Inhibition of m6A regulators for cancer treatment
There is growing research focused on developing specic in-
hibitors of m6A regulators. For instance, se v er al small molecules
have been identied as potent inhibitors of METTL3, including
UZH1a (Moroz-Omori et al. 2021 ), STM2457 (Yankova et al . 2021 ),
UZH2 (Dolbois et al . 2021 ). Among these, STM2457 has been
shown to inhibit the methyltr ansfer ase activity of METTL3 specif-
icall y and effectiv el y. In pr eclinical studies, the administration of
STM2457 signicantl y impair ed the engr aftment of acute myeloid
leukemia (AML) in mice and prolonged their survival (Yankova et
al . 2021 ). Consistentl y, our r esearc h team has found that treat-
ment with STM2457 reduces the growth of mouse CRC allograft
and enhances the efcacy of anti-PD1 treatment by modulating
anti-tumor imm une r esponse (Chen et al . 2022b ). FTO is also a
potential target for cancer ther a py. Se v er al specic inhibitors of
FTO, suc h as R-2-Hydr oxyglutar ate (R-2HG) (Su et al. 2018 ), Rhein
(Chen et al . 2012 ), FB23-2 (Huang et al . 2019b ), CS1 (Bisantrene) and
CS2 (Brequinar) (Su et al. 2020 ), and MO-I-500 (Zheng et al . 2014 ),
have been identied. Preclinical studies conducted in cell lines
or mouse models have shown that R-2HG, FB23-2, CS1, and CS2
display strong anti-proliferative effects against leukemia (Su et al .
2018 , 2020 , Huang et al . 2019b ). Furthermor e, Rhein has been r e-
ported to suppress the growth of pancreatic cancer and CRC cells
markedly (Yang et al . 2019 , Zhang et al. 2021a ). While these small
molecules targeting the aberrant m6A epitranscriptome in can-
cer hav e demonstr ated potential in cancer treatment, these nd-
ings are based solely on preclinical studies . T herefore , future clin-
ical trials are necessary to assess the safety and efcacy of these
molecules for cancer patients.
T her apeutic potential of combing probiotics and
small molecules targeting m6A regulators for
cancer treatment
Imm unother a py, particularl y imm une c hec kpoint bloc kade ther-
apy, is one of the most promising strategies for cancer treat-
ment. Tw o rst-in-human clinical trials conducted by Baruch et al.
and Davar et al. indicate that the gut microbiota composition
can impact the effectiveness of cancer imm unother a pies (Baruc h
et al . 2021 , Davar et al . 2021 ). In these clinical trials, FMT was
used in metastatic melanoma patients undergoing anti-PD-1 im-
m unother a py. The r esults showed that FMT led to an increase
in benecial bacteria, which was associated with an augmented
anti-tumor imm une r esponse when combined with anti-PD-1
treatment. T hus , it is possible that taking probiotic supplements
could impr ov e the body’s r eaction to cancer imm unother a p y b y
activ ating ada ptiv e imm une r esponses. Lacticaseibacillus casei Shi-
rota and Bidobacterium breve have been shown to promote the
maturation of bone marrow cell-derived dendritic cells (BMDCs)
and recruit mature DCs to the tumor site in mice, where DCs can
secret IL12 to induce T cells accumulation and enhance antitu-
mor immunity (Takagi et al . 2008 , Li et al. 2021b ). In addition, sup-
plementation of Lactiplantibacillus plantarum to mice can increase
CD8 + T cell inltration by secreting acetate (Wang et al. 2022a ).
It is noteworthy that targeting m6A regulators also have the po-
tential to impr ov e the host’s r esponse to cancer imm unother a py
but through distinct mechanisms. Our research team has shown
that targeting METTL3 with STM2457 compromises the ability of
CRC cells to drive the accumulation and suppressive potency of
m yeloid-deri v ed suppr essor cells (MDSCs), leading to sustained
activation and expansion of T cells in mice (Chen et al . 2022b ). Sim-
ilarly, administering an ALKBH5-specic inhibitor in tumor cells
would enhance the efcacy of imm unother a py by inhibiting the
accumulation of suppressive Tre g and MDSCs in mice (Li et al .
2020 ). Intriguingly, depleting ALKBH5 in intrahepatic cholangio-
carcinoma cells has been found to promote PD-L1 mRNA degra-
dation, resulting in enhanced antitumor T- c e l l immunity in mice
(Qiu et al . 2021 ). Building on these ndings, combining the target-
ing of m6A regulators in cancer cells and probiotic supplementa-
tion may lead to a syner gistic effect. Ta r geting m6A r egulators can
enhance the immune response against cancer cells by blocking
imm une-suppr essiv e activity, while pr obiotics may have the po-
tential to prime and activate anti-tumor CD8 + T cells. Nonethe-
less, further studies are needed to determine the optimal combi-
nation dosing and scheduling and the safety and efcacy of this
a ppr oac h in cancer patients undergoing anticancer therapy.
Conclusion and future direction
Recent advances in shotgun metagenomic sequencing and m6A
sequencing have enabled comprehensive proling of the gut mi-
crobiota and host m6A e pitranscriptome, respecti vely. Vari ou s ex-
perimental models, both in vitro and in vivo , have been developed
to study the connection between cancer and the gut microbiota or
m6A, alongside the underlying mechanisms that drive this corre-
lation. Ne v ertheless, the inter actions between the gut microbiota
and host m6A pr ogr am r emain lar gel y unclear and r equir e ex-
tensiv e inv estigations. On the one hand, changes in the gut mi-
crobiota may reshape the host m6A prole and alter the expres-
sion of m6A-modied target genes. On the other hand, these m6A-
modied genes may regulate host defense and inuence gut mi-
crobiota composition. The interplay between the gut microbiota
and RNA m6A modication could potentially inuence cancer de-
velopment by manipulating the cancer cell life cycle and host
anti-tumor immunity. Understanding their interactions will pro-
vide new insights into the mechanistic basis of cancer develop-
ment.
The use of probiotics is potentially benecial to human health.
In preclinical cancer models, probiotics have demonstrated ef-
fectiveness in inducing tumor r egr ession and impr oving surviv al,
both as a standalone ther a py and combined with conventional
Downloaded from https://academic.oup.com/femsre/article/47/4/fuad036/7220014 by The Chinese University of Hong Kong user on 26 July 2023
Su et al. | 11
tr eatments suc h as c hemother a py or imm unother a py. In mouse
models of CRC, Bidobacterium pseudolongum has been found to
enhance the efcacy of ICB (Mager et al. 2020 ). It is worth men-
tioning that a recent study investigated the use of the live bac-
terial product CBM588 as a dietary supplement for patients with
metastatic renal cell carcinoma who wer e r eceiving dual imm une
c hec kpoint bloc kade (Dizman et al . 2022 ). Although the study
had a small sample size, the results sho w ed higher objective re-
sponse rates and prolonged progression-free survival among the
treated patients (Dizman et al . 2022 ). Ther efor e, pr obiotics may
hold promise as a complementary approach to improve host anti-
tumor responses. In addition to probiotics, small-molecule in-
hibitors of m6A regulators have also been developed for cancer
tr eatment. Tar geting m6A r egulators can suppress cancer stem
cell self-r ene wal and cancer cell pr olifer ation while also elicit-
ing robust anti-tumor immune responses in various mouse can-
cer models (Su et al. 2020 , Yank ov a et al. 2021 , Chen et al . 2022b ).
Despite these promising results, it remains unclear how targeting
the m6A writer (METTL3) and erasers (FTO and ALKBH5) could
ac hie v e similar anti-cancer effects . T his ma y be partially due to
their differ ent downstr eam tar gets, and further r esearc h is needed
to elucidate the mechanisms underlying their anti-cancer effects.
Modulating either tumor-intrinsic factors (such as the m6A pro-
gram) or extrinsic factors (such as the microbiota) has been shown
to impr ov e the efcacy of cancer tr eatment and boost anti-tumor
defense mechanisms in preclinical studies. Considering the po-
tential for crosstalk between these factors , it ma y be worthwhile
to explore the synergistic effects of combining probiotics with spe-
cic inhibitors of m6A regulators for cancer tr eatment. Suc h a
combination ther a py could offer a pr omising a ppr oac h to enhanc-
ing the immune response against cancer cells, potentially leading
to impr ov ed outcomes for cancer patients.
Author contributions
HS wrote the manuscript. HC , HCHL, HYC , XTZ, NQ, YFW, MTVC,
and WKKW r e vised the manuscript, and HRC supervised and r e-
vised the paper.
Conict of interest. The authors declared no conict of interest.
Funding
This project was supported by the National Natural Science Foun-
dation of China (NSFC; 82103245, 82272989, 81972576); RGC-GRF
Hong Kong (14111621, 14107321, 14101922); Heath and Medical
Research Fund (HMRF) (18190951, 22210032); and CUHK Direct
Grant for Research (2022.003).
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Recei v ed 22 August 2022; revised 23 June 2023; accepted 28 June 2023
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