Re iew A icle
O al hygiene migh p e en
cance
Osca J. Co de o
∗
, Rub
en Va ela-Cal i~
no
Uni e si y o San iago de Compos ela, Depa men o Biochemis y and Molecula Biology, Campus Vida,
15782 San iago de Compos ela, Spain
∗
Co esponding au ho .
E-mail add ess: [email p o ec ed] (O.J. Co de o).
Abs ac
Many e idences suppo ha species om he Human O al Mic obiome Da abase
such as Fusobac e ium nuclea um o Bac e oides, linked p e iously o
pe iodon i is and appendici is, play a ole in colo ec al cance (CRC), including
me as asis. These ypically o al species a e in asi e anae obes ha o m biofilms
in hei i ulen s a e.
Aspi in (a NSAID) has been ecen ly included in o ou ine CRC p e en ion
a ionale. NSAIDs can p e en he g ow h o neoplas ic lesions by inhibi ing
COX enzymes and ano he se o ecen ly iden ified COX-independen a ge s,
which include he WNT, AMPK and MTOR signaling pa hways, he c oss alk
be ween nucleoli and NF-kB ansc ip ional ac i i y in apop osis, and he
biochemis y o pla ele s. These a e signaling pa hways ela ed o umo -
p omo ing inflamma ion. In his p ocess, pa hogens o simple de egula ion o he
mic obio a play an impo an ole in CRC. Aspi in and o he NSAIDs a e
efficien inhibi o s o biofilm o ma ion and able o con ol pe iodon i is
de elopmen p e en ing inflamma ion ela ed o he mic obio a o he gingi al
issue, so i s seems plausible o include his pa hway in he mechanisms ha
aspi in uses o p e en CRC.
We p opose a gumen s sugges ing ha cu en o al hygiene me hods and o he
u u e de elopmen s agains pe iodon i is migh p e en CRC and p obably o he
cance s, alone o in combina ion wi h o he op ions; and ha he
Recei ed:
16 May 2018
Re ised:
26 Sep embe 2018
Accep ed:
19 Oc obe 2018
Ci e as: Osca J. Co de o,
Rub
en Va ela-Cal i~
no.O al
hygiene migh p e en cance .
Heliyon 4 (2018) e00879.
doi: 10.1016/j.heliyon.2018.
e00879
h ps://doi.o g/10.1016/j.heliyon.2018.e00879
2405-8440/Ó2018 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
mul idisciplina y s udies needed o p o e his hypo hesis migh be ele an o
cance p e en ion.
Keywo ds: Mic obiology, Cance esea ch, E idence-based medicine, Den is y
1. In oduc ion
1.1. Inflamma ion and immuni y in cance
Accumula ion o mu a ions in genes encoding ei he homeos a ic egula o s o DNA
misma ch- epai ac o s, p edominan ly in s em cells becoming CSCs (cance s em
cells) is he leading e en in ca cinogenesis [1,2]. The c ucial ole o he immune
sys em in his p ocess, howe e , didn’ came in o wo ldwide a en ion un il Hanahan
& Weinbe g’s upda e o hei “Hallma ks o Cance ”in 2011 [3]. These Hallma ks
ocused on immunosupp ession, a be e -known mechanism, on one hand bu also in
inflamma ion as an enabling cha ac e is ic o umo g ow h [4].
Inflamma ion and immune sys em a e ac i a ed o elimina e pa hogens and non-sel
molecules, o o con ol a leas hei dissemina ion o sys emic coloniza ion o he o -
ganism, bu he same physiological esponses induce epai mechanisms ha eco e
he unc ion and in eg i y o issues in an o gan wi h umo [5]. Mo eo e , he inflam-
ma ion and immuni a y cellula infil a es esponsible o umo ini ia ion and ea ly
p og ession a e he same ha can des oy he umo s be o e immunosupp ession
[6,7]. The e o e, bo h hallma ks a e wo sides o he same coin.
In cance , he e a e many possible o igins o he inflamma o y esponse. The inflam-
ma ion is called in insic when he mechanisms d i ing he cell ans o ma ion and
cance ini ia ion, o e exp ession o oncogenes (such as Ras, Myc, S c, o RET) and
mic oRNAs (such as mi-R155), damage and mu a ion o DNA, and eac i e oxygen
species (ROS) p oduc ion in mi ochond ia, also ac i a e a p o-inflamma o y p o-
g am ( he p oduc ion o chemokines, in e e ons (IFNs) and issue ea anging en-
zymes) in he p ope al e ed cell [4,5,6]. Ex insic inflamma ion is media ed, by
con as , by infil a ing immune cells [4,5,6]. Again DNA o mi ochond ial damage,
oncogene ac i a ion, o endoplasmic e iculum (ER) s ess and oxida i e damage o
he al e ed cell, in addi ion o he many signals o cellula s ess gene a ed by he
damage o he malignan cell-su ounding issue (because o mechanical, chemical
o i adia ion causes, o gene ic synd omes, hypoxia, he excessi e empe a u e, o
nu ien s, o by senescence), se e o ac i a e ha infil a ion.
Ch onic inflamma ion affec s all phases o ca cinogenesis. In a eedback loop, by he
gene a ion o mu a ions, modifica ions o unc ional p o eins o epigene ic mechanisms,
i d i es cell ans o ma ion, pa icula ly when a s em cell is affec ed and become CSCs
[3,4,8,9]. A he same ime, mo e hema opoie ic inflamma o y cells a e ec ui ed on he
de eloping cance . The leukocy e infil a e includes neu ophils, dend i ic cells, mac o-
phages and lymphocy es, all o hem capable o sec e ing hose cy okines, ROS,
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memb ane pe o a ing agen s, g ow h ac o s and cellula p oduc s ha con ibu e o he
inflamma o y milieu p esen in he en i onmen o a de eloping umo , a o ing he u-
mo g ow h and, la e , dissemina ion o he ans o med cells [5,10,11].
1.2. Molecula mechanism o inflamma ion
The immune cells ec ui ed o he umo exp ess mul iple specialized amilies o
pa e n ecogni ion ecep o s (PRRs) loca ed a he plasma memb ane, wi hin in a-
cellula esicles, and in he cy osol. The mos known a e he Toll-like ecep o s
(TLRs), NLRs ( om Nod, nucleo ide binding oligome iza ion domain, -like ecep-
o s), PYHIN (py in and HIN domain) ecep o s, C- ype lec in ecep o s, RLRs
(RIG-I, e inoic acid inducible gene-I, -like ecep o s), he oligoadenyla e syn hase
(OAS) -like ecep o s, he ela ed p o ein cyclic GMP-AMP syn hase (cGAS), and
DNA senso s such as STING (s imula o o in e e on gene).
Many o hem assemble o o m signaling complexes, including inflammasomes
ini ia ed by NLR and PYHIN ecep o s and ela ed o cellula oxida i e s ess, he
myddosomes ini ia ed by TLRs and he In e leukin-1 ecep o (IL-1R) in ol ing
among o he s he MyD88 p o ein, and he mi ochond ial an i i al signaling p o ein
(MAVS) CARD filamen ini ia ed by RIG-1 [10,12].
To no e, hese “inna e ecep o s”, a leas TLR 2 and 4 and NLRP3, ha e been
ecen ly iden ified also in he p ope umo igenic al e ed cells o in me abolic issues,
adipocy es, myocy es, li e o panc eas (see below how sys emic me abolic al e -
a ions such as obesi y o diabe es also cause inflamma ion) [13,14] in wha may
ep esen eedback loops.
These ecep o s a e e y p omiscuous by defini ion, i.e. one pa icula o a e y simila
ligand may bind o diffe en ecep o s in he same o in a diffe en cell. The e o e, hey
iden i y DAMPS (damage-associa ed molecula pa e ns) as hose endogenous
componen s eleased om cells damaged by molecula s ess [10,11,12], bu hey
we e fi s iden ified as ecep o s o PAMPs (pa hogen-associa ed molecula pa -
e ns) o ecep o s ha iden i y componen s om mic obial pa hogens, his ac o
pa icula in e es o la e con en o he e iew. Recen e idence indica e ha he ma-
jo DAMP d i ing hos an i umo immune esponses is umo -de i ed DNA, sensed by
he STING pa hway in a ce ain popula ion o in a umo al DCs, d i ing he p oduc-
ion o ype I IFNs and he esul ing downs eam T cell esponse ( e iewed in [15]).
The same signal ansduc ion pa hway, adap o p o ein MyD88, is sha ed by many o
hese ecep o s. Al hough in oden models, MyD88 has shown a p o ec i e ole in he
de elopmen o colonic umo s, MyD88 inna e immune signaling and specific mic o-
RNAs mechanis ically con ol CRC chemo esis ance (see nex subheading). Likewise,
he same inflamma o y media o s induce he ansc ip ion ac o s nuclea ac o -kB
(NF-kB) and signal ansduce and ac i a o o ansc ip ion-3 (STAT-3) [1,8-16].
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The fi s one seems pa icula ly ele an o gas oin es inal cance de elopmen [5]
and, in ac , NF-kB signaling pa hway has been iden ified as a COX-independen
a ge o NSAIDs (as e iewed la e ). STAT-3 o umo , s omal and immune cells
is ac i a ed by many o ac o s eleased by he umo and umo s oma, o example
VEGF, in e leukin-6 (IL-6), IL-10, IL-11, o IL-23, a e ansc ip ionally egula ed
by STAT-3 egula es ansc ip ionally se e al o hese cy okines gene a ing a posi-
i e eedback loop [17]. In addi ion o he ca cinogenesis men ioned abo e, hey also
allow he umo o p og ess and me as asize by es ablishing a umo al mic oen i on-
men ( o example, angiogenesis), including he immunosupp essi e mechanisms
ha p e en he effec i e immune su eillance.
Finally, i mus be emphasized ha all hese inflamma o y mechanisms also affec
he esponse o he apy [1,15,18].
1.3. Gu mic obio a and CRC
As IBD pa ien s dwi h C ohn’s disease o ulce a i e coli isdha e a se e al- old
inc eased suscep ibili y o CRC p incipally, hey we e conside ed ypical examples
o coli is-associa ed cance (CAC), he fi s inflamma ion- ela ed cance [19,20]. In
his cance , he in es inal epi helial ba ie al eady includes in he heal hy indi idual
complex molecula and cellula in e ac ions o commensal mic obio a wi h he
epi helial, mesenchymal and immune cells o achie e in es inal homeos asis, egen-
e a ion, and healing ( e iewed in [21]). The gu mic obio a composi ion can be
al e ed by he p esence o a specific bac e ial species o modula ed by an en i on-
men al change. The p esence o diffe en na u al mu agens and ca cinogens, o a
me abolism p o ided by he commensal flo a ha equi es o can be egula ed by
a specific enzyma ic ac i i y, o he s aigh o wa d in e ac ion o he bac e ia o
hei p oduc s wi h hose inna e ecep o s o senso s desc ibed abo e, all can
gene a e ei he p o- o an i-inflamma o y effec s ( e iewed in [11,18]). A he begin-
ning o he millennium he fi s expe imen al CAC models mimicking human CRC
in oden s clea ly es ablished ha immune cells, cy okines and he STAT-3 and NF-
kB ansduc ion pa hways all pa icipa e in he induc ion o inflamma o y coli is
( e s [8,10,11,12]).
The IBD pa ien s also show inc eased suscep ibili y o lymphomas/leukemias and
hepa oca cinomas among o he umo s, which sugges s ha he pa hological in es i-
nal inflamma ion igge ed by he commensal mic obio a is esponsible o he local
umo -p omo ing effec s bu also, h ough he immune sys em, o ha e addi ional
deep sys emic effec s [11,18,21]. In addi ion, la e on he ex , e iewed da a sug-
ges new oles o he mic obio a, o example in CRC me as asis.
Likewise, mos o he known main isk ac o s o CRC, obesi y, lack o exe cise,
a - ich die s, use o alcohol and obacco [8,22], a e ela ed wi h nu i ion, being
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en i onmen al agen s ha can al e he commensal mic obio a [7,11,13,14,15,16].
As he wide geog aphical a ia ion in he incidence o CRC a e los in mig a ing
popula ions wi hin one gene a ion, i is likely ha hese isk ac o s a e esponsible
o CRC in he hos popula ions [22,23].
Two en e obac e ial species, Klebsiella pneumoniae and P o eus mi abilis, pa ici-
pa ed in he de elopmen o coli is and cance in TRUC (immunodeficien Tbe
/
and Rag2
/
ulce a i e coli is) mice [24,25], howe e , hey didn’ induce coli is
alone bu modi y ei he he heal hy gu mic obio a composi ion o i s physiology,
ac ing in syne gy o ac i a e colon inflamma ion.
Ac ually, ano he ac sugges ing he ole o he commensal flo a in CRC is ha
ge m ee animals [26], o ea ed wi h mildly coli ogenic bac e ium Bac e oides
ulga us ( he azoxyme hane (AOM)- ea ed Il10
L/L
model) [27], do no de elop
umo s. Helicobac e hepa icus in ec ion o he gu enhanced small in es ine and
colon cance in APC
min/þ
mice, bu also mamma y adenoca cinoma [28] o hep-
a oca cinomas [29], hus showing sys emic umo -p omo ing effec s. Likewise,
in ec ion wi h Helicoba e pylo i in humans is an example ha a single bac e ial
species can igge ca cinogenesis, in his case gas ic cance [30].
O he pa hogenic species iden ified while elucida ing molecula mechanisms
affec ed by he mic obio a we e he en e opa hogenic Bac e oides agilis (ac i-
a ed WNT and NF-kB signalling pa hways on he ca cinogenic cells) and Es-
che ichia coli, also associa ed wi h inc eased isk o CRC ( h ough ac ions
ha down- egula e misma ch- epai genes, a leas in i o [11,12,13,14,15,
16,17,31,32]). This en e ic mic obio a also influences he T helpe 17
(Th17) esponse [33,34] and APC, in pa icula dend i ic cells (DCs), ac i a ion
[24].
Mo e ecen ly in Nl p6
L/L
mice he expansion o o he anae obic genus o bac-
e ial phyla Bac e oide es (like Bac e oides), P e o ellaceae ( adi ionally ela ed
o pe iodon al disease), and TM7 (Saccha ibac e ia, in e es ingly, ecen ly
cul u ed om he human o al ca i y)in he ecal mic obio a co ela ed wi h sus-
cep ibili y o coli is [35,36]. The e o e, a leas he NLRP6 ecep o o he in-
flammasome in he inna e sys em [10,12] also egula es colonic mic obial
ecology.
Howe e , al hough IBDs a e he main isk ac o o CRC, he ela i e inc eased isk
o colo ec al cance in hese pa ien s is only h ee old wi h espec o he con ol
popula ion, he umo s a e gene a ed a e many yea s o in es inal pa hology, and
he cumula i e li e ime isk is 18% [19,20], i.e. mos CRCs a e no ela ed o any
p e-exis ing ob ious in es inal inflamma o y disease.
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2. Main ex
2.1. Gu mic obio a o o al o igin and biofilms in CRC
In pa allel, high- h oughpu DNA sequencing de elopmen s igni ed he iden ifica-
ion o mic obio a ha affec ed he p og ession o CRC, no only in he expe i-
men al animal models men ioned abo e [37] bu also in humans (in biopsies o
s ool). The ma ked o e - ep esen a ion o Fusobac e ium nuclea um sequences in
CRC umo s ela i e o con ol specimens was a s iking disco e y: Fusobac e ia
a e a e cons i uen s o he ecal mic obio a, bu had been cul u ed p e iously
om biopsies o inflamed gu mucosa [21,38], and F. nuclea um in pa icula is
an in asi e anae obe ha had been linked p e iously o pe iodon i is and appendi-
ci is, bu no o cance .
This and he o he anae obic species o he same o simila gene a including Bac e -
oides, o ypically o al species such as some Selenomonas,P e o ella, and Pa imo-
nas mic a and Pep os ep ococcus s oma is, some men ioned in he p e ious
subheadings, a e species included in he Human O al Mic obiome Da abase and
also ound in he gu mic obio a in a significan pe cen age o CRC, suppo ing a
ole o he agg ega e o hem in CRC [39,40,41], al hough no mic obial ea u e
was uni e sally p esen in he umo s. This s o y is e y simila o he ole ha bac-
e ia a e playing in he pa hogenesis o au oimmune heuma oid a h i is, opening
he doo o he s udy o au o-an ibodies agains hese bac e ia bo h o diagnos ic
uses and mechanis ical s udies [42].
In e es ingly, hese a e bac e ia capable o o ming biofilms. Biofilm s uc u es a e a
consis en ea u e o igh -sided (p oximal) (al hough no le -sided, dis al) CRC.
They a e cons i u ed by symbion s o Bac e oides agilis and o he men ioned
o al pa hogens, ha ing umo igenesis capaci y in he mucus laye o he gu [41]
by dis up ing he no mal mucosal ba ie , changing he issue homeos asis, and
inducing inflamma ion [43,44]. In addi ion, hese s uc u es con ibu e o he poly-
amine me aboli e pool al e ing he cance me abolome and inducing colon cance
g ow h and p og ession [43,45]. Howe e , bac e ia o iginally s udied in o al bio-
films we e also de ec ed in heal hy indi iduals. I was ound ha a high abundance
o Lachnospi aceae a oided he coloniza ion o colonic issue by o al-like bac e ial
ne wo ks, sugges ing ha ce ain mic obio a ypes can p o ec agains CRC, possibly
by con e ing coloniza ion esis ance. In e es ingly, hese p o ec i e ypes migh be
dependen o a heal hy die [39].
Some people expec ed a u u e simila o ha o Helicobac e pylo i and s omach
cance , and ecen ly a mouse model o CRC showed ha he an ibio ic me onida-
zole pa ially impai ed colo ec al umo g ow h [30]. Me onidazole is used o
some geni ou ina y in ec ions, bu he a ge in ha s udy was Fusobac e ium
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nuclea um [30]. One conce n o his s udy, apa o he lack o a F. nuclea um spe-
cific an ibio ic is ha o he playe s a e also in ol ed.
A no el s udy in humans has shown ha he abundance o F. nuclea um in eces is
s ongly associa ed wi h he p esence o CRC bu no wi h he p esence o ad anced
adenomas o non-ad anced adenomas, and no associa ion wi h die a y o li es yle
habi s was ound [46]. In o he s udy [47], bac e ial biofilms ound in pa ien s wi h
amilial adenoma ous polyposis showed inc eased in e leukin-17 and DNA damage
in colonic epi helium and as e umo onse and g ea e mo ali y when ans-
plan ed o mice. Howe e , hei p edominan species a e Esche ichia coli and Bac-
e oides agilis [47]. These obse a ions suppo he hypo hesis ha
Fusobac e ium is a passenge ha mul iplies when he umo en i onmen is a o -
able a he han a causal ac o in umo igenesis. Recen e iews [48,49] discuss
his issue, concluding ha bo h ini ia ion and p og ession o CRC equi e he o ga-
niza ion o hese highe -o de s uc u es o bac e ial communi ies e med biofilms
[50]. Flynn e al ha e p oposed a model in which ini ial changes in he no mal
gu mic obio a allow o al bac e ia such as F. nuclea um o colonize he gu mucosa
dis up ing he epi helial ba ie , and o o m biofilms wi h ea ly and la e-colonizing
mic obes; and he pe sis en s a e o inflamma ion in he colon sus aining bo h he
biofilm and he umo igenesis [50]. In e es ingly, al hough biofilm o ma ion has
been explained as a coope a i e en e p ise o s ains and species o a common
goal, biofilm o ma ion should be unde s ood as a esponse o ecological compe i-
ion [51].
S ikingly, he p esence o F. nuclea um in CRC has been ela ed o he p ocess o
me as asis, a leas o he li e [30] and lymph node [38]. Al hough he mechanism is
unknown, hese bac e ia migh in e ac wi h he me as a ic cells [30] and no only be
p esen in he mucosal mic obio a whe e hey can adhe e o epi helial umo cells o
be ound inside he cells [30,52]. Ve y ecen ly i has been sugges ed ha F. nucle-
a um o ches a es on umo cells a molecula ne wo k o he TLR4 and MyD88
inna e immune signaling as well as specific mic oRNAs ha ac i a e he au ophagy
pa hway and mechanis ically con ol CRC chemo esis ance [52].
Likewise, he e a e ano he examples o biofilms associa ed wi h cance , such as Sal-
monella yphi and de elopmen o gallbladde cance [53], and o he s should be ex-
pec ed in he mul iple o gan sys ems spanning hese mic obial ne wo ks [54].
In his sense, he use o p obio ics should also be es ed o a hypo he ical long- e m
effec on me as asis o ecu ence in pa ien s wi h hese CRC- ela ed mic obio a [51,
55]. Eme ging human mic obiome in e en ion s a egies ha e been ecen ly e-
iewed [18,56,57]. In addi ion, con en ional chemo he apeu ic egimens migh
be affec ed by his CRC mic obio a and/o will modi y i .
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2.2. Obesi y, me abolic synd ome, cance cachexia, s ess and
mic obio a
Recen s udies ha e confi med he associa ion be ween obesi y and cance suscep i-
bili y and su i al a e de ec ion, including CRC [58,59] despi e he so-called
“obesi y-pa adox”[60]. The e a e s ill many challenges explo ing he associa ion
o cance wi h o e weigh and obesi y, bu consensus exis s abou ha long- e m e -
o s in p e en ion should emain ocused no only on u he educ ion o smoking
bu also engaging in heal hy li es yles, balanced die s and egula physical exe cise
[58,61,62].
Me abolic synd ome is a con o e sial concep associa ed wi h abdominal obesi y,
blood lipid diso de s, inflamma ion, insulin esis ance o ull-blown diabe es, and
inc eased isk o de eloping ca dio ascula disease. Abdominal obesi y is he
mos p e alen mani es a ion o me abolic synd ome and a ma ke o ‘dys unc ional
adipose issue’[63] o me aflamma ion [64]. This me abolic inflamma o y s a e is
ch onic and low-g ade, and has been ound no only in adipocy es bu also in s omal
and immune cells o me abolic issues ha include li e , muscle, panc eas o b ain,
in esponse o an excess o nu ien s and ene gy [64]. Decades o esea ch ha e iden-
ified he complex signaling ne wo ks be ween immune esponse and me abolism,
and he cellula and molecula e en s ha ake place in si ua ions o al e ed nu ien
o ene gy flows [7,13,14,15,16,65,66]. Main aining his delica e balance is
c ucial o heal h.
How isk ac o s in gene al in e ac wi h commensal flo a in colo ec al ca cinogen-
esis has been e iewed [7,10,21]. A ecen e iew exposes how obesi y al e s he
mic oen i onmen o adipose issue affec ing he adipokine sec e ome, wi h ac ions
on emo e issues [67]. Mo eo e , adipocy es, like umo cells and mac ophages,
also exp ess TLR 2 and 4. These ecep o s in adipose issues can be eached no
only by nonbac e ial agonis s such as die sa u a ed a y acids, bu also by he
commensal flo a o hei bac e ial p oduc s such as LPS and lipopep ides, and ac i-
a e hem ( e in [11,13,21,68,69]).
Obesi y is also associa ed wi h changes in he composi ion o he gu mic obio a.
O e all, bac e ial di e si y o obese indi iduals is educed, in he a e be ween
phylum (an inc ease in Fi micu es and a co esponding dec ease in Bac e oide es),
and in he ep esen a ion o genes and me abolic pa hways ha a o ene gy ha es
in bac e ia [70].
In es inal mic obio a imbalance (dysbiosis o dismic obism) has been sugges ed as
he link be ween IBD, CRC and Type 2 diabe es (T2D) [22,40,41,42,71]. How-
e e , he a i al o he concep o en e o ype sugges s ha his knowledge will be
enhanced soon [72,73]. Al hough we did no find any epo linking gu
8h ps://doi.o g/10.1016/j.heliyon.2018.e00879
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Fusobac e ium nuclea um wi h obesi y, i has been ecen ly epo ed a ela ionship
o obesi y wi h he subgingi al mic obio a in pe iodon al disease [74].
Inflamma ion and ene gy me abolism a e linked in he was ing synd ome, also called
cance cachexia, p esen in many pa ien s o ce ain ypes o cance a ad anced
s ages [75,76,77]. Fo example, li e me abolism in cachexia leads o supp ession
o an i umo immuni y mainly h ough IL-6 [78]. Impo an ly, his axe o in e ac i e
me abolic pa hways and immune sys em can be a ge ed by psychological s ess,
pa icula ly hose pa hways media ed by he sympa he ic ne ous sys em [79]. Fo
a gene al e iew o he igh coo dina ion be ween he immune and ne ous sys ems
see he e iew by Talbo S e al [80].
The cen al ne ous sys em also influences he commensal mic obio a h ough
se e al pa hways o he gas oin es inal physiology, o example neu o ansmi e s
affec ing epi helial unc ions such as cell pe meabili y and hei p oduc ion o mucus
and an ibac e ial pep ides. Con e sely, gu mic obio a is in e ac ing wi h local and
sys emic inflamma o y and immune cells and ac i a ing he p oduc ion o inflamma-
o y me aboli es such as cy okines ha may each he b ain and affec beha io [81,
82,83]. This bidi ec ional axe ne ous sys em-in es inal mic obio a can also be,
he e o e, a ge ed by s ess. S ess is likely o al e he inna e immune esponses
o pa hogens gene a ing dysbiosis. Al e a ion o he gu en e o ypes can modi y
he inflamma o y en i onmen and, wi h he consequen eedback loop, affec he en-
e gy me abolism, no only in he umo bu also sys emically.
2.3. CRC p e en ion by nons e oidal an i-inflamma o y d ugs
A e many s udies had shown ha aspi in and o he non-s e oidal an i-inflamma o y
d ugs (NSAIDs) used in a daily basis o ex ended pe iods (a leas 5 yea s o aspi in
use) educed he isk o CRC o polyp ecu ence, and a ecommenda ion agains i s
use o he p e en ion o CRC by he U.S. P e en i e Se ices Task Fo ce
(USPSTF) in 2007 [84] because o he conside able damage induced o s omach
and in es inal lining, o e en b ain bleeding [85], he USPSTF e e sed ha posi ion
in 2015 [86,87]. Low-dose aspi in use among ce ain subg oups o adul s dis in-
guished aspi in as he fi s pha macologic agen o chemop e en ion o cance in
a popula ion no cha ac e ized as high isk [88,89]. Addi ional esea ch in o he e -
ec o long- e m aspi in use on he o e all incidence o cance acco ding o a ange
o doses and by subg oups, including age, sex, baseline cance isk, o como bid
condi ions [90,91], as well as on he addi ional impac o aspi in use in he se ing
o CRC sc eening, including colonoscopy al eady associa ed wi h a significan ly
lowe isk o CRC [89,92], was add essed in a 2016 s udy by wo la ge p ospec i e
U.S. coho s udies [93]. Regula aspi in use could p e en many housands o
gas oin es inal umo s pe yea only in he USA, aking in o accoun ha only
58% o he eligible popula ion had unde gone an accep ed sc eening op ion [94,
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