Evaluating the anti-inflammatory and antioxidant efficacy of complementary andalternative medicines (CAM) used for management of inflammatory bowel disease:a comprehensive review

Redox Repo
Communica ions in F ee Radical Resea ch
ISSN: (P in ) (Online) Jou nal homepage: www. and online.com/jou nals/y e 20
E alua ing he an i-inflamma o y and an ioxidan
efficacy o complemen a y and al e na i e medicines
(CAM) used o managemen o inflamma o y bowel
disease: a comp ehensi e e iew
Sia Shin , Siqi Chen , Kangzhe Xie , Suehad Abou Duhun & Tama a O iz-
Ce da
To ci e his a icle: Sia Shin , Siqi Chen , Kangzhe Xie , Suehad Abou Duhun & Tama a O iz-
Ce da (2025) E alua ing he an i-inflamma o y and an ioxidan efficacy o complemen a y
and al e na i e medicines (CAM) used o managemen o inflamma o y bowel disease: a
comp ehensi e e iew, Redox Repo , 30:1, 2471737, DOI: 10.1080/13510002.2025.2471737
To link o his a icle: h ps://doi.o g/10.1080/13510002.2025.2471737
© 2025 The Au ho (s). Published by In o ma
UK Limi ed, ading as Taylo & F ancis
G oup
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REVIEW ARTICLE
E alua ing he an i-in lamma o y and an ioxidan e icacy o complemen a y and
al e na i e medicines (CAM) used o managemen o in lamma o y bowel disease:
a comp ehensi e e iew
Sia Shin
a
, Siqi Chen
b
, Kangzhe Xie
b
, Suehad Abou Duhun
b
and Tama a O iz-Ce da
b,c
a
Sydney Medical School, Facul y o Medicine and Heal h, The Uni e si y o Sydney, Sydney, Aus alia;
b
School o Medical Sciences, Facul y o
Medicine and Heal h, The Uni e si y o Sydney, Sydney, Aus alia;
c
Depa amen o de Ci ología e His ología No mal y Pa ológica, Facul ad de
medicina, Uni e sidad de Se illa, Se ille, Spain
ABSTRACT
In lamma o y bowel disease (IBD) is a ch onic au oimmune condi ion whose pa hogenesis has no
been ully elucida ed, and cu en ea men s a e no de ini i e and o en ca y se e al side e ec s.
The Complemen a y and Al e na i e Medicine (CAM) o e s a new app oach o con en ional
medicine. Howe e , hei clinical applica ion and mechanisms emain limi ed.
Objec i e: The aim o his e iew is o e alua e he an i-in lamma o y, impac on mic obio a and
an ioxidan e icacy o cu en ly a ailable CAM o IBD.
Me hods: The li e a u e collec ion was ob ained om Google Schola , MEDLINE, PubMed and Web o
Science (WOS). S udies in bo h human and animal models, published in English language be ween
2018 and 2024, we e selec ed. Six y-se en s udies we e included in he cu en e iew a e
inclusion and exclusion sc eening p ocesses.
Resul s: Mos ly, s udies showed signi ican an i-in lamma o y, gu mic obio a es o ing, an ioxidan
e ec s o polyphenols, polysaccha ides, emodin, sho -chain a y acids (SCFA; including bu y a e,
p opiona e and ace a e), and p obio ics al hough some con as ing esul s we e no ed. Cu en
e idence shows ha polyphenols exhibi he mos consis en esul in alle ia ing IBD
pa hophysiology, p ima ily due o hei signi ican SCFA-ele a ing e ec .
Discussion: Fu u e s udies may ocus on human s udies, na owing down on indi idual ac o s which
may change na u al p oduc ’s me abolism. Fu he esea ch s udies a e also essen ial o ob ain
he apeu ic ecommenda ions.
Abb e ia ions: 4- HNE, 4-hyd oxynonenal; 5-ASA, 5-aminosalicyla es; ABX, an ibio ic; ACAT1, ace yl-
CoA ace yl ans e ase 1; AIEC, a s ain o adhe en -in asi e E. coli; AKT, p o ein kinase B; AMP,
a ac ylodes mac ocephala Koidz polysaccha ide; AOM, azoxyme hane; AOS, algina e
oligosaccha ides; APS3a, non-honey-p ocessed As agalus polysaccha ides; A g-1, a ginase 1; ASC,
apop osis-associa ed speck-like p o ein con aining a caspase ec ui men domain; ATB, an ibio ic
p ope ies; BCFA, b anched-chain a y acids; BDH1, 3-hyd oxybu y a e dehyd ogenase I; BHB, B-
hyd oxybu y a e; BI, bilobalide; BMDMs, bone ma ow-de i ed mac ophages; CA, ca eic acid;
CACC, coli is-associa ed colo ec al cance ; CAM, complemen a y and al e na i e medicine; cAMP,
cyclic AMP; CAT, ca alase; CC, colo ec al cance ; CCL2, chemokine ligand 2; CD, C ohn’s disease;
CFU, colony- o ming uni s; CGA, chlo ogenic acid; Chil3, chiinase-like p o ein; Ci H3, ci ullina ed
H3; CLP, cecal liga ion and punc u e; COVID, co ona i us disease-2019; COX-2, cyclooxygenase-2;
CP, calp o ec in; CRP, C- eac i e p o ein; CXCL-1, chemokine ligand 1; CXCR2, in e leukin 8
ecep o ; Cy, cyclophosphamide; Dac 3, dishe elled binding an agonis o be a ca enin 3; DAI,
disease ac i i y index; DAMPs, damage associa ed molecula pa e ns; DAO, diamine oxidase;
DAPP, d ied apple peel powde ; DCA, dichlo oace a e; DCs, dend i ic cells; DNBS, dini obenzene
sul onic acid; DO, Dend obium o icinaleon; DSS, dex an sodium sul a e; E. coli,Esche ichia coli; EA,
ellagic acid; EC, Eucheuma co onii; EcN, Esche ichia coli Nissle; EGCG, epigalloca echin-3-galla e;
EGF, epide mal g ow h ac o ; EMO/PSM NPs, emodin-loaded poly (DL-lac ide-co-glycolide)/
Eud agi S100/mon mo illoni e nanopa icles; Emodin, 1,3,8- ihid oxy-6-me hyl-an h aquinone;
EPS1-1, Rhizopus nig icans ex acellula polysaccha ide; ER, endoplasmic e iculum; ERK,
ex acellula signal- egula ed kinase; F/B, Fi micu e o Bac e oide e; F12, p obio ic mic opa icles;
FA, e ulic acid; FCP, ecal calp o ec in; FFAR, ee a y acid ecep o s; FMT, ecal mic obio a
ansplan ; FOXO3, o khead box O3; GM-CSF, g anulocy e-mac ophage colony-s imula ing ac o ;
GPCRs, G p o ein-coupled ecep o s; GSDMD, Gasde min D; GSH-PX, glu a hione-PX; GSH,
glu a hione; GSP, g ape seed p oan hocyanidin; GST, glu a hione-S- ans e ase; H
2
O
2
, hyd ogen
pe oxide; H
2
S, hyd ogen sul ide; HAPS3a, honey-p ocessed As agalus polysaccha ides; HAW1,
C a aegis pinna i ida (Haw ho n); HC, heal hy olun ee s; HDAC, his one deace ylase; HE, He icium
e inaceus; HMGB1, high mobili y g oup p o ein B; HMGCS2, 3-hyd oxyme hylglu a yl-CoA syn hase
2; HO-1, heme oxygenase-1; hu-FMT, human ecal mic obio a ansplan a ion; i. , in a- ascula ;
IBD, in lamma o y bowel disease; IC, inde e mina e coli is; IFN, in e e on; IKK, inhibi o y Kappa B
kinase α; IL, in e leukin; INCLD, in e na ional coho on li es yle de e minan s; iNOS, inducible ni ic
KEYWORDS
In lamma o y bowel disease;
polyphenols;
polysaccha ides; sho -chain
a y acids; p obio ics;
mic obio a; an ioxidan s;
an i-in lamma o y
© 2025 The Au ho (s). Published by In o ma UK Limi ed, ading as Taylo & F ancis G oup
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dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. The e ms on which his a icle has been published allow he pos ing o he Accep ed Manu-
sc ip in a eposi o y by he au ho (s) o wi h hei consen .
CONTACT Tama a O iz-Ce da [email p o ec ed] Depa amen o de Ci ología e His ología No mal y Pa ológica, Facul ad de medicina, Uni e sidad de Se illa,
Se ille, Spain
REDOX REPORT
2025, VOL. 30, NO. 1, 2471737
h ps://doi.o g/10.1080/13510002.2025.2471737
oxide syn hase; JAK2, janus kinase 2; JNK, c-Jun N- e minal kinase; LA-GOS, Lupinus albus α-galac o-
oligosaccha ides; Lac@HDP, Lac obacillus acdiphilus@Hyalu onic acid g a ed wi h dopaine p o ec ed
by phenylbo ic acid; LC3, mic o ubule-associa ed p o ein 1A/1B-ligh chain 3; LC3II/I, iso o m II/I o
mic o ubule-associa ed p o ein 1 ligh chain 3; LCN2, lipocalin-2; LPF, li e P. euden eichii KCTC
1063; LPO, lipid pe oxidase le el; MAPK, mi ogen ac i a ed p o ein kinase; MCP-1, monocy e
chemoa ac an p o ein-1; MDA, malondialdehyde; Mip2, mac ophage in lamma o y p o ein 2;
mix-sup, supe na an mix u e; MPO, myelope oxidase; M ., mi ochond ia; MUC, mucin; MYD88,
myeloid di e en ia ion p ima y esponse 88; n/i, no in o ma ion p o ided; NaB, sodium bu y a e;
NE, neu ophil elas ase; NET, neu ophil ex acellula ap; NF-κB, nuclea ac o kappa ligh chain
enhance o ac i a ed B cells; NFATC, nuclea ac o o ac i a ed T cells; NK, na u al kille ; NKU556-
Fe, Lac obacillus alimen a ius NKU556 i on-en iching om Chinese e men ed ood; NLRP3,
nucleo ide-binding domain, leucine- ich con aining amily, py in domain con aining 3; NO, ni ic
oxide; NO
2
, ni i e; NO
3
, ni a e; Noni-PLS, isola ed polysaccha ide om Mo inda ci i olia Linn; NPs,
nanopa icles; NQO1, NADH-quinone educ ase; N -2, nuclea ac o e y h oid 2- ela ed ac o 2;
Ol 78, ol ac o y ecep o 78; ORY, ood-de i ed o yzanol; OTUs, ope a ional axonomic uni s; p-IkB,
phospho-I kappa B kinase; PCC, p o ein ca bonyl compounds; PCNA, p oli e a ing cell nuclea
an igen; PDGF, pla ele -de i ed g ow h ac o ; Poly P, long-chain polyphospha e; PPM, pa s pe
million; PRISMA, p e e ed epo ing i ems o sys ema ic e iew and me a-analysis; PRR, pa e n
ecogni ion ecep o s; P -Lipid@EcN, liposome-coa ed Esche ichia coli Nissle (EcN) 1917; PYY,
pep ide YY; Redox, educ ion–oxida ion; RGal, Rhamnogalac u onan; RNS, eac i e ni ogen
species; ROS, eac i e oxygen species; SCFA, sho -chain a y acids; SDEA, Selaginella doede leinii
Hei on e yl ace a e; SFE, Sopho a la escens ex ac ; sIgA, sec e o y immunoglobulin A; SIRT1,
Si uin 1; SOD, supe oxide dismu ase; SPDEF, SAM poin ed domain con aining ETS ansc ip ion
ac o ; SPFC, supe na an o he P. euden eichii cul u e; SRB, sul a e- educing bac e ia; STAT3,
signal ansduce and ac i a o o ansc ip ion 3; T-AOC, o al an ioxidan capaci y; TED, ans-
emodin dian h ones; TFF-3, e oil ac o 3; TFPS, Camellia sinensis L. pec ic he e opolysaccha ides;
TGF-β: ans o ming g ow h ac o -β; TLR: oll-like ecep o s; TNBS: ini obenzene sul onic acid;
TNF-α: umo nec osis ac o ; T eg; T egula o y; UC: ulce a i e coli is; UCDAI: UC disease ac i i y
index; U oA: U oli hin A; VEGF: ascula endo helial g ow h ac o ; W: week; ZAVE: Zhenjiang
a oma ic inega ex ac ; ZO-1: zonula occludens 1
In oduc ion
In lamma o y bowel disease (IBD) is a ch onic and au o-
immune condi ion which consis s o C ohn’s Disease (CD)
and Ulce a i e Coli is (UC) ep esen ing he wo main sub-
ypes o clinical IBD. Inde e mina e Coli is (IC) ep esen s a
hi d sub ype o IBD, and his la e diagnosis is made when
i is no possible o dis inguish be ween UC and CD. The
p e alence o IBD has been es ima ed in 653 pe 100,000
pa ien s, wi h he numbe o UC (334 pe 100,000) being
sligh ly highe han CD (306 pe 100,000) [1]. Epidemiologic
s udies show ha he p e alence o IBD is highe in Eu ope,
No h Ame ica, and Oceania. Howe e , IBD has e ol ed in o
a global disease, wi h a ising incidence also documen ed in
de eloping coun ies in Asia, A ica, and Sou h Ame ica [2].
O e all, hese sub ypes o IBD o en p esen wi h simila
symp oms including abdominal pain, dia hea, abdominal
dis ension, hema ochezia, enesmus, and an ex ensi e lis o
ex ain es inal mani es a ions including gas oin es inal,
mucocu aneous, musculoskele al, ocula , pulmona y, ascu-
la sys em, and gene alized a igue [3], signi ican ly educing
an indi idual’s quali y o li e [4]. Con empo a y bioma ke s
include C- eac i e p o ein (CRP), ecal calp o ec in (FCP),
and lac o e in, which a e all ou inely used o he de ec ion
o in lamma o y ac i i y [5]. Howe e , gi en he nonspeci ic
symp oms o CD and UC, a di ini i e diagnosis equi es
con i ma ion by endoscopy, adiology, and his ological analy-
sis o he in es inal ac .
The e is cu en ly no cu e, and he majo i y o con empo -
a y he apies ocus on symp oms managemen ollowed by
main enance o disease emission. Induc ion and main enance
he apy h ough he p esc ip ion o co icos e oids, 5-aminosa-
licyla es (5-ASA), hiopu ines, and biologic he apy igge
ad e se e ec s and ha e signi ican impac on pa ien well-
being [6]. A pe spec i e popula ion-based coho s udy o a
o al o 330 pa ien s demons a ed ha almos 5% o pa ien s
wi h UC equi ed su ge y as p ima y in e en ion while he co -
esponding p opo ion o CD inc eased ma kedly o 21.4%.
Addi ionally, he equency o ea ly pos ope a i e clinical com-
plica ions emained high in pa ien s o bo h colon pa hologies
eaching 31% o UC and 36% o CD [6].
Cu en ly, he pa hogenic mechanism o IBD emains
unclea [7]; howe e , ac o s including a combina ion o
gene ic, changes in gu mic obio a, and en i onmen al
ac o s (such as die and li es yle), as well as indi idual a ia-
bili y ha e been well desc ibed, ul ima ely leading o a high
eac i e oxygen species (ROS) le el and ac i i y and an
exace ba ed colonic immune esponse in he gu [8].
The up egula ion o bo h inna e and adap i e immune
esponses con ibu es o colon in lamma ion and implica es
in u he issue damage in pa ien wi h UC and CD. In es inal
inna e sys em is made up o neu ophils, monocy es, mac o-
phages, dend i ic cells (DCs), and inna e lymphoid and
na u al kille (NK) cells, cha ac e ized by hei capaci y o
p oduce a apid and nonspeci ic eac ion as a i s -line
esponse [9] h ough he exp ession o pa e n ecogni ion
ecep o s (PRR), such as oll-like ecep o s (TLR) o iden i y
he molecula pa e ns o di e en mic oo ganisms [10].
Mo eo e , inna e cells, specially DCs a e esponsible o
an igen p esen ing which a e key o T-cell ac i a ion and
he induc ion o adap i e immune esponse and in he de el-
oping o IBD [11]. Mac ophages a e also in ol ed in he
pa hophysiological ea u e o IBD. Fo ins ance, a human
s udy showed ha inducible ni ic oxide syn hase (iNOS), a
ee adical p oducing enzyme and a ma ke o M1 mac o-
phage in lamma o y esponse, was p ima ily ound in ac i e
UC, implying ha in addi ion o in lamma o y esponses,
ele a ed oxida i e s ess also in ol ed in ac i e s a e o he
disease [12].
2 S. SHIN ET AL.
Addi ionally, Sch ode e al. [13] ha e demons a ed a sig-
ni ican inc ease in in lamma o y ma ke s such as neu ophil
elas ase (NE) and myelope oxidase (MPO)-indica i e o neu-
ophil ex acellula ap (NET) o ma ion in specimens
a ec ed by CD compa ed o con ol. Simila ly, o he esea ch-
e s ha e shown an o e exp ession o NET-associa ed p o eins
in in lamed colon o UC pa ien s as compa ed o CD pa ien s
and no mal con ol, whe e pa ien s diagnosed wi h UC
showed a highe capaci y o neu ophils o p oduce NETs
upon umo nec osis ac o (TNF)-α s imula ion, which is
educed in pa ien s ecei ing success ul ea men wi h
an i-TNF-α [14]. On he o he hand, IBD is also cha ac e ized
by an inc ease in colonic oxida i e s ess [15] ha can mani-
es as oxida i e damage o a ange o biomolecules. In
suppo o his no ion, plasma le els o ee hiols, a obus
bioma ke o sys emic educ ion–oxida ion ( edox) s a us,
dec ease signi ican ly in CD when compa ed o heal hy sub-
jec s [16].
Ch onici y, unp edic able cou se o he disease, lack o
de ini i e ea men , and se e al side e ec s om cu en
ea men o IBD gene a e a g ea in e es o s udy a new
he apy wi h less side e ec and highe ea men ’s adhe -
ence. F om his s andpoin , Complemen a y and Al e na-
i e Medicine (CAM), a ea men app oach ha o en
u ilizes na u al compounds o pha maceu ical pu poses,
showcasing a p omising complemen a y op ion o he con-
en ional medicine, which allows educed dosage o d ugs,
equency o o main ain he emission phase. Ha e been
widely epo ed he use o bioac i e na u al compound
om plan s o pha maceu ical p opose. P eceden s
include aspi in, which is salicylic acid i s used epo ing
back 4000 yea s by he Sume ians, who ob ained i om
Willow ee ba k [17]. Digoxin, de i ed om Digi alis
lana a plan o add essing ca diac issues [18], s e ols,
hei de i a i e compounds, and plan s anol (phy os e -
ols/phy os anols) o managing hype choles e olemia [19]
a e o he examples o na u al compounds wi h cu en
clinical use. Howe e , he e is ye o be a con en ional
plan de i a i e ea men in he ield o IBD. Plan s a e
commonly used by IBD pa ien s o alle ia e symp oms
and mos o e idence showed hem only as complemen-
a y and al e na i e medicine.
Du ing he co ona i us disease 2019 (COVID) pandemic,
an online su ey s udy o IBD pa ien s e ealed ha 5% o
esponde s ceased o educed dose o p esc ibed medi-
ca ions, 13% s a ed supplemen s such as i amin D,
i amin C, and o he he bal supplemen s. 43% o esponde s
used CAM and 34% used CAM equen ly. In e es ing, 59% o
CAM use s we e sa is ied and epo ed i o ‘wo k well’ o
‘wo k e y well’ and hei use was signi ican ly associa ed
wi h low medica ion adhe ence sco es and majo conce n,
highe pe cei ed ha m and lowe sco e in ‘necessi y’ om
IBD medica ions [20]; howe e , any impac o wo k om
home en i onmen was no e iewed. Addi ionally, a ecen
s udy e ealed ha he equency o he bal he apy use, com-
bined wi h exe cise, physical he apy, modi ied die , as
al e na i es o con empo a y d ug ea men s has inc eased
in IBD pa ien s om 2002 o 2019 [21]. Speci ically, his
s udy epo ed ha pa ien s expe iencing esis ance o con-
empo a y ea men op ions, highe disease ac i i y, o
dealing wi h pe sis en and se e e side e ec om s anda d
medica ions, co icos e oid o use o biologics, and lowe
quali y o li e we e mo e likely o seek bene i om CAM [21].
Acco dingly, s udies examining he he apeu ic e ec s
o hese plan de i a i es in animals p o ide a e sa ile
p eclinical pla o m o e alua ing ea men e icacy and
elucida ing mechanisms o ac ions. Expe imen al model
o IBD using chemical s imula o s such as dex an
sodium sul a e (DSS) o di/ ini obenzene sul onic acid
(DNBS/TNBS) is equen ly s udied as a p eclinical expe -
imen al model, as hey mani es clinical and his opa holo-
gical changes such as i egula s ool consis ency o
dia hea, bloody s ool, and mucosal damage, which a e
ypically obse ed in IBD pa ien s [22,23].
A comple e holis ic explana ion which enables connec ion
be ween IBD and po en ial he apeu ic e ec o CAM has no
been es ablished [24]. This is likely due o he complex na u e
o he bal mix u es ha a e a ailable in ma ke , whe e hey a e
de i ed om mul iple plan s and each plan also has coun -
less de i a i es indi idually. La ge amoun o p omising
nu aceu icals and na u al compounds ha e been epo ed
o IBD ea men al hough igo ous e alua ion o he
bene i s is o en lacking. These nu aceu icals can be ca ego -
ized b oadly in o he ollowing i e classes:
(i) Polyphenols a e a class o compounds consis ing o one
o mo e phenyl ings combined wi h one o mo e
hyd oxyl moie ies and a e commonly ound in plan p o-
duc s ecommended o alle ia e gas oin es inal- ela ed
discom o [25] wi h accumula i e e idence suppo ing
hei posi i e e ec on in es inal in lamma ion [26] gu
mic obio a [27], and edox imbalance ha a e linked
o al e ed cellula unc ion [28].
(ii) Polysaccha ides a e common na u al mac omolecules
consis ing o co alen ly linked monosaccha ides (gene -
ally ≥10 monome uni s) ha o m di e en polyme ic
s uc u es [29] wi h documen ed biological ac i i y o
an i umo , an ioxidan , and mois u izing ac i i ies,
immune p o ein egula ion, imp o ing dend i ic cell
ac i i y and cy okine elease o po en ially p o ec he
colon [30].
(iii) The an h aquinone emodin (1, 3, 8- ihid oxy-6-me hy-
lan h aquinone) has gained pa icula in e es on expe -
imen al models o IBD as ecen s udies ha e iden i ied
mul iple biological ac ions o emodin wi h bene icial
ac i i ies including an i-in lamma ion and gu -immuni y
symbiosis, which a e all ele an pa hophysiological
ac ions cen al o disease p og ession in IBD pa hogen-
esis [31,32].
(i ) Sho -chain a y acids (SCFA) ep esen a se ies o
me aboli es p oduced by gu mic obio a commonly
ca ego ized by bu y ic acid, p opionic acid and ace ic
acid, and has been widely ecognized c ucial o
immune homeos asis [33]. Die a y ibe supplemen s
a e o en inco po a ed o inc ease SCFA p oduc ion,
bu ypes o die a y ibe and subsequen ypes o
SCFA p oduced may lead o di e en e ec s on he
mic obial composi ion, di e si y, and he immune
sys em [34].
( ) P obio ics may be an essen ial he apeu ic agen which
can no only be used as a single agen bu o aid con-
en ional he apy as well, as p obio ics wi h nanoen-
zyme coa ing he apy led o signi ican imp o emen
in weigh loss, apop osis, mucin (MUC)-2 le el, igh
junc ion p o eins, and Disease Ac i i y Index (DAI) [35]
and Mesalamine loaded wi h p obio ics showed
REDOX REPORT 3
signi ican es o a ion o weigh , ecal consis ency, ecal
bleeding [36].
The aim o his comp ehensi e e iew is o e alua e he an i-
in lamma o y and an ioxidan e icacy o cu en ly a ailable
CAM o IBD, as well as hei ole on gu mic obio a, and o
highligh he unde lying molecula and cellula mechanisms
o hese ea men s.
Me hods
Keywo d and sea ch s a egy
This e iew u ilized he Popula ion, In e en ion, Con ol,
Ou come (PICO) sea ch s a egy o examine he an i-in lam-
ma o y and an ioxidan e ec o CAM in IBD. The keywo ds
o ‘IBD pa ien s’, ‘IBD model’, ‘Ulce a i e Coli is’, ‘C ohn
Disease’, ‘DSS model’, ‘TNBS model’, ‘DNBS model’ o Popu-
la ion and ‘polyphenol’, ‘polysaccha ide’, ‘an h aquinone’
al e na i ely ‘emodin’, ‘SCFA’, ‘p obio ics’, ‘Complemen a y
and Al e na i e medicine’, ‘He bal medicine’, and ‘Plan medi-
cine’ o In e en ion. Addi ionally, he keywo ds o ‘con ol’,
‘placebo’, ‘IBD he apy’ al e na i ely ‘mesalazine’ ‘5-ASA’ and
‘co icos e oids’ we e used o Con ol s a egy and he
Ou come s a egy includes he keywo ds o ‘an i-in lam-
ma ion’, ‘gu mic obio a’, and ‘an i-oxida ion’.
A icle collec ion and s udy inclusion and exclusion
c i e ia
Published li e a u e con aining he keywo ds desc ibed
abo e was collec ed om Google Schola , MEDLINE,
PubMed, and WOS and colla ed in o a single ile. The col-
lec ed a icles we e sc eened agains he ollowing inclusion
and exclusion c i e ia. All p ocesses in ol ing da a collec ion
(keywo d and sea ch s a egy, a icle collec ion, s udy
inclusion and exclusion and da a ex ac ion) we e pe o med
independen ly by wo esea ches (S.S and T.O.C). Disc epan-
cies in he p ocesses desc ibed abo e we e esol ed
h ough consul a ion and discussion wi h h ee o he
esea che s (S.C, K.X, and S.A.D).
S udies included based on he collec ed a icles we e
sc eened agains he ollowing inclusion and exclusion c i-
e ia: (1) mus in ol e animal models o human s udies; (2)
mus ocus on he gas oin es inal ac a ec ions; (3) mus
examine he e ec o he bal ing edien s o na u al p oduc
de i a i es (polyphenols, polysaccha ides, an h aquinone
[emodin], SCFA, p obio ics) on he pa hophysiology o IBD,
speci ically ega ding an i-in lamma o y p ope ies, an ioxi-
dan e ec s, and gu mic obio a dysbiosis. All s udies we e
il e ed acco ding o ele ancy and da e o publica ion, only
including publica ion wi hin he las 5 yea s. The s udies
included a e a combina ion o p eclinical animal expe imen ,
andomized con ol ials, longi udinal coho s udy, and
obse a ional s udies. S udies ha did no all in o he a o e-
men ioned c i e ia we e excluded om he cu en e iew.
Du ing he sc eening p ocess, s udies ha we e published
in English language ha clea ly es ablished sample size, con-
ols, and s a is ical analyses we e included in his cu en
e iew. Collec ed s udies ha did no sa is y he abo e-men-
ioned c i e ia we e excluded and disca ded om he cu en
e iew. Jou nal impac ac o o o he jou nal me ic we e no
one p ima y conside a ion o he inclusion and exclusion
c i e ia.
Da a ex ac ion
The cu en e iew ex ac ed he ollowing in o ma ion om
he selec ed a icles: expe imen al me hod, pa icipan s, CAM
in e en ion, and CAM mode o ac ion. Addi ionally, he
ac i e ing edien s o he CAM in e en ion and changes in
bioac i i ies, gu mic obio a, and an ioxidan capaci y we e
also ex ac ed om he selec ed a icles.
Resul s
The da abase sea ch began in Janua y 2023 and concluded
in Augus 2024. A o al o 5251 a icles we e ob ained. The
s udy inclusion and exclusion sc eening p ocess was high-
ligh ed in he a icle-sc eening low diag am, whe e a
o al o 67 s udies we e included in he cu en e iew
(Figu e 1). The s udy cha ac e is ics we e summa ized in
Table 1.
Polyphenols and hei bioac i e me aboli es
Na u al polyphenols a e a class o compounds consis ing o
one o mo e phenyl ings combined wi h one o mo e
hyd oxyl moie ies. These compounds a e commonly ound
in plan p oduc s and a e o en ecommended o alle ia e
gas oin es inal- ela ed discom o [25]. Acco dingly, poly-
phenols a e inc easingly gaining a en ion as a po en ial
he apeu ic agen o IBD, wi h accumula ed e idence sup-
po ing hei posi i e e ec s on in es inal in lamma ion
[26,28], gu mic obio a [37,38], and edox imbalances ha
a e linked o al e ed epi helial cell unc ion [28].
Polyphenols as an i-in lamma o y agen s
S udies wi h expe imen al animals consis en ly show ha
polyphenols adminis a ion signi ican ly inc eased colon
leng h, and alle ia ed in lamma o y cell in il a ion, weigh
loss, ecal bleeding, imp o ed s ool consis ency, and colonic
c yp dep h in he IBD expe imen al animal model
[26,28,39]. These g oss obse a ions we e accompanied by
signi ican dec ease in p oin lamma o y bioma ke s and inhi-
bi ion o al e ed mi ochond ial mo phology in colon epi helia
due o in lamma ion and p o ided he basis o he mechan-
ism o ac ion o his class o na u al p oduc s. Impo an ly,
hese combined ac o s may be c i ical in de e mining se e -
i y o ex ain es inal mani es a ions hence polyphenols may
amelio a e hese pa hological changes o he colon. In
addi ion, signi ican ela i e inc eases in popula ions o esol-
ing mac ophage pheno ype (M2) cells and an i-apop o ic
p o ein exp ession such as Bcl2, and lowe le el o p o-apop-
o ic p o ein exp ession, plasma in lamma o y bioma ke s
and acili a o s such as in e leukin (IL)-6, IL-8, IL-1β, iNOS,
cyclooxygenase-2 (COX-2), and TNF- α a e consis en ly
epo ed in p e-clinical in e en ional s udies wi h polyphe-
nols in mice models o UC and CD-like coli is model
[28,39,40]. As an i-in lamma o y e ec s gene ally show a pa -
allel link o he inhibi ion o oxida i e s ess in in- i o s udies,
i may imply ha he cumula i e da a ob ained wi h p e-clini-
cal models may also con ibu e o an i-ROS ac i i y ha leads
o dec eased oxida i e damage [41], which will be u he
explo ed in he sec ion below. In summa y, he a ailable e i-
dence la gely demons a es ha polyphenols p o ec agains
in es inal damage and alle ia es bo h colonic signs and
4 S. SHIN ET AL.

se um bioma ke s o in lamma ion, implying i s he apeu ic
po en ial o IBD.
Polyphenols as sca enge s o eac i e oxygen species
(an ioxidan capaci y)
ROS a e p oduc s o cell me abolism o en i onmen al ac o s
such as die and smoking, which h ough excessi e
accumula ion can induce hos issue damage [42]. Fu he -
mo e, cellula p oduc ion o ROS is igh ly ela ed o in lam-
ma o y ac ions which is a c ucial pa o disease
mani es a ion in IBD. Local p oduc ion o ROS may dis up
in es inal pe meabili y, damaging cells which o m igh junc-
ions along he colon epi helium [43]. Fo example, he ee
adical supe oxide adical anion is chemically educed o
Figu e 1. Flow diag am desc ibing he sc eening s a egy o iden i y he key e e ences used in his sys ema ic e iew. WOS, google schola , PubMed, and
MEDLINE we e used o selec all in i o and human s udies published in he las 5 yea s on CAM and IBD. 67 s udies we e eligible o c i ical in his e iew.
REDOX REPORT 5
Table 1. Cha ac e is ics o sc eened s udies wi h ci a ions in he Fa Le Column.
1
Re . Me hod Pa icipan s In e en ion Mode o ac ion
[26] P eclinical
in i o animal
expe imen
n= 32 male ICR mice; 8/g oup
E hanol-induced in lamma ion
‘ZAVE’ ich in polyphenols (200 o 800 mg/kg/day),
supplemen ed o 3 weeks
An i-in lamma ion,
Res o a ion o gu
mic obio a
[28] P eclinical
in i o animal
expe imen
n= 48 male C57BL6 mice; 8/g oup
DSS-induced coli is
Apple peel (DAPP) ich in polyphenols (200 o 400 mg/
kg/day), o 10 days be o e and 10 days a e
induc ion
An i-in lamma ion, an i-
oxida ion
[37] P eclinical
in i o animal
expe imen
n= 15 male BALB/c mice; 5/g oup
DSS-induced coli is
Res e a ol (100 mg/kg/ day), supplemen ed o 10
days
An i-in lamma ion,
es o a ion o gu
mic obio a
[39] P eclinical
in i o animal
expe imen
n= 24 male BALB/c mice; 6/g oup
TNBS-induced CD
Polyphenolic maqui ex ac (50 mg/kg/day) as a
p e en i e (7 days p io TNBS) and he apeu ic (4
days a e TNBS) adminis a ion
An i-in lamma ion
[40] P eclinical
in i o animal
expe imen
n= 24 Female C57BL6 mice; 8/g oup.
DSS-induced coli is
EGCG om g een ea (50 mg/kg body) supplemen ed
o 3 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[49] P eclinical
in i o Animal
expe imen
n= 32 male C57BL/6 mice; 8/g oup
DSS-induced coli is mac ophage/
neu ophil deple ion
Phenolic acid (50mg/kg) 3 imes pe ime o
adminis a ion, once in 3 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[51] Randomized Con ol
T ial, C osso e
n= 51
In es inal pe meabili y (↑zonulin
se um le el) pa ien s
Die ich in polyphenols (1391 mg /day),
supplemen ed o 8 weeks
An i-in lamma ion,
es o a ion o gu
mic obio a
[52] Longi udinal coho on
INCLD Heal h
n= 96
Heal hy adul s
Culina y he b ich in polyphenols (30,000 PPM,
>50,000 PPM, >30,000 PPM/ATB o >50,000 PPM/
ATB), es ed a 0, 6, and12 mon hs
Res o a ion o gu
mic obio a
[106] P eclinical
in i o animal
expe imen
n= 48 male CD-1 mice; 8/g oup
AOM/DSS o CACC
Mo inga olei e a lea es (5%, 10%, o 20%),
supplemen ed o 12 weeks
An i-in lamma ion, an i-
oxida ion
[119] P eclinical
in i o animal
expe imen
n= 30 male nude mice; 5/g oup
Xenog a o CC
‘SDEA’ la onoid (100, 200, o 300 mg/kg/day),
supplemen ed o 25 days
An i-in lamma ion
[163] P eclinical
in i o animal
expe imen
n= 60 male Sp ague-Dawley a s; 10/
g oup
DSS-induced coli is
SFE la onoids (50, 100, o 150 mg/kg/day),
supplemen ed o 1 week
An i-in lamma ion
[171] P eclinical
in i o animal
expe imen
n= 36 male & emale Lab ado
Re ie e s; 12/g oup IBD
‘GSP’ ich in p oan hocyanidine (30 mg/kg),
supplemen ed o 21 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[172] P eclinical
in i o animal
expe imen
n= 48 male C57BL/6 mice; 8/g oup
DSS-induced coli is
BI ex ac om Ginkgo biloba (2.5, 5, o 10 mg/kg/
day), supplemen ed o 4–10 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[58] P eclinical
in i o animal
expe imen
n= 55 emale C57BL/6J mice; 7–8/g oup
DSS-induced coli is
‘HAPS3a’ and ‘APD3a’ polysaccha ides (200 mg/kg),
days 2–5 o e a o al o 5 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[59] P eclinical
in i o animal
expe imen
n= n.i male C57BL/6 mice; n.i/ g oup
DSS-induced coli is
Noni (L.) polysaccha ide (10 mg/kg/day),
supplemen ed o 11 days
An i-in lamma ion
[60] P eclinical
in i o animal
expe imen
n= 48 male BALB/c mice; 8/g oup
DSS-induced coli is
‘EC’ polysaccha ide (0.35, 0.70, o 1.75g/kg/day),
supplemen ed o 7 days
An i-in lamma ion
[61] P eclinical
in i o animal
expe imen
n= 60 male BALB/c mice; 12/g oup
DSS-induced coli is
‘DO’ polysaccha ide (50, 100, o 200mL/kg/day),
supplemen ed o 7 days
An i-in lamma ion
[62] P eclinical
in i o animal
expe imen
n= 40 male & emale Sp ague Dawley
(SD) a s; 10/g oup
Ace ic acid-induced coli is
‘HE’ polysaccha ide (0.6 o 1.2 g/kg/day) o
supplemen ed 10 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[63] P eclinical
in i o animal
expe imen
n= 40 emale Swiss mice; 8/g oup
DSS-induced coli is
‘RGal’ polysaccha ide (3, 10, o 30 mg/kg/day),
supplemen ed o 7 days
An i-in lamma ion
[64] P eclinical
in i o animal
expe imen
n= 15 male C57BL/6j mice; 5/g oup
DSS-induced coli is
‘HAW1-2′polysaccha ide (30 mg/kg/day),
supplemen ed o 3 weeks
An i-in lamma ion,
es o a ion o gu
mic obio a
[65] P eclinical
in i o animal
expe imen
n= 40 male C57BL/6J mice; 8/g oup
DSS-induced coli is
‘AMP’ polysaccha ide (10, 20, o 40 mg/kg), 3 days
be o e induc ion and 7 days pos -induc ion
An i-in lamma ion,
es o a ion o gu
mic obio a
[66] P eclinical
in i o animal
expe imen
n= 36 male Swiss mice; 6/g oup
Ace ic acid-induced coli is
Noni-PLS (0.1, 0.3, o 3.0 mg/kg), adminis e ed o 30
min be o e eu hanasia
An i-in lamma ion, an i-
oxida ion
[67] P eclinical
in i o animal
expe imen
n= 60 male ICR mice; 20/g oup
AOM/DSS coli is associa ed colo ec al
cance
Apple polysaccha ide (10 mg/kg) supplemen ed o 15
weeks
An i-in lamma ion,
es o a ion o gu
mic obio a
[68] P eclinical
in i o animal
expe imen
n= 50 male BALB/c mice; 10/g oup
Cy-induced immunosupp ession
‘TFPS’ he e opolysaccha ide (50, 100, o 200 mg/kg/d)
supplemen ed o 10 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[69] P eclinical
in i o animal
expe imen
n= 18 BALB/c mice, Sex n/i; 6/g oup
AOM/DSS coli is associa ed colo ec al
cance
‘EPS1-1’ polysaccha ide (150 mg/kg) supplemen ed
o 14 days
An i-in lamma ion,
es o a ion o gu
mic obio a
(Con inued)
6 S. SHIN ET AL.
Table 1. Con inued.
Re . Me hod Pa icipan s In e en ion Mode o ac ion
[70] P eclinical
in i o animal
expe imen
n= 18 male Sp ague-Dawley a s; 6/
g oup
TNBS-induced coli is
Polysaccha ides (300 mg/kg/day), supplemen ed o
16 days
An i-in lamma ion,
es o a ion o gu
mic obio a, An i-
oxida ion
[122] P eclinical
in i o animal
expe imen
n= 24 Male & Female a s; S ain n/i;6/
g oup
Heal hy a s
‘AOS’ oligosaccha ide (200 mg/kg), daily,
supplemen ed o ally o 28 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[80] P eclinical
in i o animal
expe imen
n= 80 male & emale Kunming mice;
10/g oup
E. coli -induced dia hea
Emodin (8.75, 17.5, o 35
mg/kg) o 6 h be o e eu hanasia
An i-in lamma ion,
es o a ion o gu
mic obio a
[81] P eclinical
in i o animal
expe imen , in i o
n= 150 male BALB/c mice; 30/g oup
CLP-induced sepsis
Emodin (10, 20, o 40 mg/kg), supplemen ed o 7
days
An i-in lamma ion
[82] P eclinical
in i o animal
expe imen , in i o
n= 49 male BALB/c mice; 7/g oup
DSS-induced coli is
Emodin/PSM NPs (5 o 20 mg/kg/d), supplemen ed o
5 days
An i-in lamma ion
[83] P eclinical
in i o animal
expe imen , in i o
n= 48 male BALB/c mice; 8/g oup
CLP-induced sepsis
Emodin (20, 40, o 80 mg/kg/day), supplemen ed o 5
days
An i-oxida ion
[89] Human obse a ional
s udy
n= 28
UC pa ien s
Bu y a e (0–1.6 mM) on blood and in es inal T cells
om pa ien s
An i-in lamma ion
[173] Human obse a ional
s udy; P eclinical
in i o animal
expe imen
n= 187
IBD pa ien s (CD and UC);
n= 48 male C57BL/6 mice, 12/g oup
DSS-induced coli is
Bu y a e (200 mM), supplemen ed o 10 days in
animal model
An i-in lamma ion, an i-
oxida ion
[12] Human obse a ional
s udy; P eclinical
in i o animal
expe imen
n= 28, UC pa ien s (ac i e and inac i e);
n= 24 male BALB/c mice; 6/g oup
DSS-induced coli is
Bu y a e (20 mg/kg), supplemen ed o 12 days in
animal model
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[109] Human obse a ional
s udy; P eclinical
in i o animal
expe imen
n= 112; IBD pa ien s (CD and UC); n=
20–40 male C57BL/6J mice; 7–10/
g oup, DSS-induced coli is
‘BHB’ ke one (15 mg/25g), single dose An i-in lamma ion,
es o a ion o gu
mic obio a
[107] P eclinical
in i o animal
expe imen
n= 44 male C57BL/6 mice; 8–12/g oup
DSS-induced coli is
Bu y a e (NaB, 0.1 M o 500 g/kg/day), supplemen ed
12 days be o e induc ion and 10 days pos -induc ion
An i-in lamma ion, an i-
oxida ion
[113] P eclinical
in i o animal
expe imen
n= 24 male C57BL/6 mice; 4/g oup
S ep omycin o E. coli s ains (LF82 o
LF82lux)-induced in ec ion
P opionic acid (20 mM), 3 days be o e in ec ion and 21
days a e in ec ion
Res o a ion o gu
mic obio a
[112] P eclinical
in i o animal
expe imen
n= 40 male Sp ague-Dawley a s; 8/
g oup
Heal h oden
Cu ed chicken o bee p oduc die supplemen ed o
3 weeks
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[116] P eclinical
in i o animal
expe imen
n= 20 male BALB/c mice; 3–5/g oup
Oxazolone-induced UC
‘DCA’ (100 mg/kg o 3 days), 1 h be o e induc ion and
3 days a e induc ion
An i-in lamma ion, an i-
oxida ion
[117] P eclinical
in i o animal
expe imen
n= 10 male C57BL/6 mice; 5/g oup
DSS-induced coli is
Ace a e enema (10 mM), p o ided daily o 7 days An i-in lamma ion
[120] P eclinical
in i o animal
expe imen
n= 20 male C57BL/6J mice; 5/g oup
Fibe -de icien and low DSS-induced
coli is
Sodium ace a e (200 mM/day), supplemen ed o 7
days
An i-in lamma ion
[35] P eclinical
in i o animal
expe imen
n= 15 C57BL/6 mice Sex n/i; 3/g oup
DSS-induced coli is
P -Lipid@EcN p obio ic, supplemen ed o 7 days Dose
n/i
An i-in lamma ion, an i-
oxida ion
[36] P eclinical
in i o animal
expe imen
n= 30 emale and male Wis a a s; 6/
g oup
DSS-induced coli is
Mesalamine and ‘F12’ p obio ic (23 mg/kg/day),
supplemen ed o 15 days
An i-in lamma ion
[96] Human obse a ional
s udy; P eclinical
in i o animal
expe imen
n= 37
UC pa ien s; n = 30 male BALB/c mice;
6/g oup
DSS-induced coli is
Human FMT, supe nan mix u e and 7 mix p obio ics
s ains: E. hi ae, L. casei, S. sali a ius, F. p ausni zii,
A. muciniphila, C. bu y icum, L. sali a ius (1 × 10
8
CFU
pe s ain), adminis e ed o 7 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[100] P eclinical
in i o animal
expe imen
n= 60 male C57BL/6 mice; 12/g oup
DSS-induced coli is
Bu y a e-p oducing Veillonella and lac obacillus (1 ×
10
9
CFU mL
−1
each, 200 μL pe day), supplemen ed
o 14 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[102] P eclinical
in i o animal
expe imen
n= 25 male BALB/c mice; 5/g oup Lac obacillus plan a um ZJ31 (400 uL o al
adminis a ion, 2.5 × 10
9
CFU mL
–1
), supplemen ed
o 56 days
An i-in lamma ion,
Res o a ion o gu
mic obio a
[108] P eclinical
in i o animal
expe imen
n= 24 male C57BL/6 mice; 8/g oup
DNBS-induced coli is
Bu y a e-p oducing Faecalibac e ium p ausni zii s ain
A2-165 p obio ic (1 × 10
9
CFU), o 10 days a e i s
induc ion and 3 days a e second induc ion
An i-in lamma ion
[111] P eclinical
in i o animal
expe imen
n= 30 male Sp ague-Dawley a s; 6/
g oup
DSS-induced coli is
P opionibac e ium euden eichii ‘LPF’(1 × 10
8
CFU)
and ‘SPFC’ (1 mL), supplemen ed o 22 days
An i-in lamma ion
[121] P eclinical
in i o animal
expe imen
n= 40 male C57BL/6J mice; 10/g oup
DNBS-induced coli is
Ace a e-p oducing bac e ia Ch is ensenella minu a (1
× 10
9
CFU/mL), supplemen ed o 2 weeks
An i-in lamma ion
(Con inued)
REDOX REPORT 7
hyd ogen pe oxide (H
2
O
2
, a seconda y ype o ROS), by supe -
oxide dismu ases (SOD1/2). This weak wo-elec on oxidan
H
2
O
2
is hen educed u he by ca alase and o he
p o essional pe oxidase enzymes o elimina e he oxidan .
Indeed, polyphenol- ich d ied apple peel powde showed
lowe le els o H
2
O
2
coupled wi h dec eased SOD2
Table 1. Con inued.
Re . Me hod Pa icipan s In e en ion Mode o ac ion
[123] P eclinical
in i o animal
expe imen
n= 32 emale C57BL/6J mice; 8/g oup
DSS-induced coli is
Lac obacillus acidophilus KBL402 and KBL409
p obio ics (1 × 10
9
CFU), supplemen ed o 8 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[139] P eclinical
in i o animal
expe imen
n= 20 male C57BL/6 mice; 3–7/g oup
DSS-induced coli is
Lac obacillus johnsonii p obio ic (1 × 10
9
CFU/day),
supplemen ed o 14 days
An i-in lamma ion,
es o a ion o gu
mic obio a
[140] P eclinical
in i o animal
expe imen
n= 60 male BALB/C mice; 12/g oup
DSS-induced coli is
NKU556-Fe (0.2 mg mL
–1
Fe
2+
), supplemen ed o 6
days
An i-in lamma ion, an i-
oxida ion
[141] P eclinical
in i o animal
expe imen
n= 70 male Sp ague Dawley a s; 10/
g oup
DSS-induced coli is
Lac obacillus acidophilus (1 × 10
8
CFU) supplemen ed
o 7 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[142] P eclinical
in i o animal
expe imen
n= 18 male C57BL/6 mice; 6/g oup
DSS-induced coli is
Lac obacillus plan a um CBT LP3 p obio ic (1 × 10
8
CFU/day), supplemen ed o 7 days
An i-in lamma ion, an i-
oxida ion
[143] P eclinical
in i o animal
expe imen
n= 16 C57BL/6JOlaHsd mice; 4/g oup
DSS-induced coli is
Lac obacillus sali a ius p obio ic (1 × 10
9
CFU/day),
supplemen ed o 7 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[144] P eclinical
in - i o animal
expe imen
n= 20 emale C57BL/6 mice; 5/g oup
DSS-induced coli is
‘Lac@HDP’ p obio ic (1 × 10
9
CFU), supplemen ed 1 d An i-in lamma ion,
es o a ion o gu
mic obio a
[146] P eclinical
in i o animal
expe imen
n= 25 emale C57BL/6 mice; 5/g oup
DSS-induced coli is
Po phy omonas gingi alis and Lac obacillus hamnosus
GG p obio ics (50 μg mL
−1
), supplemen ed o 8
days
An i-in lamma ion
[148] P eclinical
in i o animal
expe imen
n= 60 BALB/c mice; Sex n/i; 12/g oup
DSS-induced coli is
Lac obacillus plan a um s ains (1 × 10
9
o 1 × 10
10
CFU/mL/day), supplemen ed o 28 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[149] P eclinical
in i o animal
expe imen
n= 32 emale C57BL/6J mice; 8/g oup
DSS-induced coli is
Lac obacillus casei LH23 p obio ic (1 × 10
8
CFU/day),
supplemen ed o 7 days
An i-in lamma ion, an i-
oxida ion
[150] P eclinical
in i o animal
expe imen
n= 16 BALB/c Wis a Ra us; 8/g oup
DSS-induced coli is
Lac obacillus b e is-de i ed poly Pp obio ic (5 μg/
mice/day), supplemen ed o 7 days
An i-in lamma ion
[151] P eclinical
in i o animal
expe imen
n= 90 male C57BL/6N mice; 10/g oup
DSS-induced coli is
Bi idobac e ium bi idum (FL-276.1, FL-228.1)
En e ococcus aecalis (ML329, FN249), Lac obacillus
hamnosus (FN518), Lac obacillus e men um
(CECT5716) (1 × 10
9
CFU) p obio ics, supplemen ed
o 22 days
An i-in lamma ion
[152] P eclinical
in i o animal
expe imen
n= 48 emale C57BL/6 mice; 8/g oup
DSS-induced coli is
Bi idobac e ium bi idum BGN4-SK p obio ic (1 × 10
10
CFU/day), supplemen ed o 8 days
An i-in lamma ion, an i-
oxida ion
[153] P eclinical
in i o animal
expe imen
n= 40 emale C57BL/6J and BALB/c ByJ
mice; 5–10/g oup
TNBS-induced coli is
Bi dobac e ium animalis spp. lac is (Bl 5764) and
Lac obacillus eu e i (L 5454) p obio ics (1 × 10
8
CFU/day), supplemen ed o 5 days
An i-in lamma ion
[155] P eclinical
in i o animal
expe imen
n= 12 male C57BL/6 mice; 6/g oup
DSS-induced coli is
Pediococcus pen osaceus p obio ic (1 × 10
9
CFU /day),
supplemen ed o 2 weeks
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
[156] Human obse a ional
s udy; In i o animal
expe imen
n= 12
UC pa ien s; n= 10 male C57BL/6
mice; n= 3–6/g oup
DSS-induced coli is
Akke mansia muciniphila (1 x 10
9
CFU/day),
supplemen ed o 7 days
An i-in lamma ion
[157] P eclinical
In i o animal
expe imen
n= 40 male C57/BL6 mice; 10/g oup Akke mansia muciniphila 139 and ATCC (2 × 10
8
CFU/
ml/day), supplemen ed o 56 days
An i-in lamma ion, an i-
oxida ion
[158] P eclinical
in i o animal
expe imen
n= 26 male C57BL/6 mice; 6/g oup
DSS-induced coli is
Lac ic acid (0.25 mM) and Saccha omyces ce e isiae
39# p obio ic (1 × 10
9
CFU/ml), o 7 days
An i-in lamma ion,
es o a ion o gu
mic obio a, an i-
oxida ion
ATB, an ibio ic p ope ies; APS3a, non-honey-p ocessed As agalus polysaccha ides; AMP,A ac ylodes mac ocephala Koidz polysaccha ide; AOM, azoxyme hane;
AOS, algina e oligosaccha ides; BHB, ke one body B-hyd oxybu y a e; BI, Bilobalide; CD, C ohn’s disease; CACC, coli is-associa ed colo ec al cance ; CC, colo -
ec al cance ; Cy, cyclophosphamide; CLP, cecal liga ion punc u e; CFU, colony- o ming uni s; DSS, dex an sul a e sodium; DAPP, d ied apple peel powde ; DO,
Dend obium o icinaleon; DNBS, dini obenzene sul onic acid; DCA, dichlo oace a e; EGCG, epigalloca echin-3-galla e; EC,Eucheuma co onii;EPS1-1,Rhizopus
nig icans ex acellula polysaccha ide; SFE,Sopho a la escens ex ac ; FMT, ecal mic obio a ansplan a ion; F12, p obio ic mic opa icles; GSP, g ape seed
p oan hocyanidin; HAPS3a, honey-p ocessed As agalus polysaccha ides; HAW1,C a aegis pinna i ida (Haw ho n); ‘HE’,He icium e inaceus;INCLD, In e na ional
Coho on Li es yle De e minan s o Heal h; LPF, li e P. euden eichii KCTC 1063; Lac@HDP,Lac obacillus acdiphilus@Hyalu onic acid g a ed wi h dopaine p o-
ec ed by phenylbo ic acid; Noni-PLS, isola ed polysaccha ide om Mo inda ci i olia Linn; NPs, nanopa icles; NaB, sodium bu y a e; NKU556-Fe,Lac obacillus
alimen a ius NKU556 i on-en iching om Chinese e men ed ood; n/i, no-in o ma ion p o ided; PPM, pa s pe million; PSM, poly (DL-lac ide-co-glycolide)/
Eud agi
Ⓡ
S100/mon mo illoni e; P -Lipid@EcN, liposome-coa ed Esche ichia coli Nissle (EcN) 1917; Poly P, long-chain polyphospha e; RGal, Rhamnogalac u -
onan; SPFC, supe na an o he P. euden eichii cul u e; SDEA,Selaginella doede leinii Hei on e yl ace a e; TNBS, 2,4,6-T ini obenzene sul onic acid; TFPS,
Camellia sinensis L pec ic he e opolysaccha ides; UC,Ulce a i e coli is;ZAVE, Zhenjiang a oma ic inega ex ac .
8 S. SHIN ET AL.
a e wa an ed be o e emodin can be conside ed a use ul
adjunc i e he apy o IBD pa ien s.
Emodin as an an i-in lamma o y agen
In i o s udies using animal models showed signi ican
a enua ion o pa hological sco e de ined by in es inal nec o-
sis o hemo hage his opa hological in in e en ions wi h
emodin despi e he ongoing p esence o signi ican in lam-
ma ion, alluding o emodin’s p o ec i e mechanism agains
in es inal damage [80]. In an E. coli O
1
-induced dia hea
expe imen al model, mice ea ed wi h emodin o 7 days
showed amelio a ed colon sho ening, educed colon
a ophy, inc eased mucosal goble cell densi y, and imp o e-
men o igh junc ion ba ie compa ed o he insul g oup in
he absence o in e en ion. Addi ionally, emodin was shown
o elici e signi ican ly highe MUC-2 luo escence in ensi y,
indica ing goble cell p ese a ion yielded con inued mucin
p oduc ion, along wi h a educed le els o IL-1β, IL-6, and
TNF-α [80]. Ano he s udy epo ed ha emodin p e en ed
in es inal pe meabili y by inc easing zonula occludens-1
(ZO-1) and occluding exp ession – bu no as e ec i e as
claudin-1 – in he in es ine o sep ic mice [81]. Emodin
(EMO)-loaded Poly (DL-lac ide-co-glycolide)/Eud agi S100/
mon mo illoni e nanopa icles (EMO/PSM NPs) showed com-
pa able an i-in lamma o y e ec o 5-ASA, alluding i s he a-
peu ic po en ial [82]. Once again, u he s udy is necessa y o
de e mine e icacy, oxici y, and side e ec s o nanopa icle
deli e y o emodin in human subjec s.
Emodin as sca enge s o eac i e oxygen species
(an ioxidan capaci y)
Emodin shows an ioxidan ac i i y as e idenced by signi ican
educ ion o MDA le els combined wi h enhancemen o
bo h low- (GSH) and high-molecula weigh (SOD) an ioxi-
dan s, signi ying emodin’s po en ial o p o ec agains oxi-
da i e s ess h ough a ge ing di e en pa hways linked o
issue edox modula ion [83]. When deli e ed ia nano ehi-
cle, emodin also showed enhanced biological ac i i ies as
judged by signi ican dec eases in colonic MPO and ni ic
oxide (NO) [82]. This ac i i y is likely explained by he chemi-
cal educ ion o he quinone o a co esponding phenol by
biological educ an s. Fo example, o-quinones, a p ima y
p oduc , can be educed by biological educ an s o yield
phenols and o-diphenols and hen oxidized back o he co -
esponding o-quinones by y osinase [84]. In e es ingly, he
a ailable e idence indica es ha he o-diphenolic s uc u e
in he chemically educed hyd oxyan h aquinone molecules
could ma kedly enhance he adical sca enging p ope y o
his na u al p oduc [85] wi h po en ially he edox ecycling
o he ac i e sca enge adding o he sca enge e icacy.
Emodin as modula o s o he gu mic obio a
Recen ly, emodin has been also documen ed o imp o e ich-
ness and di e si y mic obio a, signi ican ly imp o emen ich-
ness and composi ion o Bac e oide es,Fi micu es,
Ve ucomic obia, and educ ion o P o eobac e ia in in es inal
diso de s [80]. Gao e al. [80] epo ed ha emodin ees ab-
lished mic obial con en in he colon a e being dis up ed
by pa hogenic en e o oxigenic Esche ichia coli, implying he
capaci y o emodin o supp ess pa hogenic mic obio a and
enhance g ow h o heal hy composi ion and abundance.
Bene icial e ec s o emodin on oxida i e s ess, in lamma ion
and gu mic obio a a e summa ized below (Table 4) and
demons a e ha he bioac i i y o his na u al p oduc
in ol es he modula ion o many dispa a e pa hways.
Sho -chain a y acids (SCFA)
Sho -chain a y acids (SCFA) a e byp oduc s p oduced by
gu mic obio a commonly ca ego ized by ale a e (numbe
o ca bons 5; C5) and he mos abundan o ganic subs a es:
Bu y a e (C4), P opiona e (C3), and Ace a e (C2) [33]. These
SCFA a e biologically ac i e and ha e been widely ecognized
o hei bene icial e ec s and hei impo an ole in gu
heal h [8]. Die a y ibe supplemen s a e o en inco po a ed
o inc ease SCFA p oduc ion, bu di e en ibe and in e en-
ion may lead o di e en e ec s on he mic obial compo-
si ion, di e si y, and he co esponding indi idual immune
esponse [34]. In e es ingly, ibe supplemen a ion wi h
inulin ( uc o-oligosaccha ide) showed signi ican ele a ion
o Ac inobac e ia abundance and supp ession o Bac e oi-
de es, while supplemen ing isomal o-oligosaccha ide ibe
signi ican ly inc eased Bac e oide es and dec eased Fi micu es
in he mic obio a popula ion, wi hou signi ican changes on
o al SCFA le els [34].
On he ano he hand, die a y choices play a c i ical ole in
modula ing in es inal SCFA. Die s lacking in ibe exace ba e
diseases in expe imen al models o in es inal inju y and colo -
ec al cance [86]. Con e sely, die s high in ibe a e documen-
ed o p o ec agains in lamma o y diseases. Fo example,
da a p oduced by Lau ence e al. unde pin he p o ec i e
e ec s o ich- ibe die . Speci ically, hei s udy documen ed
ha ibe -de i a ed SCFA binds o GPR43 on colonic epi helial
cells leading o he s imula ion o a K(
+
)-ion e lux and cellula
hype pola iza ion, which p omo es he ac i a ion o he
NLRP3 in lammasome pa hway, c ucial o gu homeos asis
[87]. Also, i has been epo ed ha an ena al supplemen-
a ion wi h a high- ibe die leads o a educ ion in in es inal
in lamma ion amongs he co esponding adul o sp ing
ha a e subsequen ly challenged in an expe imen al model
o coli is [88].
A ailable e idence has shown ha di e en SCFAs may
exhibi a ying biological e ec s depending on he
speci ic change in le el o he me aboli e unde di e en
pa hophysiological condi ions. Fo ins ance, supplemen ing
bu y a e and p opiona e led o diminished p oli e a ion and
al e ed CD4
+
and CD8
+
T-cell popula ions; howe e , only
bu y a e educed CD25
+
T-cell exp ession in a dose-depen-
den manne . Unde he same condi ions, ace a e showed
no signi ican e ec [89]. Howe e , Viei a e al. [90]
showed ha ace a e signi ican ly supp essed in lamma ion
by inhibi ing p o-in lamma o y pa hways linked o he an-
sc ip ional ac i a ion o NF-κB and mo e b oadly he deg ee
o neu ophil ac i i y, and ins ead p omo ed he p oduc ion
o an i-in lamma o y TGF-β, annexin A1, and IL-10, he eby
elici ing an an i-in lamma o y ac i i y. Fu he mo e, ood-
de i ed o yzanol (ORY) ea men , which was signi ican ly
linked o ele a ed ecal SCFA con en s lowe ed Fi micu es
abundance while imp o ing Bac e oide es abundance
while no ma kedly al e ing bu y ic acid le el [91]. O he
au ho s ha e shown ha bu y a e syn hesis and he bac-
e ia esponsible o p oducing his SCFA ha e been
ound o exe he highes an i-in lamma o y e ec on he
gas oin es inal ac and mos signi ican egula ion o
he immune esponse h ough inhibi ion o p oin lamma-
o y cy okines and p omo ion o an i-in lamma o y
REDOX REPORT 15

cy okines such as IL-10 [92]. Thus me abolic syn hesis o
speci ic SCFA may need o be s udied sepa a ely o accu-
a ely iden i y an indi idual biological e ec .
No ably, SCFA ha e been shown o p o ide bene icial
e ec s on gas oin es inal diso de s h ough in e ac ion
wi h immune and epi helial cells in he colon issue. G
p o ein-coupled ecep o s (GPCRs) a e no only highly
exp essed on en e ocy es and en e oendoc ine cells in he
gas oin es inal ac bu also in he mac ophages, dend i ic
cells, lymphocy es, and neu ophils [93]. SCFAs bind o
GPR41 and GPR43 (also known as ee a y acid ecep o s
FFAR3 and FFAR2, espec i ely), igge ing he di e en ia ion
and ma u a ion o immune cells and he eby, ac ing as impo -
an media o s o he ma u e immune s a e. Bo h GPR41 and
GPR43 ecep o s ac i a ion leads o he inhibi ion o adenylyl
cyclase and, subsequen ly, dec eases he le els o cyclic AMP
(cAMP), ex acellula signal- egula ed kinase (ERK), and
impac s ansc ip ional ac i a ion o he nuclea ac o
kappa-ligh -chain enhance o ac i a ed B cells (NF-κB)
cascade, which hen collec i ely mani es s as a dec ease in
colon in lamma ion [94].
Ano he possible mechanism by which SCFA could
enhance in es inal ba ie unc ion and educe in lamma ion
is h ough his one deace ylase (HDAC) inhibi ion. Bu y a e
[86] and Clos idium bu y icum-de i ed bu y a e induce an
inc ease o IL-10 exp ession and up egula e egula o y B
cells ia inhibi ing HDAC1 ac i a ion. In addi ion, SCFA also
impac mac ophage pola iza ion ( ha is he a io M1 o M2
pheno ype) h ough GPR43 ac i a ion, HDAC inhibi ion [95]
and/o JAK/STAT3/ o khead box O3 (FOXO3) axis inac i a ion
[96]. Speci ically, bu y a e induces he exp ession o synap o-
podin, an ac in-binding p o ein ha enhances in es inal
ba ie unc ion, ia HDAC inhibi ion [97] and also o supp ess
he p oduc ion o neu ophil-de i ed MPO and p oin lamma-
o y media o p oduc ion, pe haps h ough i s HDAC inhibi-
o y unc ion [98]. Fu he mo e, bu y a e may inhibi
neu ophil mig a ion and he consequen ealizing o NETs
in cells om CD and UC pa ien s [98]. Thus his complica e
o da a ein o ces he supp essi e e ec o SCFA on in es inal
in lamma ion and oxida i e s ess leading o imp o ed epi-
helial ba ie unc ion.
Nume ous s udies ha e shown ha he pa hogenesis o
IBD and clinical e olu ion may be modula ed by SCFA;
howe e , he exac mechanism o ac ion and linkage o all
SCFA in IBD is s ill unclea [99]. Fo ins ance, he combina ion
o Veillonella a i (V. a i) and Lac obacillus acidophilus (LA)
leads o signi ican ly ele a ed o al SCFA le els and sup-
p essed lac a e, along wi h signi ican ly amelio a ed clinical
and his ological symp oms in expe imen al UC [100].
O e all, hese ou comes imply a connec ion be ween high
SCFA, mic obio a, and IBD in humans. A link be ween polysac-
cha ides and SCFA p oduc ion in he gu has also been p o-
posed. Fo example, α-galac o-polysaccha ide de i ed om
Lupinus albus is also a known p ebio ic leading o inc eased
SCFA h ough gu mic obio a abundance [101]. Indeed, i s
ea men also signi ican ly educed DAI, imp o emen in es-
inal pe meabili y, and goble cell coun bu mild in lam-
ma ion and mucosal damage we e s ill seen [90]. In
addi ion, Lac obacillus plan a um ZJ316 he apy, which
showed signi ican ly highe le el o SCFA compa ed o mesa-
lazine, bo h ea men s success ully es o ed colon weigh ,
clinical ma ke s and IL-1β, IL-8, and TNF-α in lamma o y cy o-
kines compa ed o he DSS (insul ) g oup, howe e , ZJ316
he apy was mo e e ec i ely in supp essing IL-6 exp ession
in oden s [102].
Along wi h bu y a e, bo h p opiona e and ace a e a e
SCFA me aboli es de i ed om gu mic obio a. Bu y a e, as
shown in he sec ion abo e, is a mo e well-known SCFA
and has shown e idence as a he apeu ic agen o IBD.
Howe e , s udies ha e also alluded o possible he apeu ic
e ec s o o he SCFAs including he p o ec i e ac ion o p o-
piona e and ace a e on colon pa hophysiology. A e all,
SCFAs seem o be igh ly ela ed o he colon, as seen in
he dis ibu ion o ol ac o y ecep o 78 (Ol 78), an SCFA
ecep o exp essed by he en e oendoc ine cell, commonly
exp essed in cecum, dis al la ge in es ine, and ec um [103].
The speci ic a ini y o bo h p opiona e and ace a e o
Ol 78 ecep o may p omo e he sec e ion o he ano exi-
genic gu pep ide YY (PYY) [104], a ho mone in ol ed in
he main enance o gas oin es inal unc ion. Indeed, PYY
has been shown o be signi ican ly lowe ed in he colon o
pa ien s wi h in lamma o y bowel synd ome, implying i s
con ibu ion o clinical symp oms [105]. Thus p opiona e
and ace a e may ha e a majo ole in inhibi ing in lamma ion
and oxida i e s ess as well. Fu he mo e, Mo inga olei e a
lea es which esul ed in ele a ed ace ic, p opionic, and
Table 4. Mechanism o ac ions o emodins in alle ia ing IBD wi h e e ence sou ces ci ed in he a -le column.
Re .
Ac i e ing edien (whe e
iden i ied) and dose
Chemical
s imulus Animal Bioac i i y summa y
Change in gu
mic obio a
P oposed
an ioxidan
mechanism
[80] Emodin; 8.75, 17.5 o 35 mg/kg E. coli
(2.5 × 10
11
CFU/mL)
Male & Female
Kunming mice; n =
80; 10/g oups
↓Pa hological sco e
↓IL-1β, IL-6, TNF-α and COX-
2
↑sIgA and MUC-2
↑Richness and
di e si y
↑Bac e oide es,
↑Fi micu es and
Ve ucomic obia
↓MPO
[81] Emodin; 10, 20 o 40 mg/kg CLP Male BALB/c Mice,
n = 150; 30/g oups
↓In es inal inju y sco e
↓IL-1β, IL-4, IL-17, IL-2, IL-3,
IL-10, TNF-α, IFN-γ, GM-CSF
↑ZO-1 and occludin
↓Caspase-3 and SIRT1
↓P o eobac e ia and
E.coli,
↑Fi micu es and
Bac e oide es
-
[82] Roo s and hizomes o
R. ho aoense – EMO/PSM NPs;
5 o 20 mg/kg
DSS
(6 g/kg/d)
Male BALB/c
mice,
n = 49; 8/g oups
↓Clinical sco e
↓Colon sho ening and
mo phological damage
↑GSH
↓MPO
[83] Emodin; 20, 40 o 80 mg/kg CLP Male BALB/c mice,
n = 48; 8/g oup
↓Sepsis sco e
↓IL-6 and TNF-α
↑GSH
↑SOD
↓MDA
CLP, cecal liga ion and punc u e; COX-2, cyclooxygenase-2; DSS, dex an sodium sul a e; E. coli,Esche ichia coli; EMO/PSM NPs, emodin-loaded poly (DL-lac ide-
co-glycolide)/Eud agi
Ⓡ
S100/mon mo illoni e nanopa icles; GM-CSF, g anulocy e mac ophage colony-s imula ing ac o ; GSH, glu a hione; IFN-γ, in e e on
gamma; MPO, myelope oxidase; sIgA, sec e o y immunoglobulin A; SIRT1, Si uin 1; TNF-α, umo nec osis ac o -alpha; ZO-1, zonula occludens 1.
16 S. SHIN ET AL.
bu y ic acid, in descending o de , led o signi ican ly
dec eased o al polyp bu den and educed p oin lamma o y
chemockine monocy e chemoa ac an p o ein 1 (MCP-1),
while inc eased mo e han wo imes IL-10 [106]. Howe e ,
u he iden i ica ion o SCFA and hei co esponding bioac-
i i y is necessa y, be o e concluding ha widesp ead SCFA
supplemen a ion is sui able as a he apy o he main enance
o emission in pa ien s diagnosed wi h IBD.
Gi en he p oximi y o he gu epi helium o he gu
mic obio a, mul iple pa hways downs eam o SCFA sensing
ha e e ol ed o p omo e gu ba ie unc ion; hese mul iple
ac i i ies a e shown in Figu e 2.
SCFA – bu y a e (C4)
Bu y a e as an i-in lamma o y agen s
In mice, bu y a e o al adminis a ion led o signi ican
educ ion in disease se e i y and his opa hological signs in
IBD such as immune cell in il a ion in colon, and p omo ed
au ophagy [12,98,107,108]. Mo eo e , o he s udies ha e
documen ed ha bu y a e pa ially educed in lamma ion
in mice h ough signi ican inhibi ion o Ci H3 and hus,
po en ially ac ing ia he inhibi ion o NET o ma ion [98].
On he o he hand, i has been obse ed ha bu y a e
e e sed he deple ion o F4/80+ mac ophages induced by
clod ona e liposomes – a common induce o mac ophage
apop osis – in mice insul ed wi h DSS, leading o a signi ican
imp o emen s in goble cell iabili y and mucus sec e ion
om he colon mucosa [12].
Fu he mo e M2 ( esol ing) mac ophage-associa ed genes
and le els o p-STAT6 phospho yla ion in F4/80+ mac o-
phages we e signi ican ly p omo ed a e supplemen ing B-
hyd oxybu y a e (BHB) and his ac i i y was ma kedly sup-
p essed by he pha macological agen AS1517499, which
inhibi s STAT6 phospho yla ion [12,108], implica ing he
STAT6 pa hway in he biological ac ion o bu y a e. In
summa y, mice s udies showed signi ican e ec o bu y a e
in lowe ing DAI and his opa hological ma ke s o colon
damage wi h signi ican p omo ion o he mac ophage M2
pheno ype ha d i es epai and esolu ion o he in lamed
colon.
Bu y a e adminis a ion in human s udies showed signi i-
can educ ion in elease o neu ophil-media ed p oin lam-
ma o y cy okines and supp ession o IBD bioma ke s such
as calp o ec in (CP) and LCN2 (lipocalin 2) [98]. Supplemen ed
pa ien s iden i ied wi h a emissi e UC condi ion also had sig-
ni ican ly lowe mac ophage numbe han ac i e UC pa ien s,
along wi h a ma kedly M2-like immunopheno ype wi hin he
colon lamina p op ia [12]. The imp o emen o bu y a e’s
ea men in mucus ba ie damage was also no ed due o
he inc easing exp ession o MUC2 and SPDEF (SAM poin ed
domain con aining ETS ansc ip ion ac o ) [12], which a e
linked o imp o ed mucosal unc ion.
O e all, bu y a e he apy leads o signi ican ly lowe
disease se e i y and in lamma o y cy okine le el wi h mac o-
phages ha ing a ole in i s mechanism o ac ion in s udies
using animal models and in human ials. Following BHB
he apy, bo h humans and mice, displayed signi ican
educ ion in colonic issue p o ein exp ession o ACAT1,
HMGCS2,BDH1 which a e genes commonly exp essed in
ac i e IBD [109]. Howe e , he e was no signi ican di e ence
in alle ia ing in es inal pe meabili y (ZO-1, occluding) o BHB
ea ed g oup compa ed o con ol g oup i espec i e o
whe he s udies we e conduc ed wi h humans o a using
mouse model. In e es ingly, BHB signi ican ly alle ia ed
DSS-induced in lamma o y signs bu had no e ec wi hou
DSS induc ion, implying i s he apeu ic e ec on only he
inju ed issues [109]. This conclusion may lead o he deduc-
ion ha bu y a e he apy is only e ec i e in damaged
issues. Howe e , ano he s udy showed ha bu y ic acid
only showed signi ican ele a ion in a heal hy g oup, while
signi ican enhancemen o he bu y yl-CoA:ace a e CoA-
ans e ase pa hway, which modula es endogenous bu y-
a e-p oduc ion in he colon, was no ed in his expe imen al
disease model g oup [101]. This leads o he ques ion o
whe he modula ion o he bu y yl-CoA:ace a e CoA- ans e -
ase pa hway and u iliza ion o inc eased bu y ic acid depend
on in lamma o y p ocess and mucosal damage o d i e he
enhanced p oduc ion o his SCFA. Howe e , in di ec con-
as wi h his no ion, supplemen ing wi h sodium bu y a e
showed no signi ican di e ence in disease-induced weigh
loss in a mouse model o IBD [107]. O e all, a pu e an i-in lam-
ma o y ole o bu y a e may no be he sole mechanism o
ac ion, bu a he he ex en o bioac i i y may show some
dependence on heal hy o disease s a e and whe he in e -
ac ion wi h colonic mac ophages occu s a a sui able ime-
ame du ing he pa hogenesis o he disease s age.
Bu y a e as sca enge s o eac i e oxygen species
(an ioxidan capaci y)
Se e al s udies ha e iden i ied ha bu y a e also displays
an ioxidan ac i i y. Fo example, bu y a e adminis a ion
led o dec eased ROS p oduc ion, accumula ed lipid oxi-
da ion (MDA), and neu ophil-MPO le els while inc easing
issue SOD and GSH le els in mice [98]. An inc ease o L-
012 in ensi y, a luminol-based chemiluminescen p obe
used o de ec ROS and eac i e ni ogen species (RNS), was
also obse ed in an expe imen al model, while a less
in ense abdominal signal obse ed in mice ea ed wi h
sodium bu y a e which was consis en wi h dec eased
amoun s o MPO, an enzyme which p oduces ROS [107]. In
addi ion, sodium bu y a e along wi h 5-ASA ea men signi i-
can ly educed lipid pe oxida ion and es o ed GSH, and
induced N -2 ac i a ion leading o enhanced HO-1
exp ession [107]. In conclusion, bu y a e plays a signi ican
ole in a enua ing oxida i e s ess in IBD.
Bu y a e as modula o s o he gu mic obio a
As ha e been men ioned, SCFA a e me aboli es de i ed om
mic obio a and can al e mic obial composi ion [110]. Mos
impo an ly, a human s udy showed ha IBD in emission dis-
played a signi ican inc ease in ecal bu y a e and mic o-
biome known o p oduce bu y a e, showing posi i e
associa ion be ween he alle ia ion o IBD and bu y a e p o-
duc ion [12].
In mouse models o IBD, ea men wi h bu y a e showed
no signi ican e ec in al e ing mic obial α-di e si y.
Howe e , supplemen ed bu y a e led o inc eased abun-
dance in s ains such as Fi micu es and Lachnospi aceae and
changes in hei ela i e composi ion [102,109]. Indeed, bu y-
a e-p oducing bac e ia success ully ele a ed Dac 3
exp ession, which in e ac s wi h c-Jun N- e minal kinase
(JNK) pa hway and was associa ed wi h he alle ia ion o
disease se e i y in lamma o y bioma ke s, esul ha non-
bu y a e p oducing mic obio a was unable o eplica e
[108]. Taken oge he hese da a show ha endogenous
REDOX REPORT 17
bu y a e le els s ongly depend on he mic obiome pheno-
ype and i s capaci y o sus ain bu y a e p oduc ion.
Ano he s udy discussing he mix u e be ween V. a i and
L. acidophilus showed ha his die a y mix u e signi ican ly
ele a ed SCFA le els and lowe ed he Fi micu es/Bac e oide es
a io [100]. T ea men wi h a mix u e o Lupinus albus α-
galac o-oligosaccha ides (LA-GOS) also ele a ed Bac e oide es
and Fi micu es abundance and supp essed he ela i e p o-
po ion o P o eobac e ia abundance [101]. In he DSS coli is
model, in e en ion wi h Lac obacillus plan a um ZJ316,
which u ilizes bu y ic acid, showed a di ec ela ionship
wi h Faecalibac e ium,Aga hobac e , and Fi micu es and
nega i e associa ion wi h Bac e oide es and Ac inobac e ia
[102]. In e es ingly, Faecalibac e ium,Aga hobac e , uniden-
i ied_Lachnospi aceae, and Fi micu es which we e associa ed
wi h bu y ic acid, showed in e se ela ionships wi h in lam-
ma o y cy okines, u he ein o cing bu y ic acid’s capaci y
o alle ia e in lamma ion [102]. Unde he same expe imen al
condi ions, Bac e oide es showed a nega i e associa ion wi h
bu y ic acid, and was linked o inc eased le els o in lamma-
o y cy okines [102], sugges ing ha he ela ionship
be ween bu y a e and mic obio a, is c i ical o amelio a ing
in lamma o y p ocess in he gu . Howe e , a di e en s udy
showed ha bu y a e he apy pos an ibio ic ea men alle-
ia ed disease se e i y, implying bu y a e’s independen
e ec om gu mic obio a while bu y a e’s dependence on
mac ophages was also e iden [109]. Thus he e seem o be
con lic ing esul s in he ela ionship be ween bu y a e and
gu mic obio a while mo e consis en e idence exis s o
bu y a e bioac i i y in p omo ing pheno ypic change in
colonic mac ophages. O e all, he ole o SCFA bu y a e in
p omo ing in es inal epi helial ba ie unc ion and
egula ing he hos mucosal immune sys em in in es inal
inju y h ough he egula ion o oxidan and
in lamma o y pa hway and mic obio a modula ion a e ou -
lined in Table 5.
SCFA – p opiona e (C3)
P opiona e as an i-in lamma o y agen s
An i-in lamma o y e ec o p opiona e has been documen-
ed in s udies ocused on di e en ypes o gu mic obio a,
die , and in di ec supplemen a ion o isola ed cells. P opio-
na e may be indica i e o in lamma ion, o p opiona e-p odu-
cing bac e ium a e s ongly linked wi h he ele a ion o colon
in lamma ion and in es inal damage [111]. Fo example,
P. euden eichii, which has been shown o enhance he p o-
duc ion o mucin, is known o p oduce p opiona e as i s
mos p ominen me aboli e. The adminis a ion o bo h li e
and supe na an de i ed om cul u ed P. euden eichii dis-
plays a simila capaci y o s abilize goble cells exposed o
in lamma o y challenge, indica i e o he an i-in lamma o y
e ec o p opiona e [111]. Consis en wi h his esul men-
ioned abo e, MUC2 p o ein sec e ion, which is a majo com-
ponen o in es inal mucin, was signi ican ly ele a ed by bo h
supe na an and li e P. euden eichii in DSS- ea ed mice
compa ed o DSS-insul alone. This mucin pheno ype was
linked wi h dec easing le els o TNF-α, IL-6, IL-1β, and en-
dency o inc ease IL-10 p oduc ion [111]. Mo eo e , na u al
compounds ha e shown a signi ican inc ease o bu y a e
and p opiona e le els in cecal and ecal con en om mice
insul wi h DSS, which a e co ela ed wi h amelio a e colon
in lamma ion [106].
Howe e , no all a ailable da a is suppo i e o a colon
p o ec i e ole o p opiona e. Thus p opiona e’s biological
e ec may be ques ioned when deli e ed by supplemen ing
in he die . Fo ins ance, a s ed on cu ed mea , which had
18% highe p opo ion o p opiona e han compa able
Figu e 2. Summa y SCFA bioac i i y on a ious in es inal and immune cell ypes. Die a y ibe is e men ed by gu mic obio a, leading o he p oduc ion o SCFAs.
SCFA a e ligands o ecep o s on colon epi helial cells o he colonic mucosa and immune cells such as mac ophages, lymphocy es, and neu ophils. Speci ically,
bu y a e in e ac s wi h in es inal synap opodin, o aid wound healing and in es inal pe meabili y h ough he supp ession o his one deace ylase (HDAC) and NF-
kB. SCFAs a e also associa ed wi h mac ophage pola iza ion owa ds an i-in lamma o y M2 mac ophages, which inc eases he sec e ion o an i-in lamma o y IL-10
cy okine. SCFA in e ac s wi h T-cell p oli e a ion and ac i a ion, enhancing T egula o y cells and supp essing p o-in lamma o y T cells, along wi h modula e
in lammasome.
18 S. SHIN ET AL.
amoun s o esh mea , did no lead o a signi ican di e ence
in CRP le els, in lamma o y cy okines such as IL-6 and p o-
in lamma o y TNF-α, which did no inc ease abo e he limi
o de ec ion in he absence o p esence o p opiona e
[112]. A simple explana ion o his lack o bioac i i y may
be ha an 18% highe load o die a y p opiona e was no
su icien o yield a biological di e ence, albei ha no mal
die a y p opiona e in ake in humans is commonly less han
he le el es ed in his s udy [112].
P opiona e as sca enge s o eac i e oxygen species
(an ioxidan capaci y)
In colon ea ed wi h Mo inga olei e a which showed a signi i-
can inc ease in bo h ace ic and p opionic acids, a pa allel and
signi ican inc ease in NADH-quinone educ ase (NQO1)
ac i i y (2.5- old) and glu a hione-S- ans e ase (GST) (1.5-
old) ac i i y was de e mined in he colon. Pa allel dec ease
o colonic neu ophil ec ui men by 2.5- old was also
de ec ed, wi h a concomi an 20% dec ease in MPO concen-
a ion leading o 2.3- old lowe de ec ion o he lipid oxi-
da ion bioma ke MDA in colon issues, which is consis en
wi h a dec ease in oxida i e damage in hese issues. These
esul s may sugges a close ela ion be ween p opionic acid
p oduc ion and alle ia e o oxida i e s ess [106].
P opiona e as modula o s o he gu mic obio a
Al hough educ ion in in lamma ion was obse ed, p opionic
acid may encou age pa hogenic mic obio a g ow h. Fo
Table 5. Mechanism o ac ions o bu y a e in alle ia ing IBD wi h e e ence sou ces ci ed in he a -le column ( o be con inued)
Re .
Ac i e Ing edien
(whe e iden i ied)
and dose
Chemical
s imulus Animal Bioac i i y Summa y
Change in gu
mic obio a
P oposed an ioxidan
mechanism
[89] Bu y a e; 0–1.6 mM -UC pa ien s
n = 28
T cell ea ed wi h Bu y a e:
↓CD4+, CD8+ T cell
p oli e a ion
↓T cell ac i a ion,
↓CD25+ cells
↓HDAC I/II
- -
[98] Bu y a e; 200 mM DSS
(2.0%)
mice only
IBD pa ien s
n = 187;
n = 112 ac i e CD,
n = 43 ac i e UC, n =
32 HC
Male C57BL/6 mice,
n = 48; 12/g oup
CD and UC pa ien s:
↓IL-6, IFN-γ, TNF-α, IL-17A, IL-
22, IL-8, S100A8/9 and LCN2
↓Neu ophil mig a ion
Mice:
↓Body weigh loss,
↓Colon sho ening,
↓Pa hological disease sco e,
↓IL-6, TNF-α, INF-γ, CXCL1,
S100A8/9, LCN2 and Ci H3.
-CD and UC pa ien s:
↓MPO
Mice:
↓ROS
[12] Bu y a e; 20 mg/kg DSS
(3.0%)
mice only
UC pa ien s
n = 28; ac i e and
inac i e UC
Male BALB/c
mice,
n = 24; 6/g oup
Inac i e UC pa ien s:
↑Bu y a e le el
↓Mac ophage exp ession
↑A g1+ (M2-like
immunopheno ype)
Mice:
↓Body weigh loss
↓DAI
↓Epi helial damage
↓Goble cell loss
↓Leukocy e in il a ion and F4/
80+ mac ophages.
↑MUC2 and SPDEF exp ession.
Inac i e UC pa ien s:
↑Lachnospi ceae
↑Ruminococcaceae
Inac i e UC pa ien s:
↓iNOS
↑CD206/iNOS
[109] BHB ke one; 15 mg/
25 g
DSS
(2.5%)
mice only
IBD pa ien s (ac i e
and emission CD
and UC);n = 112
Male C57BL/6J mice,
n = 20–40; 7–10/
g oup
Ac i e IBD pa ien s:
↓ACAT1, HMGCS2, BDH1.
Mice:
↓Body weigh loss
↓DAI and colon sho ening
↓His ology sco e
↑IL-4Ra, IL-10, A g-1, Chil3
↑F4/80+CD206+ M2
mac ophages mRNA
exp ession
↑p-STAT6 in F4/80+
mac ophages.
Mice:
↑Fi micu es
↑Lachnospi aceae
↓Lac obcillaceae
-
[107] Sodium bu y a e
(NaB); 0.1 M o 500
g/kg/day
DSS
(2.5%)
Male C57BL/6
mice,
n = 44; 8-12/g oup
↓Mo ali y a e
↓DAI and colon sho ening
↓His opa hology sco e
↓In lamma o y cell in il a ion
↓Tissue damage,
↓NF- κB/NLRP3
↑Pink1/ Pa kin axis
↑LC3 II
↓p62*,
↑COX-2
-↓L-012 luminescence
in ensi y ↓Lipid
pe oxida ion p oduc s
↑GSH le el
↑N -2/ HO-1
ACAT1, ace yl-CoA ace yl ans e ase 1; A g-1, a ginase 1; BHB, ke one body B-hyd oxybu y a e; BDH1, 3-hyd oxybu y a e dehyd ogenase I; Chil3, chiinase-like
p o ein; CD: C ohn’s disease; CXCL-1, Chemokine ligand 1; Ci H3, Ci ullina ed H3; COX-2, Cyclooxygenase-2; DSS, Dex an sodium sul a e; DAI, Disease Ac i i y
Index; HC, heal hy olun ee s; HDAC, his one deace ylases; HMGCS2, 3-hyd oxyme hylglu a yl-CoA syn hase 2; IFN-γ, In e e on gamma; MPO, Myelope ox-
idase; NF-κB, Nuclea ac o kappa B; NLRP3, NOD-like ecep o p o ein 3; LCN2, lipocalin-2; LC3, Mic o ubule-associa ed p o ein 1A/1B-ligh chain 3; TNF-
α, Tumo Nec osis Fac o -alpha; UC, Ulce a i e coli is.
REDOX REPORT 19
ins ance, O msby e al. [113] ha e showed ha p opionic acid
encou aged anae obic bio ilm o ma ion, which a e con-
side ed pa hological in he sense ha hese s uc u es a e
highly esis an o he apies o modula e bac e ial g ow h
and can lead o skewing mic obio a popula ions [114]. In e -
es ingly, i was seen ha p opionic acid was unable o al e
LF82 (a s ain o adhe en -in asi e E. coli (AIEC) in ec ion) in
ileum and la ge colon, howe e , p e-exposu e o AIEC o p o-
pionic acid combined wi h exogenous p opionic acid sup-
plemen a ion p omo ed coloniza ion and long- e m
pe sis ence [113]. This calls in o ques ion whe he p opionic
acid he apy will con ibu e o aiding su i al o pa hogenic
mic obio a due o a nu i ional e ec , which may lead o an
exace ba ion o colon in lamma ion. In ac , LF82 which
in ec ed PA- ed mice was signi ican ly mo e compe i i e
compa ed o wa e - ed mice [113]. Al hough p opionic acid
may ha e an imic obial p ope ies, adap abili y o mic obial
s ains should be conside ed.
As has been men ioned p e iously, cu ed bee compa ed
o esh bee displayed 18% highe p opiona e le el and
25% lowe bu y a e le el. Ra s ea ed wi h cu ed bee exhib-
i ed signi ican ly highe ope a ional axonomic uni ichness
and signi ican di e ence in mic obial composi ion compa ed
o a s ed on esh bee . Addi ionally, a s ed bee had sig-
ni ican ly highe cecal le els o ale a e (+10.3%), o al
b anched chain a y acids (BCFA, +16.3%), iso-bu y a e
(+14.8%) and end o highe iso- ale a e le els (+17.8%)
compa ed o a s on he chicken die s [112]. Howe e , o al
SCFA (including ace a e) did no show a signi ican di e ence
based on he g oup compa isons, which may imply p opio-
na e as he p ominen bioac i e me aboli e ha is in ol ed
in colon p o ec i e ac ions [112]. In e es ingly, e en hough
he al e a ion o p opiona e le el was obse ed, he e was
no signi ican change in abundance o Lac obacillus [112],
s ains ha ha e shown o signi ican ly p oduce SCFA [115].
O he nu i ional ac o s ha e o be in es iga ed o de ec
mic obio a al e a ion. Fo example, in his s udy he sal
con en in he cu ed mea may explain why Lac obacillus
was no signi ican ly a ec ed.
Mos ele an changes o p opiona e and i s impac on
in es inal in lamma ion a e shown in Table 6.
SCFA – ace a e (C2)
Ace a e as an an i-in lamma o y agen
Supplemen ing ace a e o ace a e-p oducing mic obio a is
documen ed o amelio a e in lamma o y esponse, leading
o p ese ed body weigh , lowe mo ali y, lowe disease
se e i y, less sho ening o colon, amelio a ion o in es inal
pe meabili y o ba ie , lowe his opa hological sco e,
lowe ed in lamma o y cell in il a ion, an icance ac i i y,
and inhibi ed cell damage and dea h in expe imen al
animal models [116–119]. Fu he mo e, IL-1β, IL-13, and
TNF-α we e also signi ican ly inhibi ed by added ace a e
[116].
The inc ease o ace a e p oduc ion and i s po en ial ben-
e icial e ec on in lamma ion can be media ed by ibe
in ake. Fo ins ance, when ace a e was adminis a ed in
mice wi h a de iciency ibe die , he supp ession o disease
se e i y, neu ophil le el, and body weigh loss bu no
colon sho ening was obse ed [120]. Signi ican supp ession
o IL-1β elease was also obse ed in mice ha ecei ed o al
Ch is ensenella minu a DSM 22607, which p oduce 5:1 a io o
ace a e and bu y a e, bu no signi ican e ec on weigh gain
[121]. The e may be ac o s in luencing hese esul s. Fo
ins ance, algina e oligosaccha ide adminis a ion – a sou ce
o die a y ibe – led o signi ican ly inc eased weigh in
male a s compa ed o emale a s, which may allude o sex
di e ence in AOS e ec i eness [122]. An ele a ed o al
SCFA con en and an inc eased mic obiome abundance/
di e si y in he p esence o bu y a e and ace a e, bu no p o-
piona e, we e seen in males compa ed o emales [122]. P e-
exis ing colonic damage may be a signi ican ac o as well, as
dichlo oace a e showed no signi ican changes in heal hy
colon, indica ing i s he apeu ic ac ion may be con ained
only o damaged colon [116]. Besides, dichlo oace a e did
no lead o a enua ion o nuclea ac o o ac i a ed T cells
1 (NFATC1), NLRP3 in lammasome, NF-κB nuclea ac ion,
clea ed caspase-1 exp ession in no mal heal hy mice.
Howe e , in expe imen al coli is in mice signi ican a enu-
a ion o p o eins men ioned abo e was seen [116]. Fu he -
mo e, mo e esea che s ha e men ioned di e en
ea men s such as Zea alenone – an es ogenic myco oxin
– has a signi ican impac in inc easing he abundance o
SCFAs p oducing bac e ia as well as he ecal ace a e
con en , along wi h supp essing Ras/Ra /ERK/cyclin D1
pa hway [118].
Ace a e as sca enge s o eac i e oxygen species
(an ioxidan capaci y)
As ace a e displays an i-in lamma o y ac ion, an i-ROS ac ion
was expec ed as well. Indeed, bioma ke s o in lamma ion
and oxida i e s ess we e signi ican ly a enua ed by dichlo -
oace a e, including NO and MPO [116]. MPO was also signi i-
can ly lowe ed in mice ea ed wi h L. acidophilus and
C. minu a, likely due o supp ession o LCN-2 and cy okines
such as IL-1β in he colon [121,123]. The e a e limi ed da a
o demons a e an ioxidan e ec o ace a e; howe e , i is
possible o suspec ha he educ ion in in lamma o y cy o-
kines le el may also con ibu e o educing oxida i e s ess
in he same local issue en i onmen .
Ace a e as modula o s o he gu mic obio a
Besides al e a ion on in lamma o y pa hways and oxida i e
s ess, signi ican changes o gu mic obial composi ion
we e seen in he apies ha signi ican ly a ec ace a e
le els, which can be ound in Table 7. Amino acids such as
yp ophan and phenylalanine showed associa ion wi h gu
mic obio a, which call in o ques ion whe he he e ec s a e
due o ace a e i sel o an accumula ion o mul iple ac o s
[124]. In suppo o his poin , L. bacillus shows di ec ela ion-
ships wi h he ele a ion o endogenous ace a e, glycine, and
aspa ic acid, and P e o ella is linked wi h he ele a ion
glycine and aspa ic acid [123], hence any biological ac ion
canno be asc ibed o ace a e alone.
Zea alenone, which showed a signi ican an i-in lamma-
o y esponse, also led o a signi ican inc ease in uniden i ied
Ruminococcaceae,Pa abac e oides,Blaus ia, which a e known
as SCFA p oducing bac e ia. Consequen ly, signi ican ly ele -
a ed ecal ace a e was de ec ed, and ecal ace a e showed
in e se ela ionship wi h smalle umo s (<2 mm), implying
an icance quali y o ace a e [118].
Howe e , he he apeu ic esponse may be associa ed
wi h he capaci y o espond o al e ed gu mic obio a o
endogenous SCFA p oduc ion. In suppo o his idea, an
inc ease o goble mucus-sec e ing cells occu s in pa allel
20 S. SHIN ET AL.

wi h inc eased abundance o Ve ucomic obio a,Bi idobac e -
ium,Anae os ipes,Anae oplasma,Blau ia, and Akke mania in
male a s compa ed o emale a s a e algina e oligosaccha -
ide he apy, along wi h a signi ican pa allel inc ease in
ace a e and bu y a e compa ed o emale a s [122]. This
may imply ha he ex en o he apeu ic esponse may
depend on an indi idual’s espond o SCFA p oducing
he apy, as male a s showed signi ican ly enhanced he a-
peu ic esponse when ace a e and bu y a e p oduc ion
inc eased in pa allel.
P obio ics
P obio ics may be an essen ial he apeu ic agen ha can
modula e he hos –mic obe in e ac ion leading o po en ially
bene icial ou comes o IBD pa ien s, which can be used bo h
as a single agen and an adjunc i e supplemen con en ional
he apeu ics [125]. P obio ics, along wi h p ebio ics and sym-
bio ic, a e die a y supplemen s which can p oduce a syne gis-
ic e ec when aken oge he . P ebio ics, which usually
consis s o non-diges ible ibe , is a nu i ional sou ce o p o-
bio ics h ough ac i e e men a ion in he GI ac ha yields
se e al bene i s o he hos including p omo ion o selec i e
bac e ial g ow h, which may con e a heal h bene i [126]. Fla-
onoids and ibe can be conside ed p ebio ics, as desc ibed
abo e. A he same ime, synbio ics a e a combina ion o p o-
bio ics and p ebio ics. The no ion o induce syne gis ic e ec s
by combining p o and p ebio ics is commonly o mula ed
wi h a combina ion o lac obacillus GG o Bi idobac e ia, and
inulin o oligosaccha ides in a ange o p opo ions and
hese o mula ions in IBD [127].
A me a-analysis o andomized con olled ials e ealed
bo h ecal mic obio a ansplan (FMT) and VSL#3 (a
mix u e o p obio ics, including s ains o lac obacilli,bi ido-
bac e ia, AND S ep ococcus sali a ius) showed bene icial
he apeu ic esponse in UC wi h signi ican ly mo e pa ien s
achie ing clinical emission compa ed o placebo con ols.
Ou comes om his e iew also highligh ed ewe se ious
side e ec s om VSL#3′s compa ed o FMT ea men [128].
In e ms o mechanism o ac ion, he a ailable da a shows sig-
ni ican educ ion o TNF-α, IL-1β, IFN-γ, and signi ican
ele a ion o IL-10 in pouchi is o he ileal ese oi a e
VSL#3 he apy implying a speci ic p obio ic e ec in he
ileal pouch [129]. Simila ly, VSL#3 showed ma ked e icacy
o pos ileo-anal pouch su ge y o an ibio ic-induced emis-
sion o pouchi is [130]. Indeed, when VSL#3 adju an he apy
was added o balsalazide (as a con en ional an i-in lamma-
o y IBD d ug), signi ican ly mo e pa ien s (p< 0.02) we e
able o achie e emission and imp o e hei endoscopic, clini-
cal, and his ology sco es compa ed o ea men wi h balsala-
zide alone, including a aining emission signi ican ly as e
compa ed o he con en ional ea men [131]. Mo e ecen
e idence has shown he clinical bene i o combining VSL#3
(p esc ibed a dose o 3.6 × 10
12
CFU [132,133]) wi h p ima y
yields imp o ed a es o emission and clinical sco e (UC
Disease Ac i i y Index; UCDAI) o UC pa ien s compa ed o
con en ional he apy alone. Howe e , despi e hese docu-
men ed posi i e ou comes, he e ec i eness o p obio ics
as a po en ial ea men o UC emains unce ain. Fo
ins ance, ano he e iew o andomized con olled ials
showed a e y low ce ain y ha p obio ics adminis e ed
ei he alone o combined wi h 5-ASA, help o p e en clinical
elapse and main enance o emission [134]. Simila ly, he
cu en guidelines o IBD managemen in child en do no
ecommend p obio ic adju an he apy o CD and u he -
mo e, is unclea on whe he VSL#3 o E. coli Nissle 1917 is
bene icial o he ea men in child en wi h UC [135]. Al e na-
i ely, VSL#3 oge he wi h an ibio ic he apy has shown
he apeu ic bene i s in he p e en ion o pos -ope a i e
ecu ence o CD [136]. On balance i is easonable o con-
clude ha he cu en body o a ailable e idence is con lic -
ing and does no p o ide a clea pa hway o de elop
guidelines on he use o p obio ic he apy o IBD.
Con empo a y app oaches ha may imp o e he use o
p obio ics o clinical applica ion include p obio ic deli e y
wi h nanoenzyme coa ing he apy. Tes ing o his no el p o-
bio ic o m led o signi ican imp o emen in weigh loss, epi-
helial cell apop osis, which subsequen ly enhanced MUC2
exp ession le els, igh junc ion p o ein in e ac ions, and
dec eased DAI in an animal model o IBD [35]. In addi ion,
in i o s udies using mesalamine loaded wi h p obio ics
showed signi ican es o a ion o body weigh , ecal consis -
ency, and dec eased ecal bleeding [36]. Below, we b ie ly
discuss he an i-in lamma o y, gu mic obio a es o a i e,
and an i-oxida i e e ec s o p obio ics; mo e de ails a e
shown in Table 8.
P obio ics as an an i-in lamma o y adju an he apy
Mic obio a ha e been conside ed a key ac o in he de elop-
men o IBD, which can be modi ied by die and/o sup-
plemen s using bene icial bac e ia o bene icial compound
Table 6. Mechanism o ac ions o p opiona e in alle ia ing IBD wi h e e ence sou ces ci ed in he a -le column (To be con inued).
Re .
Ac i e Ing edien (whe e iden i ied)
and dose
Chemical
s imulus Animal
Bioac i i y
Summa y Change in gu mic obio a
P oposed
an ioxidan
mechanism
[113] Bu y a e; 200 mM E. coli s ains
(1 × 10
9
CFU)
Male C57BL/6
mice,
n = 24; 4/
g oup
–↑Adhesion and in asion,
↑Bio ilm,
↑Acid ole ance,
↑Pe sis ence in ileum and colon
–
[112] Cu ed chicken o bee ; con aining 20 g/
kg ni i e sal and 0.5 g/kg sodium
asco ba e.
– Male Sp ague-
Dawley a s,
n = 40; 8/
g oup
Cu ed mea :
↑U ine
p oduc ion,
↓Mesen e ic a ,
↓Re ope i oneal
a ,
↑PCC in a s.
Cu ed mea (mainly Bee ):
↑BCFA,
↑Vale a e, o al iso-bu y a e,
ca bon disul ide, indole and
c esol
↑OTU,
↑18% p opiona e,
↓25% bu y a e.
Cu ed mea
(mainly Bee ):
↓Oxida i e s ess
↑s omach 4-HNE
↑GSH-Px.
BCFA, b anched-chain a y acids; CFU, Colony- o ming uni ; GSH-Px, Glu a hione pe oxidase; 4- HNE, 4-hyd oxynonenal; OTUs, Ope a ional axonomic uni s; PCC,
P o ein ca bonyl compounds.
REDOX REPORT 21
de i a es om bac e ia (pos -bio ic) [137,138]. O no e, Lac-
obacillus and Bi idobac e ium s ains a e mo e likely o be
s udied in he managemen o IBD. Fo ins ance, Lac oba-
cillus adminis a ion led o signi ican amelio a ion o
disease se e i y including educing goble cell and
colonic c yp damage, imp o emen in DAI, colon sho en-
ing, in lamma o y cell in il a ion, epi helial damage,
in lamma o y ac o exp ession, and mig a ion o CD206
+
mac ophages in o he colon issue [139–143]. Fu he mo e,
he exp ession o p o eins such as occludin, claudin-1, and
ZO-1 was signi ican ly ele a ed wi h Lac obacillus sup-
plemen a ion [140,144], leading o enhanced in es inal
pe meabili y and ba ie unc ion [145]. Signi ican ly
lowe ed Th17 cell le el and ele a ed T eg cells we e also
obse ed in pa allel, implying p obio ics’ abili y o egula e
T cells [146]. The e idence o speci ic bac e ial s ain and
hei impac on IBD is lis ed below:
-Lac obacillus hamnosus s ain GG has no shown obus e i-
dence o induce o main ain emission in CD a e 6
mon hs [147]. Such di e ence in he he apeu ic e ec
o Lac obacillus may be dependen on he p esence o
ongoing insul o damage. Lac obacillus hamnosus GG
showed g ea e an i-apop o ic e ec when combined
wi h a pa hogen bac e ia [146], implying p obio ics’
e ec may depend on h ea o damage.
- Li e Lac obacillus acidophilus signi ican ly inhibi ed IL-18, IL-
1β, NLRP3 ac i a ion, enhancing au ophagy. Howe e ,
no educ ion o hese in lamma o y ma ke s was
obse ed when L. acidophilus was p o ided in non-
iable bac e ial o supe na an (con aining sec e ed
compound) o ms [141].
-Lac obacillus sali a ius UCC118 imp o ed IL-10 le el includ-
ing M2 mac ophages bu showed no signi ican di e -
ence in e ms o colon sho ening, and in es inal
pe meabili y shown by igh junc ion p o ein exp ession
[143].
-Lac obacillus plan a um s ains showed e icacious e ec s on
body weigh , colon leng h, and an i-in lamma o y cy o-
kine p oduc ion. In addi ion, high dose o L. plan a um
L1 ma kedly diminished DAI sco e and simul aneously
educed p o-in lamma o y cy okine p oduc ion, by
down egula ing he exp ession o TLR4, MyD88, and
NF-κB [148].
-Lac obacillus casei s ains LH23, LH1129, and LH1134
showed signi ican ly ele a ed capaci y o adhe e o
mucosal cells in in i o s udies, indica ing i s po en ial
o be mo e e ec i e compa ed o o he s ains wi h
lowe adhesi e quali ies. Imp o ed SCFA le el and p o-
mo ion o T eg di e en ia ion lead o diminished
immune esponses [149].
-Lac obacillus b e is-de i ed long-chain polyphospha e sig-
ni ican ly inc eased pla ele accumula ion and agg ega-
ion and in i o, leading o enhanced healing o he
colonic mucosa. In e es ingly, i did no signi ican ly
ele a e o he known ac o s con ibu ing o mucosal
healing such as ascula endo helial g ow h ac o
(VEGF), epide mal g ow h ac o (EGF), pla ele -de i ed
g ow h ac o (PDGF), and ans o ming g ow h ac o -
β (TGF-β) [150], sugges ing i s mechanism o ac ion
emains o be iden i ied.
On he o he hand, he mos equen ly in es iga ed p o-
bio ic as an al e na i e ea men o IBD is Bi idobac e ium.
No ably:
-Bi idobac e ium bi idum s ains (FL-276.1 and FL-228.1) a e
gene ally conside ed o o e he bes bene icial impac
on IBD when compa ed wi h o he s ains o he an i-
in lamma o y agen 5-ASA. Fo example, he adminis-
a ion o FL276.1 and FL228.1 amelio a es he decline
in DAI and body weigh while also inhibi ing colon sho -
ening. Addi ionally, mice ea ed wi h hese wo s ains
showed an up- egula ion o he ZO-1, claudin-4, occlu-
din, and Muc2 genes in colon issue, while TNF-α, IL-1β,
and IL-6 we e down egula ed [151].
-Bi idobac e ium bi idum BGN4 signi ican ly amelio a ed he
symp oms o DSS-induced coli is, inc easing he
exp ession o igh junc ion genes and dec easing p o-
in lamma o y cy okines such as IL-6, IL-1β, and TNF-α
[152].
-Bi dobac e ium animalis spp. Lac is (BI 5764) s ain showed
an imic obial e ec agains C. oden ium in ec ion,
Table 7. Mechanism o ac ions o ace a e in alle ia ing IBD wi h e e ence sou ces ci ed in he a -le column (To be con inued).
Re .
Ac i e ing edien (whe e
iden i ied) and dose Chemical s imulus Animal Bioac i i y summa y
Change in gu
mic obio a
P oposed
an ioxidan
mechanism
[116] Dichlo oace a e; 100 mg/kg Topical Oxazolone (3%) →
Enema oxazolone (1%)
Male BALB/c
mice;
n = 20; 3-
5/g oup
↓His opa hological sco e and
disease ac i i y index
↑Colon leng h
↓NLRP3, NFATC, NF-κB and
caspase-1
↓IL-1β and IL-13
-↓MPO
↓NO
[117] Ace a e enema; 10 mM DSS
(2.5%)
Male C57BL/
6
mice;
n = 10; 5/
g oup
↓DAI
↓Mucosal b eak a io
- -
[120] Sodium ace a e; 200 mM DSS
(0.5–2.5%)
No Fibe
Male C57BL/
6J mice;
n = 20; 5/
g oup
↓DAI
↑Body weigh
↓Colon leng h
↓Blood neu ophils
↓CXCR2
- -
CXCR2, In e leukin 8 ecep o ; DSS, Dex an sodium sul a e; DAI, Disease Ac i i y Index; MPO, Myelope oxidase; NFATC, Nuclea ac o o ac i a ed T cells; NF-κB,
Nuclea ac o kappa B; NLRP3, NOD-like ecep o p o ein 3; NO, Ni ic oxidase; NLRP3, NOD-like ecep o p o ein 3.
22 S. SHIN ET AL.
Table 8. Mechanism o ac ions o p obio ics in alle ia ing IBD wi h e e ence sou ces ci ed in he a -le column ( o be con inued)
Re .
Ac i e ing edien (whe e iden i ied) and
dose
Chemical
s imulus Animal Bioac i i y Summa y Change in gu mic obio a
P oposed
an ioxidan
mechanism
[35] P -Lipid@EcN; dose n/i DSS (3%) Sex unspeci ied,
C57BL/6
Mice;
n = 15; 4
g oup
↑Body weigh
↓DAI
↑Colon leng h
↓His opa hology sco e
↓IL-6, TNF-α and IL-1β
↑Occludin-1 and ZO-1
-↓MPO ac i i y
[36] Mesalamine and Lac obacillus
acidophilus mic opa icles (F12);23
mg/kg/day
DNBS (15
mg/kg)
Female and
Male Wis a
a s: n = 30; 6/
g oup
↓Body weigh loss,
↑S ool consis ency,
↓Lesion sco e
↓Mac oscopy sco e
-↑GSH
↓MPO
↓LPO
[96] 7-mix s ains (E. hi ae, L. casei,
S. sali a ius, F. p ausni zii,
A. muciniphila, C. bu y icum,
L. sali a ius), mix-sup o hu-FMT;
1×10
8
CFU pe s ain and 0.1 mL/10 g
o body weigh o hu-FMT.
DSS (3%) Male BALB/c
Mice;
n=30; 6/g oup
↑Body weigh
↓Colon sho ening
↓His ology sco e
↑Occludin, ZO-1 and
Muc2
↓IL-6, IL-1β, IL-12 and
TNF-α
↑IL-5
↓M1 (CD86+) o mix-
sup only
↑M2(CD206+)
mac ophages o mix-
sup and 7 mix only.
↓JAK/STAT3/FOXO3 o
mix-sup and 7 mix only.
Mix-sup and 7-mix:
↑α-di e si y
↑A. muciniphila
↑L. sali a ius
↑F. p ausni zii
↑Ace ic acid
↑P opionic acid
↑Bu y ic acid
↑Vale ic acid
↑Lac obacillaceae,
Lac obacillus, Lachnospi aceae,
Lac obacillus mu inus in mix-
sup
↑Bac e oidales in he 7-mix
g oup
↓MPO
↓iNOS o 7-
mix and mix-
sup only.
[100] Bu y a e-p oducing Veillonella and
lac obacillus; 1 × 10
9
CFU mL
−1
DSS
(2.5%)
Male C57BL/6
mice;
n = 60; 12/
g oup
↓Body weigh loss
↓DAI sco e
↓Fecal occul blood
↓Colon sho ening
↓His ological sco es
↑Occludin
↑Ace ic acid
↑Isobu y ic,
↑To al SCFA
↓Lac a e
↑Ligilac obacillus
↑ o al Lac ic acid bac e ia
↑Ve ucomic obio a
↑Akke mansia
↑bac e oides
↑SOD
↑GSH
↓MDA
↓MPO
[102]Lac obacillus plan a um ZJ31; 2.5 × 10
9
CFU mL
−1
DSS
(2.5%)
Male BALB/c
mice;
n = 25; 5/
g oup
↑Colon weigh
↑Colon leng h
↓His ological sco e
↓IL-6, IL-8, IL-1β and
TNF-α
↑Faecalibac e ium
↑Aga hobac e ,
↑Rosebu ia.
↑Fi micu es
↓Bac e oide es
↓Ac inobac e ia
↑In es inimonas
↑Bu y icoccus
↓Pa acoccus
↓E ysipela oclos idium
↓Acine obac e
↓Lu eimonas
↑Ace ic acid
↑P opionic acid
↑Isobu y ic and Bu y ic acid
↑Vale ic acid
-
[108] Bu y a e-p oducing Faecalibac e ium
p ausni zii A2–165; 1 × 10
9
CFU
DNBS
(200
mg/kg)
Male C57BL/6
mice;
n = 24; 8/
g oup
↑Dac 3
↓Body weigh loss
↓IFN-γ, IL-6, IL-17A,
MCP-1
-↓MPO ac i i y
[111]P opionibac e ium euden eichii; ‘LPF’; 1
× 10
8
CFU and ‘SPFC’; 1 mL
DSS
(5%)
Male Sp ague-
Dawley a s;
n = 30; 6/
g oup
SPFC:
↓His opa hology sco e
↑Goble cell and Mucin
LPF:
↑Body weigh change ↓
DAI
↓His opa hology sco e
↑Goble cells and MUC2
le el
↓TNF-α, IL-6, IL-1β
SPFC:
↑Ace a e
↑P opiona e
↑Bu y a e
LPF:
↑Ace a e
↑P opiona e
↑Bu y a e
-
[121] Ace a e-p oducing bac e ia
Ch is ensenella minu a; 1 × 10
9
CFU/
mL
DNBS
(175
mg/kg)
Male C57BL/6J
mice;
n = 40; 10/
g oup
↓Mac oscopic and
mic oscopic sco e ↓
Colon weigh
↓IL-1β
-↓MPO
[123]Lac obacillus acidophilus KBL402 and
KBL409; 1 × 10
9
CFU
DSS
(2%)
Female C57BL/
6J mice;
n = 32; 8/
g oup
↑Body weigh change %
↓DAI
↑Colon leng h
↓His ological sco e
↓FN-γ, IL-1β, IL-4, IL-6,
IL-17A, TNF-α
↑Akke mansia
↓Bac e oide es
↓Mucispi illum
↑P e o ella
↓CCL2
↓CXCL-1
↓MPO
(Con inued)
REDOX REPORT 23
Table 8. Con inued.
Re .
Ac i e ing edien (whe e iden i ied) and
dose
Chemical
s imulus Animal Bioac i i y Summa y Change in gu mic obio a
P oposed
an ioxidan
mechanism
[139]Lac obacillus johnsonii; 1 × 10
9
CFU/day DSS
(2%)
Male C57BL/6
mice;
n = 10; 5/
g oup
↑Colon leng h
↓His ology sco e
↑Muc2 and ZO-1+
↓Mac ophages
in il a ion
↑F4/80+CD11b+Ly-6G
↑IL-10 in ↑C206+ om
BMDMs
↑P e o ellaceae,
↑Clos idia,
↑Bac e oido a,
↓Ac inobac io a,
↓Lachnospi aceae,
↓E ysipelo ichaceae,
↓Oscillospi aceae
↓Fe micu s
-
[140] Chinese e men ed oods Lac obacillus
alimen a ius NKU556; 0.2 mg mL
–1
Fe
2+
DSS
(4%)
Male BALB/C
mice,
n = 60; 12/
g oup
↓Colon sho ening
↓His ological sco e
↓DAI
↓Body weigh loss
↓TNF-α, IL-17, IL-1β,
↓LCN2
↑Claudin-1, occluding
and ZO-1
↑Hepcidin
-↓MDA
↑SOD
↑GSH-PX
[141]Lac obacillus acidophilus; 1×10
8
CFU DSS
(5%)
Male Sp ague
Dawley a s;
n = 70; 10/
g oup
Li e L. acidophilus:
↑Body weigh
↓DAI
↑Colon leng h
↓His ologic sco e
↑Occludin, Claudin, ZO-
1 and TFF-3
↓TNF-α, IL-6 and MCP-1
↑IL-10
↓NLRP3, Caspase 1 and
ASC
↓IL-1β and IL-18
↑LC3II/I and ↓P62
↑Fecal ace ic acid
↑P opionic acid
↑Bu y ic acid
↑Cap oic acid
↑Blau ia ae
↑Faecalibac e ia p ausni zii
↑Rumicococcus o ques
↑GSH-PX
↓MDA
↑CAT
[142]Lac obacillus plan a um CBT LP3; 1 ×
10
8
CFU/day
DSS
(2.5%)
Female C57BL/6
mice;
n = 25; 5/
g oup
↓Body weigh loss
↓DAI
↓His omo phological
sco e
↑Colon leng h
↑Goble cell coun
↓TNF-α, IL-1β and IL-17
-↓iNOS
[143]Lac obacillus sali a ius; 1 × 10
9
CFU/day DSS
(2.5%)
C57BL/6JOlaHsd
mice;
n = 16; 4/
g oup
↑Blood sco e
↓S ool sco e
↓DAI
↑Colon leng h
↑T ansepi helial
esis ance
↑IL-10
↑Ve ucomic obia
↑Lac obacillus
↑Clos idia XIVa
↑Akke mansia
↓P e o ella
↓Allop e o ella,
↓Bac e oides
↓Po phy omonadaceae
↓Alis ipes
↓MPO ac i i y
[144]Lac obacillus acidophilus@hyalu onic
acid g a ed wi h phenylbo ic acid
(Lac@HDP); 1 × 10
9
CFU
DSS
(3%)
Female C57BL/6
mice:
n = 20; 5/
g oup
↑Colon leng h
↓IL-6, IL-1β, TGF-β
↑IL-10
↑ZO-1 and occludin-1
↑Bac e ial coun s
↑Adhesion abili y Lac@HDP
↑Bac e ial abundance
↓Desul o ib ionaceae
↑Lac obacillus
↑Akke mansia
-
[146]Po phy omonas gingi alis and
Lac obacillus hamnosus GG
p obio ics; 50 μg mL
−1
DSS
(3%)
Female C57BL/6
mice;
n = 25; 5/
g oup
↑Colon leng h
↓DAI
↓His ological ac i i y
index
↓IL-17/ Foxp3+ cell
a io
↓Th17/ T eg a io
↓IL-17A, IL-17F and IL-6
- -
[148]Lac obacillus plan a um s ains; 1 × 10
9
(Low dose) o 1 × 10
10
(High Dose)
CFU/mL/day
DSS
(3.5%)
BALB/c mice
Sex n/i;
n = 60;12/
g oup
Low Dose:
↑Body weigh change%
↓DAI
↑Colon leng h
↑IL-10
↓TNF-α, IL-1β and IL-12
High Dose:
Same esul s as he ‘low
dose’ PLUS
↓His ological sco e
↓TLR-4
↓MyD88, p-p65 and p-
IkB
High Dose:
↑Bu y icoccus
↑Bac e oides
↑Lachnospi aceae_NK4A136
↑Lac obacillus
↑Bi idobac e ium
↑Tu icibac e
↑Faecalibac e ium
↓Campylobac e
↓Alies ipes
↓Pa abac e oides
↓Allop e o ella
↓Helicobac e
↓Desul o ib io
↓Odo ibac e
↓Blau ia
↓Esche ichia-Shigella
Low and High
Dose:
↓MPO
ac i i y
(Con inued)
24 S. SHIN ET AL.
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