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 Published online: 08 Ma 2025. Submi you a icle o his jou nal A icle iews: 962 View ela ed a icles View C ossma k da a Full Te ms & Condi ions o access and use can be ound a h ps://www. and online.com/ac ion/jou nalIn o ma ion?jou nalCode=y e 20 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 This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, 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. expe imen al coli is. Phy omedicine. 2020;78:153293. doi:10.1016/ j.phymed.2020.153293 [83] Shang L, Liu Y, Li J, e al. Emodin p o ec s sepsis associa ed damage o he in es inal mucosal ba ie h ough he VDR/ N 2 /HO-1 pa hway. F on Pha macol. 2021;12:724511. doi:10.3389/ pha .2021.724511 [84] I o S, Suguma an M, Wakama su K. Chemical eac i i ies o o ho- quinones p oduced in li ing o ganisms: a e o quinonoid p o- duc s o med by y osinase and phenoloxidase ac ion on phenols and ca echols. In J Mol Sci. 2020;21(17):6080. doi:10. 3390/ijms21176080 [85] Cai, Sun M, Xing J, e al. An ioxidan phenolic cons i uen s in oo s o Rheum o icinale and Rubia co di olia: s uc u e− adical sca en- ging ac i i y ela ionships. J Ag ic Food Chem. 2004;52(26):7884– 7890. doi:10.1021/j 0489116 [86] Zou F, Qiu Y, Huang Y, e al. E ec s o sho -chain a y acids in inhibi ing HDAC and ac i a ing p38 MAPK a e c i ical o p omo - ing B10 cell gene a ion and unc ion. Cell Dea h Dis. 2021;12(6):582. doi:10.1038/s41419-021-03880-9 [87] Macia L, Tan J, Viei a AT, e al. Me aboli e-sensing ecep o s GPR43 and GPR109A acili a e die a y ib e-induced gu homeos asis h ough egula ion o he in lammasome. Na Commun. 2015;6(1):6734. doi:10.1038/ncomms7734 [88] Ba bian ME, Owens JA, Naudin CR, e al. A high ibe die o sup- plemen a ion wi h Lac ococcus lac is subspecies c emo is o p eg- nan mice con e s p o ec ion agains in es inal inju y in adul o sp ing. Gu Mic obes. 2024;16(1). doi:10.1080/19490976.2024. 2337317 [89] Magnusson MK, Vidal A, Maas eh L, e al. Impai ed bu y a e induced egula ion o T cell su ace exp ession o CTLA-4 in pa ien s wi h ulce a i e coli is. In J Mol Sci. 2021;22(6):3084. doi:10.3390/ijms22063084 [90] Viei a AT, Gal ão I, Macia LM, e al. Die a y ibe and he sho - chain a y acid ace a e p omo e esolu ion o neu ophilic in lam- ma ion in a model o gou in mice. J Leukoc Biol. 2017;101(1):275– 284. doi:10.1189/jlb.3A1015-453RRR [91] Xia X, Lin H, Luo F, e al. O yzanol amelio a es DSS-s imula ed gu ba ie damage ia a ge ing he gu mic obio a accompanied by he TLR4/NF-κB/NLRP3 cascade esponse in i o. J Ag ic Food Chem. 2022;70(50):15747–15762. doi:10.1021/acs.ja c.2c04354 [92] Liu H, Wang J, He T, e al. Bu y a e: a double-edged swo d o heal h? Ad Nu . 2018;9(1):21–29. doi:10.1093/ad ances/nmx009 [93] Tan JK, Macia L, Mackay CR. Die a y ibe and SCFAs in he egu- la ion o mucosal immuni y. J Alle gy Clin Immunol. 2023;151(2):361–370. doi:10.1016/j.jaci.2022.11.007 [94] Ca e a MD, Qui oga J, López R, e al. Pa icipa ion o sho -chain a y acids and hei ecep o s in gu in lamma ion and colon cance . F on Physiol. 2021;12:662739. doi:10.3389/ phys.2021. 662739 [95] Huang C, Du W, Ni Y, e al. The e ec o sho -chain a y acids on M2 mac ophages pola iza ion in i o and in i o. Clin Exp Immunol. 2022;207(1):53–64. doi:10.1093/cei/uxab028 [96] Zhao H, Zhou Y, Xu J, e al. Sho -chain a y acid-p oducing bac- e ial s ains a enua e expe imen al ulce a i e coli is by p omo - ing M2 mac ophage pola iza ion ia JAK/STAT3/FOXO3 axis inac i a ion. J T ansl Med. 2024;22(1):369. doi:10.1186/s12967- 024-05122-w [97] Wang RX, Lee JS, Campbell EL, e al. Mic obio a-de i ed bu y a e dynamically egula es in es inal homeos asis h ough egula ion o ac in-associa ed p o ein synap opodin. P oc Na l Acad Sci USA. 2020;117(21):11648–11657. doi:10.1073/pnas.1917597117 [98] Li G, Lin J, Zhang C, e al. Mic obio a me aboli e bu y a e con- s ains neu ophil unc ions and amelio a es mucosal in lam- ma ion in in lamma o y bowel disease. Gu Mic obes. 2021;13(1):1968257. doi:10.1080/19490976.2021.1968257 [99] Akh a M, Chen Y, Ma Z, e al. Gu mic obio a-de i ed sho chain a y acids a e po en ial media o s in gu in lamma ion. Anim Nu . Ma . 2022;8:350–360. doi:10.1016/j.aninu.2021.11.005 [100] Li N, Wang H, Zhao H, e al. Coope a i e in e ac ions be ween Veillonella a i and Lac obacillus acidophilus amelio a e DSS- induced ulce a i e coli is in mice. Food Func . 2023;14(23):10475–10492. doi:10.1039/D3FO03898J [101] Godínez-Méndez LA, Gu ola-Díaz CM, Zepeda-Nuño JS, e al. In i o heal hy bene i s o galac o-oligosaccha ides om Lupinus albus (LA-GOS) in bu y a e p oduc ion h ough in es inal mic o- bio a. Biomolecules. 2021;11(11):1658. doi:10.3390/biom11111658 [102] Gu Q, Xia C, Liu N, e al. Lac obacillus plan a um ZJ316 alle ia es ulce a i e coli is by inhibi ing in lamma ion and egula ing sho -chain a y acid le els and he gu mic obio a in a mouse model. Food Func . 2023;14(9):3982–3993. doi:10.1039/ D2FO02567A [103] Nishida A, Miyamo o J, Shimizu H, e al. Gu mic obial sho -chain a y acids-media ed ol ac o y ecep o 78 s imula ion p omo es ano exigenic gu ho mone pep ide YY sec e ion in mice. Biochem Biophys Res Commun. 2021;557:48–54. doi:10.1016/j. bb c.2021.03.167 [104] Nishida A, Miyamo o J, Shimizu H, e al. Gu mic obial sho -chain a y acids-media ed ol ac o y ecep o 78 s imula ion p omo es ano exigenic gu ho mone pep ide YY sec e ion in mice. Biochem Biophys Res Commun. 2021;557:48–54. doi:10.1016/j. bb c.2021.03.167 [105] El-Salhy M, Ha lebakk JG, Hausken T. Possible ole o pep ide YY (PYY) in he pa hophysiology o i i able bowel synd ome (IBS). Neu opep ides. 2020;79:101973. doi:10.1016/j.npep.2019.101973 [106] Cuella -Núñez ML, Gonzalez de Mejia E, Loa ca-Piña G. Mo inga olei- e a lea es alle ia ed in lamma ion h ough down egula ion o IL-2, IL-6, and TNF-α in a coli is-associa ed colo ec al cance model. Food Res In . 2021;144:110318. doi:10.1016/j. ood es.2021.110318 [107] Bian Z, Zhang Q, Qin Y, e al. Sodium bu y a e inhibi s oxida i e s ess and NF-κB/NLRP3 ac i a ion in dex an sul a e sodium sal -induced coli is in mice wi h in ol emen o he N 2 signaling pa hway and mi ophagy. Dig Dis Sci. 2023;68(7):2981–2996. doi:10.1007/s10620-023-07845-0 [108] Lenoi M, Ma ín R, To es-Ma a illa E, e al. Bu y a e media es an i- in lamma o y e ec s o Faecalibac e ium p ausni zii in in es inal epi helial cells h ough Dac 3. Gu Mic obes. 2020;12(1):1826748. doi:10.1080/19490976.2020.1826748 [109] Huang C, Wang J, Liu H, e al. Ke one body β-hyd oxybu y a e amelio a es coli is by p omo ing M2 mac ophage pola iza ion h ough he STAT6-dependen signaling pa hway. BMC Med. 2022;20(1):148. doi:10.1186/s12916-022-02352-x [110] Pe e son CT, Pe ez San iago J, Iabloko SN, e al. Sho -chain a y acids modula e heal hy gu mic obio a composi ion and unc- ional po en ial. Cu Mic obiol. 2022;79(5):128. doi:10.1007/ s00284-022-02825-5 [111] Ma S, Yeom J, Lim Y-H. Dai y P opionibac e ium euden eichii ame- lio a es acu e coli is by s imula ing MUC2 exp ession in in es inal goble cell in a DSS-induced coli is a model. Sci Rep. 2020;10(1):5523. doi:10.1038/s41598-020-62497-8 [112] Van Hecke T, Vossen E, Goe hals S, e al. In i o and in i o diges- ion o ed cu ed cooked mea : oxida ion, in es inal mic obio a and ecal me aboli es. Food Res In . 2021;142:110203. doi:10. 1016/j. ood es.2021.110203 [113] O msby MJ, Johnson SA, Ca pena N, e al. P opionic acid p omo es he i ulen pheno ype o C ohn’s disease-associa ed adhe en - in asi e Esche ichia coli. Cell Rep. 2020;30(7):2297–2305.e5. doi:10.1016/j.cel ep.2020.01.078 [114] Mo a J-P, Wallace JL, Bu e AG, e al. Gas oin es inal bio ilms in heal h and disease. Na Re Gas oen e ol Hepa ol. 2021;18(5):314–334. doi:10.1038/s41575-020-00397-y [115] Xie Z, Li M, Qian M, e al. Co-cul u es o Lac obacillus acidophilus and Bacillus sub ilis enhance mucosal ba ie by modula ing gu mic obio a-de i ed sho -chain a y acids. Nu ien s. 2022;14(21):4475. doi:10.3390/nu14214475 [116] Abdel-Razek EA-N, Mahmoud HM, Azouz AA. Managemen o ulce a i e coli is by dichlo oace a e: impac on NFATC1/NLRP3/ IL1B signaling based on bioin o ma ics analysis combined wi h in i o expe imen al e i ica ion. In lammopha macology. 2024;32(1):667–682. doi:10.1007/s10787-023-01362-2 [117] Nakano T, Uchiyama K, Ushi oda C, e al. P omo ion o wound healing by ace a e in mu ine colonic epi helial cell ia c-Jun N- e minal kinase ac i a ion. J Gas oen e ol Hepa ol. 2020;35(7):1171–1179. doi:10.1111/jgh.14987 [118] Leung HKM, Lo EKK, Chen C, e al. Zea alenone a enua es coli is associa ed colo ec al umo igenesis h ough Ras/Ra /ERK pa hway supp ession and SCFA-p oducing bac e ia p omo ion. Biomed Pha maco he . 2023;164:114973. doi:10.1016/j.biopha. 2023.114973 REDOX REPORT 31 [119] Li S, Wang X, Wang G, e al. E hyl ace a e ex ac o Selaginella doe- de leinii Hie on induces cell au ophagic dea h and apop osis in colo ec al cance ia PI3K-Ak -mTOR and AMPKα-signaling pa hways. F on Pha macol. 2020;11:565090. doi:10.3389/ pha . 2020.565090 [120] Shen S, P ame Kuma K, Wen SW, e al. De iciency o die a y ibe modula es gu mic obio a composi ion, neu ophil ec ui men and wo sens expe imen al coli is. F on Immunol. 2021;12:619366. doi:10.3389/ immu.2021.619366 [121] K opp C, Le Co K, Relizani K, e al. The keys one commensal bac- e ium Ch is ensenella minu a DSM 22607 displays an i-in lamma- o y p ope ies bo h in i o and in i o. Sci Rep. 2021;11(1):11494. doi:10.1038/s41598-021-90885-1 [122] Wei X, Yu L, Ye Z, e al. Responses o he colonic mic obio a and me aboli es du ing e men a ion o algina e oligosaccha ides in no mal indi iduals: an in i o and in i o s udy. Food Biosci. 2023;52:102413. doi:10.1016/j. bio.2023.102413 [123] Kim W-K, Han DH, Jang YJ, e al. Alle ia ion o DSS-induced coli is ia Lac obacillus acidophilus ea men in mice. Food Func . 2021;12(1):340–350. doi:10.1039/D0FO01724H [124] Dodd D, Spi ze MH, Van T eu en W, e al. A gu bac e ial pa hway me abolizes a oma ic amino acids in o nine ci cula ing me ab- oli es. Na u e. 2017;551(7682):648–652. doi:10.1038/na u e24661 [125] Ta asiuk A, Eibl G. Nu i ional suppo and p obio ics as a po en ial ea men o IBD. Cu D ug Ta ge s. 2020;21(14):1417–1427. doi:10.2174/1389450121666200504075519 [126] Yada MK, Kuma i I, Singh B, e al. P obio ics, p ebio ics and syn- bio ics: sa e op ions o nex -gene a ion he apeu ics. Appl Mic obiol Bio echnol. 2022;106(2):505–521. doi:10.1007/s00253- 021-11646-8 [127] Ma yniak A, Medyńska-P zęczek A, Węd ychowicz A, e al. P ebio ics, p obio ics, synbio ics, pa ap obio ics and pos bio ic compounds in IBD. Biomolecules. 2021;11(12):1903. doi:10.3390/ biom11121903 [128] Dang X, Xu M, Liu D, e al. Assessing he e icacy and sa e y o ecal mic obio a ansplan a ion and p obio ic VSL#3 o ac i e ulce a- i e coli is: A sys ema ic e iew and me a-analysis. PLoS One. 2020;15(3):e0228846. doi:10.1371/jou nal.pone.0228846 [129] Ulisse S, Gionche i P, D’Alo S, e al. Exp ession o cy okines, indu- cible ni ic oxide syn hase, and ma ix me allop o einases in pou- chi is: e ec s o p obio ic ea men . Am J Gas oen e ol. 2001;96(9):2691–2699. doi:10.1111/j.1572-0241.2001.04139.x [130] Gionche i P, Rizzello F, Ven u i A, e al. O al bac e io he apy as main enance ea men in pa ien s wi h ch onic pouchi is: a double-blind, placebo-con olled ial. Gas oen e ology. 2000;119(2):305–309. doi:10.1053/gas .2000.9370 [131] Tu si A, B andima e G, Gio ge i GM, e al. Low-dose balsalazide plus a high-po ency p obio ic p epa a ion is mo e e ec i e han balsalazide alone o mesalazine in he ea men o acu e mild- o-mode a e ulce a i e coli is. Med Sci Moni . 2004;10(11):PI126– PI131. [132] Ma dini HE, G igo ian AY. P obio ic Mix VSL#3 Is e ec i e adjunc- i e he apy o mild o mode a ely ac i e ulce a i e coli is. In lamm Bowel Dis. 2014;20(9):1562–1567. doi:10.1097/MIB. 0000000000000084 [133] Sood A, Midha V, Makha ia GK, e al. The p obio ic p epa a ion, VSL#3 induces emission in pa ien s wi h mild- o-mode a ely ac i e ulce a i e coli is. Clin Gas oen e ol Hepa ol. 2009;7(11):1202–1209.e1. doi:10.1016/j.cgh.2009.07.016 [134] Iheozo -Ejio o Z, Kau L, Go don M, e al. P obio ics o main en- ance o emission in ulce a i e coli is. Coch ane Da abase Sys Re . 2020;3(3):CD007443. doi:10.1002/14651858.CD007443.pub3 [135] Cheng H, Ma Z, Yu B, e al. Quali y assessmen o clinical guidelines on p obio ics he apy in child en wi h IBD using he AGREE II ins umen . J Clin Pha m The . 2021;46(4):1155–1165. doi:10. 1111/jcp .13422 [136] Campie i M, Rizzello F, Ven u i A, e al. Combina ion o an ibio ic and p obio ic ea men is e icacious in p ophylaxis o pos -ope - a i e ecu ence o C ohn’s disease: a andomized con olled s udy VS mesalamine. Gas oen e ology. 2000;118(4):A781. doi:10.1016/ S0016-5085(00)85267-1 [137] Bou ebaba Y, Ma ycz K, Mula czyk M, e al. Pos bio ics as po en ial new he apeu ic agen s o me abolic diso de s managemen . Biomed Pha maco he . 2022;153:113138. doi:10.1016/j.biopha. 2022.113138 [138] Shamoon M, Ma in NM, O’B ien CL. Recen ad ances in gu mic o- bio a media ed he apeu ic a ge s in in lamma o y bowel dis- eases: eme ging modali ies o u u e pha macological implica ions. Pha macol Res. 2019;148:104344. doi:10.1016/j.ph s. 2019.104344 [139] Jia D-J-C, Wang Q-W, Hu Y-Y, e al. Lac obacillus johnsonii alle ia es coli is by TLR1/2-STAT3 media ed CD206 + mac ophages IL-10 ac i a ion. Gu Mic obes. 2022;14(1):2145843. doi:10.1080/ 19490976.2022.2145843 [140] Zhao N, Liu J-M, Yang F-E, e al. A no el media ion s a egy o DSS- induced coli is in mice based on an i on-en iched p obio ic and in i o bioluminescence acing. J Ag ic Food Chem. 2020;68(43):12028–12038. doi:10.1021/acs.ja c.0c05260 [141] Li P, Chen G, Zhang J, e al. Li e Lac obacillus acidophilus alle ia es ulce a i e coli is ia he SCFAs/mi ophagy/NLRP3 in lammasome axis. Food Func . 2022;13(5):2985–2997. doi:10.1039/D1FO03360C [142] Kim DH, Kim S, Ahn JB, e al. Lac obacillus plan a um CBT LP3 ame- lio a es coli is ia modula ing T cells in mice. In J Med Mic obiol. 2020;310(2):151391. doi:10.1016/j.ijmm.2020.151391 [143] Iye N, Williams MA, O’Callaghan AA, e al. Lac obacillus sali a ius UCC118TM dampens in lamma ion and p omo es mic obio a eco e y o p o ide he apeu ic bene i in a DSS-induced coli is model. Mic oo ganisms. 2022;10(7):1383. doi:10.3390/ mic oo ganisms10071383 [144] Huang Q-X, Liang J-L, Yang C-H, e al. S imula ion- esponsi e mucoadhesi e p obio ics o in lamma o y bowel disease ea - men by sca enging eac i e oxygen species and egula ing gu mic obio a. Bioma e ials. 2023;301:122274. doi:10.1016/j. bioma e ials.2023.122274 [145] Chaiyasu C, Si ama u hi BS, Laile d N, e al. P obio ics supplemen- a ion imp o es in es inal pe meabili y, obesi y index and me abolic bioma ke s in elde ly Thai subjec s: a andomized con olled ial. Foods. 2022;11(3):268. doi:10.3390/ oods11030268 [146] Jia L, Wu R, Han N, e al. Po phy omonas gingi alis and Lac obacillus hamnosus GG egula e he Th17/T eg balance in coli is ia TLR4 and TLR2. Clin T ansl Immunology. 2020;9(11):e1213. doi:10. 1002/c i2.1213 [147] Schul z M, Timme A, He a h HH, e al. Lac obacillus GG in inducing and main aining emission o C ohn’s disease. BMC Gas oen e ol. 2004;4:5. doi:10.1186/1471-230X-4-5. [148] Yu P, Ke C, Guo J, e al. Lac obacillus plan a um L15 alle ia es coli is by inhibi ing LPS-media ed NF-κB ac i a ion and amelio a es DSS- induced gu mic obio a dysbiosis. F on Immunol. 2020;11:575173. doi:10.3389/ immu.2020.575173 [149] Liu M, Ding J, Zhang H, e al. Lac obacillus casei LH23 modula es he immune esponse and amelio a es DSS-induced coli is ia sup- p essing JNK/p-38 signal pa hways and enhancing his one H3K9 ace yla ion. Food Func . 2020;11(6):5473–5485. doi:10.1039/ D0FO00546K [150] Isozaki S, Konishi H, Fujiya M, e al. P obio ic-de i ed polypho- spha e accele a es in es inal epi helia wound healing h ough inducing pla ele -de i ed media o s. Media o s In lamm. 2021;2021:1–14. doi:10.1155/2021/5582943 [151] Cui Q, Tian X-Y, Liang X, e al. Bi idobac e ium bi idum elie ed DSS- induced coli is in mice po en ially by ac i a ing he a yl hyd o- ca bon ecep o . Food Func . 2022;13(9):5115–5123. doi:10.1039/ D1FO04219J [152] Kang S, Lin Z, Xu Y, e al. A ecombinan Bi idobac e ium bi idum BGN4 s ain exp essing he s ep ococcal supe oxide dismu ase gene amelio a es in lamma o y bowel disease. Mic ob Cell Fac . 2022;21(1):113. doi:10.1186/s12934-022-01840-2 [153] H dý J, Ala d J, Cou u ie -Mailla d A, e al. Lac obacillus eu e i 5454 and Bi idobac e ium animalis ssp. lac is 5764 imp o e coli is while di e en ially impac ing dend i ic cells ma u a ion and an imic o- bial esponses. Sci Rep. 2020;10(1):5345. doi:10.1038/s41598-020- 62161-1 [154] Ma L, Lyu W, Song Y, e al. An i-in lamma o y e ec o Clos idium bu y icum-de i ed ex acellula esicles in ulce a i e coli is: impac on hos mic oRNAs exp essions and gu mic obiome p o iles. Mol Nu Food Res. 2023;67(13):e2200884. doi:10.1002/mn . 202200884 [155] Hua H, Pan C, Chen X, e al. P obio ic lac ic acid bac e ia alle ia e pedia ic IBD and emodel gu mic obio a by modula ing mac o- phage pola iza ion and supp essing epi helial apop osis. F on Mic obiol. 2023;14:1168924. doi:10.3389/ micb.2023.1168924 32 S. SHIN ET AL. [156] Qu S, Fan L, Qi Y, e al. Akke mansia muciniphila alle ia es dex an sul a e sodium (DSS)-induced acu e coli is by NLRP3 ac i a ion. Mic obiol Spec . 2021;9(2):e0073021. doi:10.1128/Spec um. 00730-21 [157] Zhai R, Xue X, Zhang L, e al. S ain-speci ic an i-in lamma o y p ope ies o wo Akke mansia muciniphila s ains on ch onic coli is in mice. F on Cell In ec Mic obiol. 2019;9:239. doi:10. 3389/ cimb.2019.00239 [158] Sun S, Xu X, Liang L, e al. Lac ic acid-p oducing p obio ic Saccha omyces ce e isiae a enua es ulce a i e coli is ia supp es- sing mac ophage py op osis and modula ing gu mic obio a. F on Immunol. 2021;12:777665. doi:10.3389/ immu.2021.777665 [159] San ana PT, Rosas SLB, Ribei o BE, e al. Dysbiosis in in lamma o y bowel disease: pa hogenic ole and po en ial he apeu ic a ge s. In J Mol Sci. 2022;23(7):3464. doi:10.3390/ijms23073464 [160] Singh SB, Co man CN, Va ga MG, e al. In es inal alkaline phospha- ase p e en s sul a e educing bac e ia-induced inc eased igh junc ion pe meabili y by inhibi ing snail pa hway. F on Cell In ec Mic obiol. 2022;12:882498. doi:10.3389/ cimb.2022.882498 [161] Na YR, S akenbo g M, Seok SH, e al. Mac ophages in in es inal in lamma ion and esolu ion: a po en ial he apeu ic a ge in IBD. Na Re Gas oen e ol Hepa ol. 2019;16(9):531–543. doi:10. 1038/s41575-019-0172-4 [162] Fusco W, Lo enzo MB, Cin oni M, e al. Sho -Chain a y-acid-p o- ducing bac e ia: key componen s o he human Gu mic obio a. Nu ien s. 2023;15(9):2211. doi:10.3390/nu15092211 [163] Chen L, Shao J, Luo Y, e al. An in eg a ed me abolism in i o analysis and ne wo k pha macology in UC a s e eal an i-ulce a- i e coli is e ec s om Sopho a la escens E OAc ex ac . J Pha m Biomed Anal. 2020;186:113306. doi:10.1016/j.jpba.2020.113306 [164] Long-Smi h C, O’Rio dan KJ, Cla ke G, e al. Mic obio a–gu –b ain axis: new he apeu ic oppo uni ies. Annu Re Pha macol Toxicol. 2020;60(1):477–502. doi:10.1146/annu e -pha m ox-010919-023628 [165] Li Y, Zhang S-X, Yin X-F, e al. The gu mic obio a and i s ele ance o pe iphe al lymphocy e subpopula ions and cy okines in pa ien s wi h heuma oid a h i is. J Immunol Res. 2021;2021:1– 9. doi:10.1155/2021/6665563 [166] Wilchowski SM. The ole o he gu mic obiome in pso iasis: om pa hogens o pa hology. J Clin Aes he De ma ol. 2022;15(3 Suppl 1):S25–S28. [Online]. h p://www.ncbi.nlm.nih.go /pubmed/ 35382440. [167] Fede ici S, K edo-Russo S, Valdés-Mas R, e al. Ta ge ed supp es- sion o human IBD-associa ed gu mic obio a commensals by phage conso ia o ea men o in es inal in lamma ion. Cell. 2022;185(16):2879–2898.e24. doi:10.1016/j.cell.2022.07.003 [168] Vich Vila A, Collij V, Sanna S, e al. Impac o commonly used d ugs on he composi ion and me abolic unc ion o he gu mic obio a. Na Commun. 2020;11(1):362. doi:10.1038/s41467- 019-14177-z [169] Was yk HC, F agiadakis GK, Pe elman D, e al. Gu -mic obio a- a - ge ed die s modula e human immune s a us. Cell. 2021;184(16):4137–4153.e14. doi:10.1016/j.cell.2021.06.019 [170] Wang Y, Qi W, Song G, e al. High- uc ose die inc eases in lamma- o y cy okines and al e s gu mic obio a composi ion in a s. Media o s In lamm. 2020;2020:1–10. doi:10.1155/2020/6672636 [171] Zhang M, Mo R, Wang H, e al. G ape seed p oan hocyanidin imp o es in es inal in lamma ion in canine h ough egula ing gu mic obio a and bile acid composi ions. FASEB J. 2023;37(12): e23285. doi:10.1096/ j.202300819RR [172] Zhang H, Wang Y, Su Y, e al. The alle ia ing e ec and mechanism o Bilobalide on ulce a i e coli is. Food Func . 2021;12(14):6226– 6239. doi:10.1039/D1FO01266E [173] Li G, Lin J, Zhang C, e al. Mic obio a me aboli e bu y a e con- s ains neu ophil unc ions and amelio a es mucosal in lam- ma ion in in lamma o y bowel disease. Gu Mic obes. 2021;13(1):1968257. doi:10.1080/19490976.2021.1968257 REDOX REPORT 33