Health benefits and risks of fermented foods-the PIMENTO initiative

F on ie s in Nu i ion 01 on ie sin.o g Heal h bene i s and isks o e men ed oods— he PIMENTO ini ia i e SmiljaTodo o ic 1, AsliAkpina 2, Rica doAssunção 3, Co neliaBä 4, SimonaL.Ba a o 5, MuzeyyenBe kelKasikci 2,6, Julie aDomínguez-Sobe anes 7, Vi o ioCapozzi 8, PaulD.Co e 9, Eun-HeeDoo 10, Bu cuGündüzE gün 11, Mus a aGuzel 12, Hay iyeS.Ha sa 13, Em eHas aoglu 14, Ch is èleHumblo 15, Bah i Hyseni 16, MugeI.Hosoglu 17, AlineIssa 18, Ba çınKa akaş-Budak 19, SibelKa akaya 20, Ha unKesenkas 21, E hanKey an 22, Ib ahimE.Künili 23, Ma y-LiisKü 24, Ma aLa anjo 25, Sand ineLouis 26, FaniT.Man zou idou 27, An oniaMa alas 28, Bal asa Mayo 29, Sand aMojso a 30, A ghyaMukhe jee 9, Anas asiosNikolaou 31, Fa ihO akci 32, DianaPa eljšek 33, Gianca loPe one 34, EugeniaPe zige 35,36, DushicaSan a 37, Tane Sa 38, IsabelleSa a y-Auzeloux 39, Cla issaSchwab 40, Małgo za aS a owicz 41, Ma koS ojano ić 42, MichailSy pas 43, Jyo iP.Tamang 44, Ok ayYe likaya 21, Bi senYilmaz 45,46, Jead anMalagon-Rojas 47, SeppoSalminen 48, JuanaF ias 49, Ch is opheChassa d 39 and GuyVe gè es 35* 1 Ins i u e o Biological Resea ch Sinisa S anko ic, Na ional Ins i u e o Republic o Se bia, Uni e si y o Belg ade, Belg ade, Se bia, 2 Depa men o Food Enginee ing, Manisa Celal Baya Uni e si y Facul y o Enginee ing and Na u al Science, Manisa, Tü kiye, 3 Egas Moniz Cen e o In e disciplina y Resea ch (CiiEM), Egas Moniz School o Heal h and Science, Almada, Po ugal, 4 Compe ence Di ision Me hod De elopmen and Analy ics, Ag oscope, Be ne, Swi ze land, 5 Ins i u e o Sciences o Food P oduc ion (ISPA), Na ional Resea ch Council (CNR), Ba i, I aly, 6 STLO, INRAE, Ins i u Ag o-Rennes Ange s, Rennes, F ance, 7 Facul ad de Ingenie ía, Uni e sidad Paname icana, Aguascalien es, Mexico, 8 Depa men o Food Science, Uni e si y o Foggia, Foggia, I aly, 9 Depa men o Food Biosciences, Teagasc Food Resea ch Cen e, Fe moy, I eland, 10 School o Li ing and En i onmen al Enginee ing, Dongyang Mi ae Uni e si y, Seoul, Republic o Ko ea, 11 Bio echnology Resea ch Cen e , Field C ops Cen al Resea ch Ins i u e, Anka a, Tü kiye, 12 Depa men o Food Enginee ing, Hi i Uni e si y, Co um, Tü kiye, 13 Depa men o Food Enginee ing, Izmi Ins i u e o Technology, Izmi , Tü kiye, 14 Cumhu iye Uni e si y, Si as, Tü kiye, 15 F ench Na ional Resea ch Ins i u e o Sus ainable De elopmen (IRD), Mon pellie , F ance, 16 Facul y o Food Technology, Uni e si y “Isa Bole ini”, Mi o ica, Republic o Koso o, 17 Bio echnology Ins i u e, Gebze Technical Uni e si y, Kocaeli, Tü kiye, 18 Facul y o Nu sing and Heal h Sciences, No e Dame Uni e si y-Louaize, Zouk Mosbeh, Lebanon, 19 Depa men o Food Enginee ing, Akdeniz Uni e si y Facul y o Enginee ing, An alya, Tü kiye, 20 Depa men o Food Enginee ing, Facul y o Enginee ing, Ege Uni e si y, Izmi , Tü kiye, 21 Depa men o Dai y Technology, Facul y o Ag icul u e, Ege Uni e si y, Izmi , Tü kiye, 22 Depa men o Food Hygiene and Technology, Facul y o Ve e ina y Medicine, Bu du Mehme Aki E soy Uni e si y, Bu du , Tü kiye, 23 Depa men o Fishing and Fish P ocessing Technology, Facul y o Ma ine Sciences and Technology, Canakkale Onsekiz Ma Uni e si y, Canakkale, Tü kiye, 24 ÄIO, Tallinn, Es onia, 25 MED-Medi e anean Ins i u e o Ag icul u e, En i onmen and De elopmen -CHANGE- Global Change and Sus ainabili y Ins i u e and Depa amen o de Medicina Ve e iná ia-Escola de Ciências e Tecnologia (ECT), Uni e sidade de É o a, É o a, Po ugal, 26 Depa men o Physiology and Biochemis y o Nu i ion, Max Rubne -Ins i u , Ka ls uhe, Ge many, 27 Labo a o y o Food Chemis y and Technology, School o Chemis y, A is o le Uni e si y o Thessaloniki, Thessaloniki, G eece, 28 Depa men o Nu i ion and Die e ics, Ha okopio Uni e si y, A hens, G eece, 29 Depa amen o de Mic obiología y Bioquímica, Ins i u o de P oduc os Lác eos de As u ias (IPLA), Consejo Supe io de In es igaciones Cien í icas (CSIC), Villa iciosa, Spain, 30 Depa men o Food Sa e y and Ve e ina y Public Heal h, Food Ins i u e, Facul y o Ve e ina y Medicine, Skopje, Ss. Cy il and Me hodius Uni e si y, Skopje, No h Macedonia, 31 Depa men o Molecula Biology and Gene ics, Democ i us OPEN ACCESS EDITED BY Ma ia João F aqueza, Uni e si y o Lisbon, Po ugal REVIEWED BY Chia a De i giliis, CREA (Consiglio pe la ice ca in ag icol u a e l’analisi dell’economia ag a ia), I aly Luis Pa a a a, Uni e si y o T ás-os-Mon es and Al o Dou o, Po ugal *CORRESPONDENCE Guy Ve gè es guy. e ge [email p o ec ed] RECEIVED 02 July 2024 ACCEPTED 14 Augus 2024 PUBLISHED 03 Sep embe 2024 CITATION Todo o ic S, Akpina A, Assunção R, Bä C, Ba a o SL, Be kel Kasikci M, Domínguez-Sobe anes J, Capozzi V, Co e PD, Doo E-H, Gündüz E gün B, Guzel M, Ha sa HS, Has aoglu E, Humblo C, Hyseni B, Hosoglu MI, Issa A, Ka akaş-Budak B, Ka akaya S, Kesenkas H, Key an E, Künili IE, Kü M-L, La anjo M, Louis S, Man zou idou FT, Ma alas A, Mayo B, Mojso a S, Mukhe jee A, Nikolaou A, O akci F, Pa eljšek D, Pe one G, Pe zige E, San a D, Sa T, Sa a y-Auzeloux I, Schwab C, S a owicz M, S ojano ić M, Sy pas M, Tamang JP, Ye likaya O, Yilmaz B, Malagon-Rojas J, Salminen S, F ias J, Chassa d C and Ve gè es G (2024) Heal h bene i s and isks o e men ed oods— he PIMENTO ini ia i e. F on . Nu . 11:1458536. doi: 10.3389/ nu .2024.1458536 COPYRIGHT © 2024 Todo o ic, Akpina , Assunção, Bä , Ba a o, Be kel Kasikci, Domínguez-Sobe anes, Capozzi, Co e , Doo, Gündüz E gün, Guzel, Ha sa, Has aoglu, Humblo , Hyseni, Hosoglu, Issa, Ka akaş-Budak, Ka akaya, Kesenkas, Key an, Künili, Kü , La anjo, Louis, Man zou idou, Ma alas, Mayo, Mojso a, Mukhe jee, Nikolaou, O akci, Pa eljšek, Pe one, Pe zige , San a, Sa , Sa a y-Auzeloux, Schwab, S a owicz, S ojano ić, Sy pas, Tamang, Ye likaya, Yilmaz, Malagon-Rojas, Salminen, F ias, Chassa d and Ve gè es. 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 (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. TYPE Concep ual Analysis PUBLISHED 03 Sep embe 2024 DOI 10.3389/ nu .2024.1458536 Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 02 on ie sin.o g Uni e si y o Th ace, Alexand oupolis, G eece, 32 Food Enginee ing Depa men , Is anbul Technical Uni e si y, Is anbul, Tü kiye, 33 Ins i u e o Dai y Science and P obio ics, Depa men o Animal Science, Bio echnical Facul y, Uni e si y o Ljubljana, Domžale, Slo enia, 34 Consiglio Nazionale delle Rice che, Is i u o di Scienze delle P oduzioni Alimen a i, Ba i, I aly, 35 Resea ch Di ision Mic obial Food Sys ems, Ag oscope, Be ne, Swi ze land, 36 Depa men o Epidemiology and Heal h Sys ems, Cen e o P ima y Ca e and Public Heal h (Unisan é), Uni e si y o Lausanne, Lausanne, Swi ze land, 37 Facul y o Ag icul u al Sciences and Food, Ss. Cy il and Me hodius Uni e si y in Skopje, Skopje, No h Macedonia, 38 Swedish Cen e o Resou ce Reco e y, Uni e si y o Bo ås, Bo ås, Sweden, 39 Human Nu i ion Uni , INRAE, Uni e si é Cle mon -Au e gne, Cle mon -Fe and, F ance, 40 Depa men o Biological and Chemical Enginee ing, Aa hus Uni e si y, Aa hus, Denma k, 41 Depa men o Chemis y and Biodynamics o Food, Ins i u e o Animal Rep oduc ion and Food Resea ch o he Polish Academy o Sciences, Olsz yn, Poland, 42 Facul y o Medicine, Uni e si y o Belg ade, Belg ade, Se bia, 43 Depa men o Food Science and Technology, Kaunas Uni e si y o Technology, Kaunas, Li huania, 44 Depa men o Mic obiology, School o Li e Sciences, Sikkim Uni e si y, Gang ok, India, 45 Depa men o Biological Sciences, Ta a Ins i u e o Fundamen al Resea ch, Hyde abad, India, 46 Depa men o Nu i ion and Die e ics, Facul y o Heal h Sciences, Çuku o a Uni e si y, Adana, Tü kiye, 47 Ins i u o Nacional de Salud de Colombia, Bogo á, Colombia, 48 Func ional oods Fo um, Facul y o Medicine, Uni e si y o Tu ku, Tu ku, Finland, 49 Depa men o Technological P ocesses and Bio echnology, Ins i u e o Food Science, Technology and Nu i ion (ICTAN-CSIC), Mad id, Spain Wo ldwide, e men ed oods (FF) a e ecognized as heal hy and sa e. Despi e he apid inc ease o esea ch pape s, he e is a lack o sys ema ic e alua ion o he heal h bene i s and isks o FF. The COST Ac ion CA20128 “P omo ing inno a ion o e men ed oods” (PIMENTO) aims o p o ide a comp ehensi e assessmen on he a ailable e idence by compiling a se o 16 e iews. Se en e iews will co e clinical and biological endpoin s associa ed wi h majo heal h indica o s ac oss se e al o gan sys ems, including he ca dio ascula , gas oin es inal, neu ological, immune, and skele al sys ems. Nine e iews will add ess b oade biological ques ions associa ed wi h FF including bioac i e compounds and i amin p oduc ion, nu ien bioa ailabili y and bioaccessibili y, he ole o FF in heal hy die s and pe sonalized nu i ion, ood sa e y, egula o y p ac ices, and inally, he heal h p ope ies o no el and e hnic FF. Fo each ou come assessed in he e iews, an inno a i e app oach will beadop ed based on EFSA’s published guidance o heal h claim submissions. In pa icula , each e iew will be composed o h ee pa s: (1) a sys ema ic e iew o a ailable human s udies; (2) a non-sys ema ic e iew o he mechanism o ac ion ela ed o he clinical endpoin s measu ed by he human s udies iden i ied in pa 1; and (3) a non-sys ema ic e iew o he cha ac e iza ion o he FF in es iga ed in he human s udies iden i ied in pa 1. The e idence and esea ch gaps de i ed om he e iews will besumma ized and published in he o m o a s a egic oad map ha will pa e he way o u u e esea ch on FF. KEYWORDS e men ed oods, ood cha ac e iza ion, ood sa e y, unc ional claims, heal h bene i s, heal h claims, mechanism o ac ion, sys ema ic e iew In oduc ion Need o coo dina ed esea ch on FF— PIMENTO The impac o ood sys ems on plane a y heal h is a socie al issue o pa amoun impo ance eques ing a ansi ion owa ds mo e sus ainable die s (1, 2). This ansi ion esona es wi h he g owing consume demand o na u al and heal hie p oduc s a ailable a a o dable p ices (3). On he o he hand, while a body o e idence indica es he impo ance o die a y di e si y o human heal h (4), biodi e si y is dec easing wo ldwide (5). In imes when die s a e apidly changing owa ds highly p ocessed oods, he e is a c i ical need o main ain and imp o e ood as a sou ce o di e se nu ien s as well as bene icial mic obes (6, 7). FF hold a s a egic place in all Eu opean die s due o he bene i s hey o e in e ms o nu i ion, cul u al he i age, inno a ion, sus ainabili y, and consume in e es . In pa icula , he po en ial o FF as pa o he die o imp o ing human heal h has become highly ele an (8, 9). FF can mee he demands ou lined abo e owing o hei unique p ope ies (10), which include he p esence o li e mic oo ganisms and mic obial me aboli es, i amins, and bioac i e compounds as well as ex ended shel -li e. Howe e , o ully ealize hei po en ial, he e is a need o coo dina ing he weal h o new scien i ic e idence on FF eme ging om he s udies on ood ecosys ems, sys emic app oaches o ood mic obiology, oodomics, Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 03 on ie sin.o g and nu igenomics as well as on he ole o he gu mic obio a and he gas oin es inal (GI) ac in heal h and disease onse (9, 11). This consolida ed knowledge and, he e o e, FF can beul ima ely in eg a ed in o e ec i e public heal h and sus ainabili y policies (12). PIMENTO is a Eu opean ini ia i e unded by he COST Ac ion (CA20128) o add ess he needs indica ed abo e h ough esea ch on FF. In pa icula , PIMENTO con ibu es o an open-access iden i ica ion, s anda diza ion, and mapping o exis ing and po en ial bene icial mic oo ganisms and communi ies. PIMENTO also collec i ely ad ances he scien i ic e idence on he heal h e ec s o FF, building a isk–bene i app oach and igh ly connec ing and cla i ying he scien i ic e idence on he heal h-p omo ing p ope ies o FF. Fu he mo e, PIMENTO con ibu es o he Eu opean G een Deal s a egy “Fa m o Fo k” by enhancing esea ch and inno a ion on e men a ion-based solu ions and p ocesses, imp o ing ood’s nu i ional, s uc u al and unc ional p ope ies. Th ough i s mul i- modal inno a i e app oach, PIMENTO no only esponds o he expec a ions o di e en Eu opean communi ies o heal hy and sus ainable ood p oduc s by boos ing he de elopmen o FF, bu also places Eu ope as a leade in FF inno a ion wo ldwide. Inno a i e s a egy o e alua e he heal h bene i s and isks o FF In line wi h PIMENTO’s mission Wo king G oup3 o PIMENTO (PIMENTO WG3) aims a e alua ing he heal h bene i s and isks o FF. Compa ed o o he componen s o he human die , FF add a unique dimension o he ela ionship be ween die and heal h because his ca ego y o oods con ains e men a i e mic oo ganisms and hei e men a ion p oduc s in addi ion o he mac o- and mic onu ien s classically s udied by nu i ionis s. Al hough nu i ion science is an in e disciplina y ield, published esea ch epo s a e o en cha ac e ized by a limi ed scope, esul ing in a lack o holis ic assessmen o he complex a ay o elemen s ha cha ac e ize he in e ac ion o ood componen s wi h he human body. This agmen ed app oach o nu i ion esea ch makes i di icul o objec i ely cha ac e ize he heal h p ope ies o die s, oods, o nu ien s. A p agma ic, ye inno a i e app oach o he academic sec o o ackle he heal h p ope ies o die s is o use he “Eu opean Food Sa e y Au ho i y” (EFSA) heal h claim guidelines (13, 14). The EFSA guidance equi es no only ha he esul s o human s udies a e sys ema ically epo ed and e alua ed bu also an assessmen o he p ope ies o a ood o ing edien o which he e ec is claimed. This cha ac e iza ion comp ises in o ma ion on he composi ion and s abili y o he ac i e compounds in he ood o in e es . Fu he mo e, EFSA asks o addi ional da a on he mechanism o ac ion o bep o ided, de i ed om in i o o animal models. The mechanis ic da a should becomplemen ed by in o ma ion abou he bioa ailabili y and bioaccessibili y o he ac i e compounds. Al hough e men ed oods a e di e se, unde lying mechanisms con ibu ing o hei po en ial impac on heal h migh besimila . A ha monized and sys ema ic e iew on he scien i ic e idence o he heal h p ope ies o FF can hus lead o he iden i ica ion o common unc ional p ope ies. PIMENTO WG3 will e alua e he heal h p ope ies o FF by ollowing an inno a i e app oach ha will bebased on he compila ion o a se ies o e iews based on he EFSA guidance o heal h claims. This s a egy includes he h ee pilla s human s udies, p oduc cha ac e is ics, and mechanism o ac ion as well as wo complemen a y opics closely associa ed wi h FF, i.e., ood sa e y and he in e ac ion be ween FF and gu mic obio a. In May 2022, a wo kshop was held in Belg ade o de ine he unc ional hema ic a eas ha he PIMENTO COST Ac ion should in es iga e. A se ies o 16 hema ic a eas co e ing he mos ele an heal h indica o s in key o gan sys ems we e selec ed. These hema ic a eas we e o ganized in o wo g oups acco ding o whe he hey could be e iewed in close alignmen wi h he EFSA guidance. Se en “EFSA p ojec s” (E1-E7) we e de ined, co e ing he ollowing clinical a eas: GI heal h (E1), alle gy (E2), immuni y (E3), me abolic heal h (E4), ca dio ascula heal h (E5), bone heal h (E6), and cogni i e heal h (E7). Nine “Sa elli e p ojec s” (S1-S9) we e also o med, co e ing impo an opics on FF ha a e less amenable o adap a ion o he EFSA guidance: bioac i e compounds (S1), i amin p oduc ion (S2), nu ien bioa ailabili y and bioaccessibili y (S3), e hnic oods (S4), heal hy die s (S5), pe sonalized nu i ion (S6), ood sa e y (S7), no el oods (S8), and byp oduc s o e men a ion (S9). Following his ini ial phase, a i s ound o li e a u e analyses was conduc ed o de ine a speci ic esea ch ques ion o each o he opics. These ques ions should be sys ema ically add essed o assess he a ailable e idence and iden i y knowledge gaps o ocus u u e esea ch. The inal e iew ques ions a e p esen ed in Table1. As he p elimina y wo k p og essed, he e iew p ocess became inc easingly ha monized and he dis inc ion be ween he wo ca ego ies o e iews blu ed so ha he 16 e iews we e no longe e e ed o as EFSA o Sa elli e e iews. Finally, a gene ic s udy p o ocol (PIMENTO-SP; Supplemen a y File 1) was de eloped based on he PROSPERO guidance o sys ema ic e iews (13, 15) and u he adap ed o in eg a e he non-sys ema ic pa s o he e iews. In addi ion, a gene ic sea ch s a egy o he li e a u e in PubMed, Scopus, and he Coch ane Lib a y Cen al (PIMENTO-LS) was de eloped o sys ema ically sea ch o human s udies epo ing on he heal h e ec s o FF (Supplemen a y File 2). PIMENTO-SP and PIMENTO-LS o ms will beused as a amewo k o he con en o each e iew and adap ed acco ding o he speci ics o he biological o clinical endpoin s being add essed. A summa y o he aims and me hodology o each o he 16 e iews unde p epa a ion is p esen ed in he ollowing sec ions. Al hough he sec ions below ocus hei esea ch summa y on he analysis o he human clinical s udies, each o he 16 p ojec s will also add ess he non-sys ema ic pa s discussed abo e. Speci ic s udy p o ocols we e p epa ed o each e iew and we e deposi ed in he Open Science F amewo k (OSF). In addi ion o he e iew plans, he s udy p o ocols documen he names and ins i u es o he e iewing eams. Resea ch ques ions add essed by he PIMENTO WG3 e iews Gas oin es inal heal h In ecen yea s, FF ha e been he ocus o a esu gence in in e es among he gene al public, p ima ily owing o hei pu po ed heal h bene i s. Indeed, g owing e idence shows ha FF posi i ely modula es GI heal h h ough di e se mechanisms, including he po en ial p obio ic e ec o hei cons i uen mic obes, educ ion o Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 04 on ie sin.o g an i-nu ien s, and bioac i i y o no el compounds p oduced du ing e men a ion, among o he s (16). Conce ning he o me , i is no able ha se e al p obio ic mic obes, which a e o en closely ela ed o hose ound in FF (17, 18), ha e been shown o bebene icial in he managemen o GI symp oms in di e en popula ions, such as p egnan women, a hle es, and pa ien s wi h i i able bowel synd ome (IBS) and neu odegene a i e diso de s (19–22). Howe e , despi e his g owing body o e idence, a sys ema ic e iew o he impac o FF consump ion on GI discom o and GI unc ions, such as de eca ion, in heal hy adul s has no been conduc ed. This sys ema ic e iew will add ess he ollowing ques ion: “Does consump ion o e men ed oods ha e a bene icial e ec on gas oin es inal discom o and no mal de eca ion in a heal hy adul popula ion?” To answe his esea ch ques ion, wewill in es iga e he e ec o FF consump ion on GI discom o and de eca ion as guided by he “Guidance on he scien i ic equi emen s o heal h claims ela ed o he immune sys em, he gas oin es inal ac and de ense agains pa hogenic mic oo ganisms” (23). Acco ding o EFSA, symp oms associa ed wi h GI discom o include abdominal pain, c amps, bloa ing, s aining, bo bo ygmi ( umbling) and a sensa ion o incomple e e acua ion, along wi h excessi e in es inal gas accumula ion. Reducing GI discom o is conside ed an indica o o imp o ed GI unc ion and, hence, a bene icial physiological e ec (23). Simila ly, main enance o no mal de eca ion is ega ded as a bene icial physiological e ec o he gene al popula ion, gi en ha i does no esul in dia hea. The e o e, he e iew will addi ionally in es iga e he e ec o FF consump ion on de eca ion in he con ex o main enance o acili a ion o no mal de eca ion h ough one o mo e o he ollowing means: imp o ed equency o bowel mo emen s, inc eased ecal bulk, imp o ing s ool consis ency, o dec easing ansi ime. OSF link o s udy p o ocol: PIMENTO-SP-E1. Alle gies Food alle gy (FA) is an abno mal eac ion o he immune sys em a e exposu e o speci ic oods, which is a se ious ood sa e y and public heal h p oblem wo ldwide. Cu en ly, ood alle gies a ec up o 10% o child en and 2–3% o adul s and appea o beinc easing in p e alence ac oss he wo ld (24). Based on he immunological mechanisms in ol ed, FA may beclassi ied as (1) IgE-media ed, he mos well- unde s ood o m, which is caused by IgE an ibodies agains ood an igens; (2) non-IgE-media ed, in which he immune esponse is hough o ac mainly h ough cell-media ed mechanisms; (3) o mixed, in which bo h IgE-media ed and cell-media ed immunological mechanisms a e in ol ed (25). The IgE-media ed alle gies occu mos equen ly in he i s yea s o li e and may lead o u ica ia, angioedema, o al alle gic synd ome, hini is, o acu e as hma and anaphylaxis, while cu aneous, espi a o y, o GI eac ions cha ac e ize non-IgE alle gies. The mechanism o ac ion o FA usually occu s in wo di e en phases: a sensi iza ion phase and an elici a ion phase, wi h he la e TABLE1 O e iew o he hema ic a eas and e iew ques ions add essed by PIMENTO WG3. Re iew numbe and hema ic a ea Resea ch ques ion E1. Gas oin es inal heal h Does consump ion o e men ed oods ha e a bene icial e ec on gas oin es inal discom o and no mal de eca ion in a heal hy adul popula ion? E2. Alle gies Wha is he e ec o he consump ion o e men ed ood on he de elopmen o ood alle gic symp oms in he ood alle gic popula ion and a popula ion a high isk o ood alle gy? E3. Immuni y Can consump ion o e men ed oods aid in p e en ion o bac e ial aginosis and/o ul o aginal candidiasis? E4. Me abolic heal h Does e men ed oods consump ion help o educe pos p andial glucose esponse o main ain as ing blood glucose concen a ions o insulin sensi i i y in heal hy o p ediabe ic adul s? E5. Ca dio ascula heal h Does consump ion o e men ed dai y p oduc s impac blood lipids in heal hy adul s? E6. Bone heal h Wha is he e ec o consuming e men ed oods on he bone heal h o heal hy adul s and adul s wi h os eopo osis and os eopenia? E7. Cogni i e heal h Does he consump ion o oods e men ed wi h Lac obacillus sp. and/o Bi idobac e ium sp. ha e a bene icial e ec on cogni i e pe o mance in a heal hy adul popula ion, including adul s wi h mild cogni i e impai men ? S1. Bioac i e compounds Wha compounds de i ed om ood e men a ion a e associa ed wi h e ec s on clinical endpoin s in human s udies? S2. P oduc ion o i amins Does he consump ion o e men ed oods, o i ied in i amin by e men a ion, con ibu es o i amin co e age o a heal hy popula ion o o a i amin-de icien popula ion? S3. Bioa ailabili y and bioaccessibili y o nu ien s Does sou dough and egula b ead e men a ion inc ease i on bioa ailabili y, abso p ion, and s a us in humans? S4. E hnic oods Wha a e he heal h e ec s o e hnic e men ed oods? S5. Heal hy die s Wha is he impac o e men ed oods consump ion on mo ali y isk? S6. Pe sonalized nu i ion Does he impac o e men ed oods on di e en heal h ou comes depend on speci ic cha ac e is ics o popula ion g oups, and, consequen ly, can e men ed oods beused in ailo ed nu i ional s a egies? S7. Food sa e y Wha a e he main mic obiological and chemical haza ds posed by e men ed oods and hei associa ed isks? S8. No el e men ed oods Wha a e he heal h e ec o no el e men ed oods? S9. Food byp oduc s Wha a e he heal h e ec o e men ed whey? E1–E7 e e o each o he se en “EFSA p ojec s.” S1–S9 e e o each o he nine “Sa elli e p ojec s.” Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 05 on ie sin.o g esul ing in clinical symp oms o alle gic disease (26). Sensi iza ion is he phase du ing which immunological p iming o he inducing alle gen occu s, associa ed wi h he e olu ion o a Th2-biased immune esponse. I he sensi ized subjec is subsequen ly exposed o a su icien amoun o he inducing ood alle gen, an alle gic eac ion may beelici ed, esul ing in he clinical mani es a ions desc ibed abo e. Food p ocessing can impac he IgE-binding p ope ies o ood p o eins’ an igenic si es and hei abili y o elici alle gic eac ions (27). Compa ed o o he ood p ocessing echniques, ood e men a ion has shown unique ad an ages in educing he alle genici y o oods; hus, i may ep esen a new end in p e en ing ood-induced alle gies in child and adul popula ions. Fo example, consuming ully ma u ed Pa migiano Reggiano cheese seems o inhibi he IgE binding o milk alle gens and bewell ole a ed by a subse o cow’s milk alle gic pa ien s (28). In he same way, he consump ion o e men ed dai y p oduc s appea s o beassocia ed wi h educed as hma and a opic de ma i is in child en bo n by caesa ean sec ion and a ec ed by FA (29). Simila ly, whea -based swee baked goods wi h glu en deg aded by sou dough e men a ion seem o bewell ole a ed by pa ien s a ec ed by coeliac disease (30). Al hough he consump ion o FF migh bean e ec i e way o educe he se e i y o alle gic eac ions, a sys ema ic e iew is needed o e alua e he e idence mo e objec i ely. This e iew will hus add ess he ollowing ques ion: “Wha is he e ec o he consump ion o e men ed ood on he de elopmen o ood alle gic symp oms in he ood alle gic popula ion and a popula ion a high isk o ood alle gy?” OSF link o s udy p o ocol: PIMENTO-SP-E2. Immuni y Human clinical s udies on immuni y in es iga e a b oad a ay o opics, some being add essed in o he PIMENTO WG3 e iews (e.g., alle gy, gu heal h). Wi h ega d o pa hogenic diseases, immuni y e e s o he sa egua ding o heal h h ough he p e en ion o dysbiosis. This highligh s he impo ance o main aining a balance o commensal mic oo ganisms o sus ain immune unc ion. As ue o o he pa s o he human body, he composi ion o he communi y o mic obial esiden s in luences a balanced immune esponse in he emale geni al sys em. Bac e ial aginosis (BV) and ul o aginal candidiasis (VVC) a e he mos common pa hogenic condi ions in women ha no only cause discom o bu also esul in inc eased suscep ibili y o o he in ec ions o isk o obs e ic complica ions (31). Con en ional he apies o BV and VVC in ol e o al and opical applica ion o an imic obial agen s wi h a high isk o ecu ence (32). Bo h condi ions a ise when he na u al mic obio a is dis u bed. Inc easing he p opo ion o lac obacilli and dec easing he p opo ion o po en ially pa hogenic bac e ia o yeas s in he agina hus becomes he a ge o p e en ion and ea men o bo h condi ions. Clinical s udies ha e demons a ed he e icacy o o al adminis a ion o speci ic p obio ics (33), ye he mechanism o ansloca ion emains o beelucida ed. A ew human s udies sugges he bene icial e ec s o he consump ion o FF o he p e en ion and ea men o agini is. Howe e , clinical sciences and ood sciences ake a dis inc app oach o using bac e ia, wi h he o me ocusing on e icacy s udies in ol ing p obio ic s ains as supplemen s and he la e employing he same s ains as cul u e o ganisms o e men ood ma ices. This sys ema ic e iew aims o add ess his gap and ocus on he po en ial ole o FF in he die o modula e agini is by answe ing he ques ion: “Can consump ion o e men ed oods p e en bac e ial aginosis o ul o aginal candidiasis?” OSF link o s udy p o ocol: PIMENTO-SP-E3. Me abolic heal h Type 2 diabe es (T2D) is one o he majo diseases among me abolic diso de s. The p e alence o T2D is ising wo ldwide and ep esen s a signi ican bu den o he heal hca e sys em (34). The Wo ld Heal h O ganiza ion (WHO) de ines diabe es as a condi ion wi h ele a ed as ing plasma glucose and ele a ed pos p andial plasma glucose in he o al glucose ole ance es (35). T2D is o en cha ac e ized by insulin esis ance and hype insulinemia, which con ibu es o he disease de elopmen . Se e al s udies e iew he e ec o speci ic FF, pa icula ly e men ed milk, on glycaemia pa ame e s, among o he heal h ou comes. O he e iews conside se e al kinds o e men ed oods bu include di e en s udies independen ly o he heal h s a us o he pa icipan s (36–38). In his con ex , a sys ema ic e iew o he e ec s o consump ion o di e en FF on glucose homeos asis in a heal hy popula ion is, o ou knowledge, missing. By conduc ing a sys ema ic sea ch o human s udies, his sys ema ic e iew aims o assess whe he egula FF consump ion posi i ely impac s T2D me abolic isk ac o s in heal hy adul s wi hou medica ion, including pa icipan s wi h p ediabe es and obesi y. The main ou comes will include glucose and insulin homeos asis pa ame e s, such as he main enance o no mal as ing blood glucose le els o a pos p andial glucose esponse. The e iew will add ess he ollowing ques ion: “Does e men ed oods consump ion help o educe pos p andial glucose esponse o main ain as ing blood glucose concen a ions o insulin sensi i i y in heal hy o p ediabe ic adul s?” OSF link o s udy p o ocol: PIMENTO-SP-E4. Ca dio ascula heal h Ca dio ascula diseases (CVD) emain he leading cause o mo bidi y and mo ali y wo ldwide, wi h signi ican con ibu ion o loss o heal h and excessi e heal hca e cos s (39). No iceably, dea hs om CVD nea ly doubled om 12.1 million in 1990 o 20.5 million in 2021, accoun ing o 32% o all dea hs. O e h ee-qua e s o CVD dea hs ake place in low- and middle-income coun ies (40). Die has a signi ican impac bo h on disease pa hogenesis and p e en ion. Al hough se e al coho s udies ha e examined he associa ion o objec i e endpoin s (e.g., CVD incidence o mo ali y) wi h e men ed dai y oods in ake, he esul s emained unclea , as sugges ed by null o in e se associa ions (38, 41). Speci ic blood lipids, such as lipop o eins and iglyce ides, a e isk ac o s o CVD (42). Al hough e men ed dai y p oduc s a e an impo an pa o he die wo ldwide, he impac o hei consump ion on blood lipid p o ile in heal hy adul s is unclea . This e iew aims o add ess whe he e men ed dai y p oduc consump ion can impac he blood lipid p o ile in heal hy adul s. Among all e men ed ood g oups, e men ed dai y p oduc s may p o ide he bes scien i ic e idence o a posi i e impac o e men ed oods on ca dio ascula Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 06 on ie sin.o g heal h h ough hei ac ion on ci cula o y lipids. In addi ion, e men ed dai y p oduc s a e ela i ely well cha ac e ized and bioac i e compounds ha e been iden i ied ha may media e hei impac on ca diome abolic heal h (43). The ocus on e men ed dai y p oduc s is hus mo i a ed by hei po en ial o p o ide key elemen s in his e iew, which will co e all h ee elemen s o he e iewing s a egy, namely human s udies, p oduc cha ac e is ics, and mechanism o ac ion. All human s udies wi h adul s wi hou medica ion and disease will beconside ed. The p ima y ou come in es iga ed will be he blood lipid p o ile, which includes o al choles e ol, HDL-c, LDL-c, iglyce ides, o hei combina ion. Seconda y ou comes will include blood glucose and insulin le els, hs-CRP, TNF-alpha, IL-1, IL-6, blood p essu e, and an h opome ic measu emen s, including body mass index (BMI). The e iew will add ess he ollowing ques ion: “Does consump ion o e men ed dai y p oduc s impac blood lipids in heal hy adul s?” OSF link o s udy p o ocol: PIMENTO-SP-E5. Bone heal h Bones unde go con inuous emodeling and epai , and hei p ope unc ion elies on he in ake o essen ial die a y nu ien s, wi h calcium being o pa amoun impo ance (44). Calcium consump ion alone is insu icien o main ain bone heal h unless i is e icien ly abso bed. Many ac o s, such as age, heal h s a us, o p egnancy, may in luence abso p ion. Fu he , die a y calcium is abso bed in he small in es ine in i s ionized o m (Ca 2+ ). This p ocess depends on he in es inal pH, a ac o modula ed by die as he pH o he chyme apidly ises du ing he diges ion p ocess as i en e s he small in es ine, po en ially hinde ing he abso p ion o ions (45). FF ha e ga ne ed subs an ial a en ion as po en ial die a y in e en ions agains os eopenia and os eopo osis (46, 47). As o milk o igin, dai y p oduc s a e excellen sou ces o calcium (48). The low pH ound in mos dai y FF could delay he neu aliza ion o chyme, hus p olonging calcium ioniza ion and enhancing i s abso p ion. In plan - based oods, he abso p ion o calcium (and o he mine als) can bead e sely a ec ed by an i-nu i ional ac o s such as oxala es and phy a es, whose le els can be educed by e men a ion (49). Some o he me aboli es esul ing om he e men a ion p ocesses also possess he po en ial o modula e he physiology o cells, including bone cells. Associa ion s udies ha e highligh ed he signi ican ole o i amins in main aining bone heal h, including i amin D, i amin K, and B-g oup i amins (50). FF s ands ou as a po en ially ich sou ce o bo h i amin K (menaquinones) and B-g oup i amins (such as ibo la in and ola e). These i amins a e p oduced by e men a i e mic oo ganisms, pa icula ly hose in he lac ic acid bac e ia (LAB) g oup. Addi ionally, FF could modula e he gu mic obio a, eme ging as a ac o in bone homeos asis and he pa hogenesis o os eopo osis (51). In ligh o hese insigh s, a sys ema ic e iew will beconduc ed o comp ehensi ely e alua e he exis ing scien i ic e idence on he e ec o FF consump ion on bone heal h. The e idence will bed awn om andomized clinical ials (RCT) and obse a ional s udies in ol ing heal hy adul s and adul s diagnosed wi h ei he os eopo osis o os eopenia. The cen al esea ch ques ion guiding his e iew is: “Wha is he e ec o consuming e men ed oods on he bone heal h o heal hy adul s and adul s wi h os eopo osis and os eopenia?” OSF link o s udy p o ocol: PIMENTO-SP-E6. Cogni i e heal h In oday’s pe o mance-o ien ed wo ld, whe e li espan is ex ending and, as a esul , he heal h bu den on he olde popula ion is inc easing, main aining cogni i e heal h h oughou li e in o old age is c i ical. In ecen yea s, esea ch on he mic obio a-gu -b ain axis has p o ided insigh s in o he e ec s o gu mic obio a on cogni i e heal h. As a esul , he e ec s o consuming FF con aining bene icial mic obes has become an ac i e a ea o esea ch. Consump ion o FF may a ec he cen al ne ous sys em unc ion, al hough he mechanisms unde lying he e ec o FF on cogni i e pe o mance a e s ill unknown. Th ee non-exclusi e hypo heses ha e been p oposed ega ding he bene icial e ec s o e men a ion on b ain heal h, each elying on da a de i ed p ima ily om p obio ic s udies (52). Fi s , e men a ion modula es he p oduc ion and bioa ailabili y o compounds such as bioac i e pep ides and phy ochemicals (53). Among hese, sho -chain a y acids (SCFA) posi i ely in luence he hos ’s me abolism h ough hei e ec on he cen al ne ous and he immune sys ems (54). The second hypo hesis is ocused on he neu obiology o he s ess esponse h ough he associa ion o he hypo halamic–pi ui a y–ad enal (HPA) axis and he gu mic obio a: p obio ic adminis a ion appea s o imp o e cogni i e unc ion by no malizing he HPA ac i i y and educing sys emic in lamma ion (55). The hi d hypo hesis sugges s ha FF may con ol he elease o neu o ansmi e s and hus a ec cogni i e pe o mance. Taken oge he , he abili y o bac e ia o al e he chemical composi ion o oods and, upon consump ion, he composi ion o he gu mic obio a communi y may accoun o he bene icial e ec s o FF on human cogni i e pe o mance. In his con ex , he p obio ic p ope ies o Bi idobac e ium sp. and Lac obacillus sp. ha e ecen ly a ac ed a en ion, as se e al s ains ha e been epo ed o ha e bene icial e ec s on cogni i e abili ies (52). Bioac i e compounds syn hesized by hese bac e ia ha may di ec ly o indi ec ly a ec cogni i e pe o mance, include neu o ansmi e s (e.g., gamma-aminobu y ic acid (GABA), se o onin), SCFA (e.g., bu y a e, ace a e), pep ides, and i amins (56). As hese bac e ial species a e commonly p esen in FF, a sys ema ic li e a u e e iew will beconduc ed o e alua e he cogni i e pe o mance o humans who consume hese ood p oduc s. This e iew will hus add ess he ques ion: “Does he consump ion o oods e men ed wi h Lac obacillus sp. and/o Bi idobac e ium sp. ha e a bene icial e ec on cogni i e pe o mance in a heal hy adul popula ion, including adul s wi h mild cogni i e impai men ?” OSF link o s udy p o ocol: PIMENTO-SP-E7. Bioac i e compounds Bioac i e compounds, such as polyphenols, pep ides, exopolysaccha ides, conjuga ed linoleic acid (CLA), o i amins, a e p esen in oods ac oss all ood g oups and co e a b oad ange o biological ac i i ies, such as an ioxidan , an i-in lamma o y, an imic obial, and an ihype ensi e e ec s (57). Food e men a ion o e s a unique oppo uni y o inc ease he concen a ion o bioac i e compounds in oods (58, 59). Many publica ions highligh he ole o e men a ion in p oducing bioac i e molecules, po en ially explaining he bene icial e ec s o FF in ake on di e en aspec s o heal h (60– 63). Howe e , e idence linking hese bioac i e compounds in FF o Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 07 on ie sin.o g hei e ec on clinical endpoin s in human s udies is sca ce and has no been sys ema ically add essed. This sys ema ic na a i e e iew aims a ca aloguing compounds in FF o which e idence o bioac i i y has been epo ed in human s udies by add essing he ollowing esea ch ques ion: “Wha compounds de i ed om ood e men a ion a e associa ed wi h e ec s on clinical endpoin s in human s udies?” This ques ion will beanswe ed by sea ching all human s udies, speci ically in es iga ing he po en ial ole o one o se e al bioac i e compounds p esen in FF on clinical ou comes. A ca alogue o he FF, o which an associa ion be ween he bioac i e compounds and clinical endpoin s has been epo ed, will bees ablished. OSF link o s udy p o ocol: PIMENTO-SP-S1. P oduc ion o i amins Vi amins a e essen ial mic onu ien s equi ed o many i al human unc ions. The human body canno syn hesize mos i amins due o i s limi ed biosyn he ic capaci y and equi es ex e nal p o ision h ough he die . Despi e he p esence o i amins in a wide ange o oods, de iciencies emain high in many con ex s, leading o heal h p oblems speci ic o each i amin (64). Fo example, i amin A de iciency esul s in isual impai men , ail y, and inc eased mo ali y isk, while i amin B9 ( ola e) can lead o neu al ube de ec s in he o sp ing. Con en ional ea men and p e en ion app oaches, such as supplemen a ion and o i ica ion, ha e no always p o en e ec i e and may ha e undesi able side e ec s (64, 65). FF ha e he po en ial o p o ide a ange o heal h bene i s, including i amin syn hesis (66). The scien i ic li e a u e also epo s on he possibili y o inc easing i amin le els in he gene al popula ion by consuming FF na u ally en iched in i amins as an al e na i e die a y app oach o o i ica ion o supplemen a ion (67, 68). Thus, his sys ema ic na a i e e iew aims o in es iga e i consuming oods en iched in i amins h ough e men a ion con ibu es o he i amin needs o a heal hy popula ion wi h a ying i amin s a us. The speci ic esea ch ques ion will be: “Does he consump ion o e men ed oods, o i ied in i amin by e men a ion, con ibu es o i amin co e age o a heal hy popula ion o o a i amin-de icien popula ion?” In he human s udies included in he e iew, he p ima y ou come o in e es will be he i amin s a us in he s udy pa icipan s assessed in ela ion o FF consump ion, while he seconda y ou come will be he i amin con en in FF. OSF link o s udy p o ocol: PIMENTO-SP-S2. Bioa ailabili y and bioaccessibili y o nu ien s Mic onu ien de iciencies a e an ala ming global heal h p oblem. In pa icula , i on de iciency anemia a ec s a la ge pa o he wo ld’s popula ion, mainly child en and p egnan women, and is conside ed one o he leading con ibu o s o he global disease bu den (69). Since he e is no physiological mechanism o exc e ion, he i on balance in he human body is only con olled by abso p ion (70). Phy a e, polyphenols, calcium, asco bic acid, and muscle issue a e die a y ac o s ha ha e been epea edly shown o a ec i on abso p ion in se e al s udies (71, 72). E idence sugges s ha e men a ion signi ican ly imp o es he bioa ailabili y o i on in oods, and especially o plan -based oods such as ce eals and legumes, which o en se e as impo an sou ces o i on in many die s (73). Sou dough and yeas -lea ened b eads a e s aple oods p oduced in many pa s o he wo ld. Fe men a ion can enhance he bioa ailabili y o non-hem i on in sou dough b ead (74) h ough a ious mechanisms, such as educing phy a e le els, inc easing acidi y, and gene a ing o ganic acids. The p ima y pu pose o his sys ema ic e iew is o comp ehensi ely examine he a ailable clinical s udies ha assessed he associa ion be ween e men ed sou dough and yeas -lea ened b ead and i on bioa ailabili y, abso p ion, and s a us in human subjec s. This e iew will add ess he ollowing ques ion: “Does sou dough and egula b ead e men a ion inc ease i on bioa ailabili y, abso p ion, and s a us in humans?” The sea ch s a egy and inclusion c i e ia will bede e mined a p io i. Mo e speci ically, all ypes o sou dough and yeas -lea ened b ead, p epa ed om ce eal lou (s) ha may o may no ha e been p e iously o i ied will beconside ed exposu e o in e en ion. The ou comes o in e es will include i on- ela ed bioma ke s (i.e., hemoglobin, hema oc i , se um i on, se um e i in, se um ans e in ecep o , o al i on-binding capaci y, o i on iso ope abso p ion). O e all, he e iew is an icipa ed o con ibu e o a be e unde s anding o he impac o e men a ion on i on bioa ailabili y in hese s aple ood p oduc s. OSF link o s udy p o ocol: PIMENTO-SP-S3. E hnic e men ed oods Acco ding o he Uni ed Na ions, he wo ld popula ion may inc ease o 9.7 billion in he nex i e decades (75). The al eady exis ing p oblem o inadequa e access o nu i ious ood o e e yone will be u he exace ba ed. I is also p ojec ed ha in 2030, o e 670 million people will be expe iencing hunge . Finding al e na i e solu ions o ensu e a heal hy ood en i onmen o e e yone is hus o pa amoun impo ance. E hnic FF can bede ined as oods o igina ing om he he i age and cul u e o an e hnic g oup o people who use hei e hno- mic obiological knowledge o ood e men a ion (76) wi h local ing edien s om plan o animal sou ces (77). E hnic FF a e o en a isanal and hus a isk o disappea ing oge he wi h he di e si y o na i e mic oo ganisms used in hei p oduc ion due o u baniza ion and changing ood habi s (76). The scien i ic li e a u e sugges s ha consuming e hnic FF like koumiss, kimchi, and doenjang may posi i ely a ec heal h, including imp o emen s in hema ological and biochemical ac o s. E hnic FF may educe iglyce ides and choles e ol le els, inc ease high-densi y lipop o ein (HDL) choles e ol, imp o e blood glucose con ol and, consequen ly, imp o e heal h and well-being (78–81). While speci ic e hnic FF like na o, kinema, kimchi, empeh, and pulque ha e ecei ed subs an ial a en ion in esea ch, many o he e hnic FF a e neglec ed despi e hei po en ial heal h bene i s. Rega dless o he wide a ie y o e hnic FF p oduced and consumed wo ldwide (76, 82), a comp ehensi e e iew examining he heal h bene i s and po en ial isks associa ed wi h hese oods has ye o be conduc ed. This na a i e sys ema ic e iew will hus add ess he ollowing ques ion: “Wha a e he heal h e ec s o e hnic Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 08 on ie sin.o g e men ed oods?” In answe ing he e iew ques ion, a lis o e hnic FF based on published li e a u e will be i s compiled (76, 82), ollowed by iden i ying clinical s udies associa ing he consump ion o e hnic FF wi h clinical endpoin s i espec i e o he heal h condi ion s udied. Addi ional in o ma ion on he cha ac e is ics o he e hnic FF, including hei egion o o igin, will also bep esen ed. OSF link o s udy p o ocol: PIMENTO-SP-S4. Heal hy die s Die composi ion is one o he mos impo an de e minan s o mo ali y isk (83). Fe men ed dai y p oduc s and o he FF a e cu en ly being s udied o hei po en ial heal h e ec s in nume ous clinical s udies, e alua ing he e ec s o FF on ch onic disease isk ac o s, immune sys em pe o mance, and cogni i e unc ion. Howe e , only a ew s udies ha e ocused on he ela ionship be ween FF consump ion and li e expec ancy o mo ali y (17). The e o e, his e iew aims o e alua e he e idence on he associa ion be ween he consump ion o FF and mo ali y isk in ee-li ing popula ions and answe he ques ion: “Wha is he impac o e men ed oods consump ion on mo ali y isk?” A sys ema ic e iew o he li e a u e, inco po a ing a me a- analysis i a signi ican numbe o pe inen human s udies a e a ailable, will beunde aken. The e alua ion will ocus on coho s udies wi h he p ima y objec i e o unco e ing he impac o die s, including FF, on mo ali y. Mo ali y a e, mo ali y isk, and dea h a e will beex ac ed as p ima y ou comes o his e iew. Con ounding ac o s such as demog aphic da a, li e quali y indices, gene al heal h s a us, die quali y, alcoholic d ink consump ion and smoking habi s, as well as ch onic mo bidi y de eloped du ing he epo ed s udy, will beconside ed. Suppo ing e idence will bede i ed om s udies ha examined he bene icial heal h e ec s o e men ed oods and he p obable unde lying mechanisms o ac ion, wi h po en ial ad e se e ec s also being no ed (84). The indings o his s udy will in o m u u e esea ch on he ole o FF in heal hy die s. Finally, i is expec ed o highligh he need o mo e de ailed inclusion o FF in na ional and Eu opean die a y guidelines and popula ion nu i ion su eys. OSF link o s udy p o ocol: PIMENTO-SP-S5. Pe sonalized nu i ion The gu mic obio a has ecen ly been iden i ied as a pe son- speci ic ac o de e mining a iable me abolic esponse o die a y in ake (85). In e es ingly, he e men a ion o ood by echnological mic oo ganisms and he ans o ma ion o inges ed nu ien s by he gu mic obio a sha e common enzyma ic eac ions (86). Taken oge he , hese analogies sugges ha die a y e men ed oods could also modula e he in e -indi idual a iabili y in esponse o ood in ake (87, 88). This sys ema ic na a i e e iew aims o de e mine whe he heal h ou comes in esponse o FF show a signi ican in e - pe sonal a iabili y. I heal h ou comes a y be ween indi iduals, FF can beconside ed as po en ial le e s in pe sonalized o p ecision nu i ion s a egies. Acco ding o he ecen Food Fo um o he Na ional Academies o Sciences, Enginee ing, and Medicine (89), human a iabili y in esponse o ood can be ega ded as a basis o de eloping pe sonalized nu i ion and a ge ed nu i ional guidelines. To his end, human s udies (all popula ions s udied) ha include sho - o long- e m nu i ional o die a y e alua ions will becollec ed sys ema ically. The e iew will hus ocus on s udies epo ing a iable heal h esponses ollowing he consump ion o FF, which could bea ibu ed o well-de ined o ye - o-be-de ined cha ac e is ics o popula ions. Addi ionally, conside ing ha he ield is ela i ely no el and explo a o y, e iews o o he ypes o publica ions (e.g., epo s, posi ion pape s) in which die a y FF a e discussed in ela ion o pe sonalized o p ecision nu i ion will also beincluded. Pa icula emphasis will begi en o ac o s ha may explain a a iable heal h esponse: (1) popula ions (e.g., gende , age, loca ion, physical ac i i y), (2) heal h s a us (global o speci ic ma ke s, wi h pa icula ocus on gu mic obio a composi ion o unc ion), (3) e alua ion o he die s and supplemen a ions, including he de ailed desc ip ion o FF (e.g., ype, nu i ional composi ion, ma ix desc ip ion). This wo k will bea i s s ep owa ds e alua ing he easibili y o using FF in ailo ed nu i ional s a egies. This e iew will add ess he ollowing ques ion: “Does he impac o e men ed oods on di e en heal h ou comes depend on speci ic cha ac e is ics o popula ion g oups, and, consequen ly, can e men ed oods beused in ailo ed nu i ional s a egies?” OSF link o s udy p o ocol: PIMENTO-SP-S6. Food sa e y Foodbo ne diseases a e illnesses ha esul om consuming con amina ed ood. Clinical signs and symp oms di e depending on he cause o haza d in ol ed (90). Food sa e y is a high-p io i y opic, conside ing ha su icien amoun s o sa e, sus ainably-p oduced ood mus besecu ed o a g owing wo ld popula ion o comply wi h Sus ainable De elopmen Goal 12 o he 2030 Agenda o he Uni ed Na ions (91). Fe men a ion is one o he oldes adi ional p ocesses o achie ing sa e ood p oduc ion (92); howe e , enewed in e es in FF equi es e-examining hei sa e y. This sys ema ic na a i e e iew will ask he ques ion: “Wha a e he main mic obiological and chemical haza ds posed by e men ed oods and hei associa ed isks?” In o he wo ds, a e e men ed oods sa e o humans? A sys ema ic e iew o he scien i ic li e a u e will bepe o med o add ess his ques ion. Repo s associa ing he occu ence o ood haza ds o mic obiological and/o chemical o igin wi h he consump ion o FF by he gene al popula ion, including ulne able g oups (such as, p egnan and b eas eeding women, child en, and elde ly), will becompiled wi hou limi a ion by age o gende . In addi ion o p esen ing he illnesses associa ed wi h FF consump ion, he e iew will p o ide scien i ic e idence on 1) he occu ence (le els/magni ude, equency) o haza ds associa ed wi h he consump ion o e men ed oods; 2) he associa ed isks o exposu e, aking in o accoun hei p obabili y and se e i y; and 3) he epo ed ou b eaks as well as he ex en o which he diseases occu (93). OSF link o s udy p o ocol: PIMENTO-SP-S7. No el oods Fe men a ion con e s unc ional p ope ies o ood ha migh con ibu e o human heal h (94). Th ough a a ional choice o aw ma e ial and s a e cul u e, no el FF wi h imp o ed unc ional p ope ies ha posi i ely impac heal h can begene a ed (12, 67, 95). Todo o ic e al. 10.3389/ nu .2024.1458536 F on ie s in Nu i ion 09 on ie sin.o g These no el FF can bep oduced using ei he a new species as a s a e cul u e, a new aw ma e ial, o a combina ion o bo h. The Eu opean Commission de ines oods as no el i hey “had no been consumed o a signi ican deg ee by humans in he EU be o e 15 May 1997.” In e es ingly, he cu en lis o no el oods includes one e men ed p oduc , namely e men ed whea ge m ex ac (96). This sys ema ic na a i e e iew aims o e alua e he scien i ic e idence on whe he no el FF con e heal h bene i s o consume s. The esea ch ques ion add essed by his e iew will hus be: “Wha a e he heal h e ec s o no el e men ed oods?” The lis o FF de eloped in he li e a u e sea ch s ing PIMENTO-LS will becombined wi h keywo ds ela ing o “no el ood” and sea ched in combina ion wi h human s udies. S udies ela ed o “ e men ed whea ge m ex ac ” will also beincluded. Gi en ha his e iew lea es he in es iga ed heal h condi ions open, all p ima y and seconda y endpoin s epo ed by he publica ions will be ex ac ed and e alua ed. The e idence o po en ial heal h bene i s o speci ic no el FF will bediscussed in ligh o he signi icance and ele ance o he epo ed endpoin s. The e iew will iden i y esea ch gaps ha should os e u u e s udies o p omo e inno a ion on no el FF and, e en ually, hei consump ion (12). OSF link o s udy p o ocol: PIMENTO-SP-S8. Food by-p oduc s The inc easing p essu e on socie y o p oduce sus ainable ood sys ems has highligh ed he impo ance o minimizing was e and making be e nu i ional use o by-p oduc s (97, 98). Whey, eleased in la ge amoun s in he dai y p ocessing indus y, is an impo an milk by-p oduc ich in p o eins, lac ose, mine als and i amins (99). The nu ien composi ion o whey, pa icula ly lac ose and p o eins, makes i a sui able sou ce o e men a ion by mic oo ganisms. When e men ed by Lac obacillaceae and Bi idobac e ium, whey can be u ned in o a p oduc wi h appealing ex u e and senso y p ope ies (100). One o he mos impo an bene icial heal h e ec s o e men ed why is i en ichmen in bioac i e compounds compa ed o non- e men ed whey. Indeed, in i o and animal s udies indica e ha whey e men a ion migh inc ease i s an ioxida i e p ope ies (101). Se e al human s udies epo ed using whey as a p obio ic ca ie o imp o e amino acid abso p ion in physically ac i e males (102) o educe ood alle gies (103, 104). Cu en ly, no clea o e iew is a ailable on he po en ial heal h- p omo ing e ec s o whey e men ed by adi ional me hods, e.g., spon aneous e men a ion o he addi ion o mic oo ganisms as s a e s. This sys ema ic na a i e e iew will hus add ess he ollowing ques ion: “Wha a e he heal h e ec s o e men ed whey?” Thus, his e iew aims o p o ide an o e iew on exis ing li e a u e on he p oduc ion, iden i ica ion, and unc ional p ope ies o e men ed whey p oduc s. All human s udies wi h e men ed whey as pa o hei nu i ional in ake assessmen will be included. I espec i e o he a ge ed heal h condi ions, he p ima y and seconda y endpoin s will be ex ac ed and analyzed o hei signi icance and clinical ele ance. Special a en ion will begi en o cha ac e iza ion o he nu i ional p ope ies o e men ed whey and di e en ia ing i om un e men ed whey o which p obio ics we e added. The e iew will iden i y esea ch gaps ha should os e u u e s udies and p omo e inno a ion on e men ed whey and, e en ually, he consump ion o e men ed whey p oduc s bene icial o heal h. OSF link o s udy p o ocol: PIMENTO-SP-S9. Discussion Towa ds a s a egic esea ch oadmap on he unc ionali y o FF A ood company ha aims a ma ke ing a ood p oduc by claiming a speci ic heal h p ope y, needs o documen , and e en ually g ade, he s eng h o he a ailable scien i ic e idence o he in ended claim based on guidelines es ablished by egula o y au ho i ies such as he EFSA (13, 14). The body o e idence ha should be p o ided o a success ul claim encompasses he sys ema ic e iewing o well designed, conduc ed, analyzed, and epo ed human s udies (105). In pa icula , he PICO c i e ia (Popula ion, In e en ion, Con ol, Ou come) should be me , meaning ha he cha ac e is ics o he en olled pa icipan s, he in es iga ed die a y componen s, he con ol, and he measu ed clinical endpoin s should bein line wi h he esea ch ques ion unde lying he claim. Fu he mo e, quali a i ely good human s udies should a oid he isk o bias a ising om me hodological laws along he s udy wo k low, including andomiza ion bias, missing da a, o selec i e epo ing. In addi ion, he die a y componen s in es iga ed should bewell cha ac e ized wi h espec o hei composi ion, s abili y, and sa e y. Finally, human s udies epo ing associa ions be ween die a y in ake and clinical endpoin s should becomplemen ed wi h da a (in i o, animal, human) on he in ol ed mechanism(s) o ac ion in o de o mo e he scien i ic e idence om associa i e o causa i e. Whe eas hese egula o y guidelines p ima ily aim a p o ec ing consume s, hei ole in p omo ing inno a ion o he indus y is also ecognized, al hough hei e icacy has been deba ed (106–109). The ood and nu i ion esea ch communi y could make use o egula o y guidelines (13, 14) and guidance o sys ema ic e iewing o human s udies (105) o imp o e he e ec i eness o i s p e-compe i i e esea ch. Independen ly om hei impac on inno a ion, hese guidelines p o ide aluable in o ma ion o esea che s on design o s udies ha , when conduc ed and analyzed p ope ly, will signi ican ly con ibu e o he u u e e alua ion o he impac o die a y componen s on heal h. The U.S. Food and D ug Adminis a ion (FDA) ecen ly announced a quali ied heal h claim on yoghu and diabe es, which s a es “Ea ing yogu egula ly may educe he isk o ype 2 diabe es acco ding o limi ed scien i ic e idence” (110). This claim is in e es ing in he amewo k o his concep ual a icle o se e al easons. Fi s ly, al hough submi ed o he FDA by he p i a e sec o , he ood p oduc e alua ed by he FDA is a gene ic yoghu . In ha ega d, mos o he da a used o suppo he claim, in pa icula human s udies, was p oduced by he academic esea ch communi y, illus a ing he ole o public esea ch in p o iding scien i ic e idence o he impac o ood on heal h, in his pa icula case on he con ibu ion o yoghu o he educ ion o ype 2 diabe es isk. On he o he hand, he esea che s ha ing conduc ed hese s udies did ce ainly no speci ically design hem o bepa o he FDA heal h claim! Indeed, among he 66 human s udies published on yoghu and diabe es (20 in e en ion s udies, 46 obse a ion s udies) only 28 obse a ion s udies we e e ained by he FDA. In pa icula , all o he in e en ion s udies we e excluded as hey we e no su icien ly con olled o p o ide use ul in o ma ion o assessmen o his pa icula heal h claim. Also, isk o bias, e.g., due o imp ope baseline dis ibu ion o