Impact of Exercise on Gut Microbiota in Obesity

nu ien s Re iew Impac o Exe cise on Gu Mic obio a in Obesi y Je ónimo A agón-Vela 1,2,* , Pa icio Solis-U a 3,4 , F ancisco Ja ie Ruiz-Ojeda 2,5,6,7, Ana Isabel Ál a ez-Me cado 2,5,6 , Jo ge Oli a es-A ancibia 8,9 and Julio Plaza-Diaz 5,6,10,*   Ci a ion: A agón-Vela, J.; Solis-U a, P.; Ruiz-Ojeda, F.J.; Ál a ez-Me cado, A.I.; Oli a es-A ancibia, J.; Plaza-Diaz, J. Impac o Exe cise on Gu Mic obio a in Obesi y. Nu ien s 2021,13, 3999. h ps://doi.o g/ 10.3390/nu13113999 Academic Edi o s: Na halie Boisseau and Nicolas Ba nich Recei ed: 15 Oc obe 2021 Accep ed: 8 No embe 2021 Published: 10 No embe 2021 Publishe ’s No e: MDPI s ays neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a il- ia ions. Copy igh : © 2021 by he au ho s. Licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion (CC BY) license (h ps:// c ea i ecommons.o g/licenses/by/ 4.0/). 1Depa men o Physiology, School o Pha macy, Uni e si y o G anada, Campus de Ca uja s/n, 18071 G anada, Spain 2Ins i u e o Nu i ion and Food Technology “JoséMa aix”, Cen e o Biomedical Resea ch, Uni e si y o G anada, A da. del Conocimien o s/n, 18016 G anada, Spain; [email p o ec ed] (F.J.R.-O.); al a ezme cado@ug .es (A.I.Á.-M.) 3PROFITH “PROmo ing FITness and Heal h h ough Physical Ac i i y” Resea ch G oup, Depa men o Physical Educa ion and Spo s, Facul y o Spo s Science, Uni e si y o G anada, 18071 G anada, Spain; [email p o ec ed] 4Facul y o Educa ion and Social Sciences, Uni e sidad And es Bello, Viña del Ma 2531015, Chile 5Depa men o Biochemis y and Molecula Biology II, School o Pha macy, Uni e si y o G anada, 18071 G anada, Spain 6Ins i u o de In es igación Biosani a ia IBS.GRANADA, Complejo Hospi ala io Uni e si a io de G anada, 18014 G anada, Spain 7 RG Adipocy es and Me abolism, Ins i u e o Diabe es and Obesi y, Helmhol z Diabe es Cen e a Helmhol z Cen e Munich, Neuhe be g, 85764 Munich, Ge many 8G upo AFySE, In es igación en Ac i idad Física y Salud Escola , Escuela de Pedagogía en Educación Física, Facul ad de Educación, Uni e sidad de las Amé icas, San iago 8370035, Chile; jo ge.oli a [email p o ec ed] 9IRyS Resea ch G oup, School o Physical Educa ion, Pon i icia Uni e sidad Ca ólica de Valpa aíso, Valpa aíso 2374631, Chile 10 Child en’s Hospi al o Eas e n On a io Resea ch Ins i u e, O awa, ON K1H 8L1, Canada *Co espondence: je oa @ug .es (J.A.-V.); j plaza@ug .es (J.P.-D.); Tel.: +34-958220319 (J.A.-V.); +34-958241599 (J.P.-D.) Abs ac : Physical ac i i y, exe cise, o physical i ness a e being s udied as help ul nonpha maco- logical he apies o educe signaling pa hways ela ed o in lamma ion. S udies desc ibing changes in in es inal mic obio a ha e s a ed ha physical ac i i y could inc ease he mic obial a iance and enhance he a io o Fi micu es/Bac e oide es, and bo h ac ions could neu alize he obesi y p og ession and diminish body weigh . The aim o his e iew is o p o ide an o e iew o he li e a u e desc ibing he ela ionship be ween physical ac i i y p o iles and gu mic obio a and in obesi y and some associa ed como bidi ies. P omo ing physical ac i i y could suppo as a ea men o main ain he gu mic obio a composi ion o o es o e he balance owa d an imp o emen o dysbiosis in obesi y; howe e , hese mechanisms need o be s udied in mo e de ail. The oppo uni y o con ol he mic obio a by physical ac i i y o imp o e heal h esul s and dec ease obesi y and ela ed como bidi ies is e y a ac i e. Ne e heless, se e al incomple ely answe ed ques ions need o be add essed be o e his s a egy can be implemen ed. Keywo ds: gu mic obio a; physical ac i i y; heal h; obesi y; child en; humans; non-communicable diseases 1. In oduc ion A posi i e ene gy balance causes excessi e lipid accumula ion in adipose issue ha in luences he a ec ed indi idual in ega ds o o he diseases such as insulin esis ance, ca - dio ascula diseases ha can culmina e in ce ain ypes o cance s and ype 2 diabe es [ 1 ]. Indeed, isce al a a he han o al a is he main d i e o insulin esis ance and o he como bidi ies such as dyslipidemia and ch onic low-g ade in lamma ion s a us in indi id- uals [ 2 ]. A he cellula le el, adipocy e hype ophy esul s in comp omised blood supply Nu ien s 2021,13, 3999. h ps://doi.o g/10.3390/nu13113999 h ps://www.mdpi.com/jou nal/nu ien s Nu ien s 2021,13, 3999 2 o 15 o adipose issue, highe ib osis, hypoxia, sys emic and local in lamma ion, and insulin esis ance in he adipocy es [3,4]. Al hough scien is s con inue making subs an ial p og ess in unde s anding adipose issue unc ion, p e en ion, and ea men o obesi y, he pandemic con inues o sp ead and is one o he main heal h complica ions in indus ialized and de eloping coun ies [ 5 ]. In Eu ope, he o e weigh p e alence is expec ed o be nea 50%, and he obesi y p e alence o be app oxima ely 24% o he popula ion [ 6 ], inc easing om 11% in 2000 o 24% in 2018, on ypical h ough Eu opean membe s a es [ 6 , 7 ]. I is no ewo hy ha high-calo ie die s and he absence o physical ac i i y, which is s ongly a ec ed by a a ie y o ac o s such as li es yle and socioeconomic s a us, play a pa in he ad ance o me abolic diseases [8]. Despi e he mul iple ac o s ha in e ac in he p og ess o obesi y, he gu mic obio a seems o be a c i ical ole as a bodyweigh egula o [ 9 ]. In ac , Liu e al. ha e epo ed ele a ed body mass index (BMI) and adiposi y, dyslipidemia, insulin esis ance, and a mo e ma ked in lamma o y s a us in indi iduals who ha e also exhibi ed signi ican ly lesse di e si y in gu bac e ia [ 10 ]. Nume ous mechanisms ha e been sugges ed o elucida e he po en ial ole o gu mic obio a in obesi y p og ess. The e m mic obio a includes he ull collec ion o mic obes (bac e ia, ungi, and i uses, among o he s) ha na u ally subsis wi hin a pa icula biological niche, a ound 500–1000 species, and hei impac on human heal h [ 11 ]. Se e al endogenous and exoge- nous ac o s a e in ol ed in he gu mic obio a such as he deli e y me hod o a neona e, hos immune esponse, die , an ibio ics, hos gene ic ea u es, o he d ugs, in ec ions, diu nal hy hm, and en i onmen al mic obial exposu es [12,13]. Wi h ega ds o obesi y, a high- a die causes sys emic insulin esis ance and me abolic dys unc ion in mice, which d i es a unc ional and s uc u al dysbiosis o he gu mic o- bio a, de ined as “a educ ion in mic obial di e si y and a combina ion o he loss o bene icial bac e ia such as Bac e oides s ains and bu y a e-p oducing bac e ia” [ 12 , 14 , 15 ], inc easing Lac ococcus and lowe ing Tu icibac e , which con e an enhanced in lamma o y esponse [ 16 ]. The sys emic in lamma ion in obesi y is ela ed o augmen ed in es inal pe - meabili y, which is linked wi h “leaky gu ” and gu dysbiosis, which is a new objec i e o he apy and disease p e en ion [ 17 ]. Indeed, dis u bances o gu mic obio a composi ion may upsu ge he leakage o he mucosa, inc easing he seepage o bac e ia and bac e ia componen s such as lipopolysaccha ide (LPS) ac oss he in es inal mucosa [ 18 ]. In addi ion, i is well-known ha obesi y causes a educ ion in he a io o Bac e oide es/Fi micu es and g ea e le els o P e o ella [ 19 ]. Thus, main aining and es o ing a heal hy gu mic obio a can help p e en he ini ial s a and p og ess o me abolic diseases, including obesi y. Mic obial dysbiosis could be de e mined using bioin o ma ic analysis wi h ecological a iables, such as di e si y (alpha o be a), species ichness [ 20 ], mic obial abundances such as Bac e oide es/Fi micu es a io [ 21 ], and clinical measu es such as o ganic acid es [22] and hyd ogen b ea h es [23]. Nume ous me aboli es a e c ea ed by gu mic obio a om he die a y me abolism such as sho -chain a y acids (SCFAs), ime hylamine, and ime hylamine N-oxide, among o he s, which a e linked o me abolic diso de s pa hogenesis [ 24 ]. In his con ex , new ea men s (including p e and p obio ics) such as ecal mic obio a ansplan a ion [ 25 ], pe sonalized nu i ion, die a y educa ion, and physical ac i i y [ 26 ] may help o ees ablish and/o p ese e he composi ion o gu mic obio a, changing he b ain–gu axis and dec easing pa hology isk [ 27 ]. In pa icula , physical exe cise induces changes in mic obial di e si y, ca dio espi a o y i ness, and insulin esis ance among o he s [28]. The composi ion o gu mic obio a is di ec ly linked o sys emic me abolic homeos asis and adiposi y, which in luences he p og ess o obesi y. Though se e al mechanisms be- ween mic obial di e si y and me abolic heal h ha e been desc ibed, he causal ela ionship is no comple ely unde s ood [29–31]. Exe cise is ecognized o s abilize he p og ession o obesi y and modi y he gu mic obio a composi ion by inc easing he mic obial di e si y [ 32 , 33 ], imp o ing he Fi - micu es/Bac e oide es a io ha could po en ially con ibu e o dec easing body weigh , Nu ien s 2021,13, 3999 3 o 15 obesi y-associa ed pa hologies, and gas oin es inal diso de s [ 32 ]. In addi ion, exe cise is conside ed an e icien non-pha macological he apy by dec easing in lamma o y sig- naling pa hways [ 34 ]. O e all, p omo ing exe cise could help as a ea men o main ain he composi ion o gu mic obio a o o es o e he balance owa d an imp o emen o dysbiosis in obesi y; howe e , hese mechanisms need o be s udied in mo e de ail. In he p esen wo k, we e iew he li e a u e desc ibing he associa ion be ween exe cise and gu mic obio a in obesi y and i s associa ed como bidi ies. 2. Physical Ac i i y, Exe cise, and Physical Fi ness and Thei Rela ionship wi h Obesi y and Heal h Main enance Physical ac i i y, exe cise, and physical i ness a e e ms ha de ine dis inc concep s. Physical ac i i y is well desc ibed as e e y physical mo emen using skele al muscles ha p oduce an ene gy expendi u e in daily li e ha can be ca ego ized in o occupa ional, household, spo s, condi ioning, o o he ac i i ies [ 35 ]. Exe cise is a subsec ion o physical ac i i y ha is s uc u ed, p emedi a ed, and cyclic and has as a inal o an in e media e objec i e he p og ess o physical i ness main enance, ha is, a g oup o aspec s ha a e bo h skills- o heal h- ela ed [36]. The mos in-dep h and s aigh o wa d consequence associa ed wi h exe cise bene i s is weigh loss, wi h he p obable o mi iga e o e e se he cou se o obesi y and co- mo bidi ies e en wi h no die a y in e en ion [ 37 – 39 ]. Physical ac i i y impo ance o weigh loss e alua ed by BMI is deba ed, bu i is well es ablished he e ec o exe cise on adiposi y and se e al ch onic diseases. Ins ead, he e is obus e idence desc ibing how physical ac i i y le els and exe cise in e en ion a e impo an o a oid weigh egain a e weigh loss [40–45]. Acco ding o an h opome y, he e a e o he measu es ins ead BMI ha migh be ela ed o he gu mic obio a, wais ci cum e ence, hip ci cum e ence, and wais - o-hip a io, which ha e become impo an indica o s o adiposi y, disease isk, and mo ali y isk [ 46 , 47 ]. Recen ly, Osbo ne e al. ha e epo ed he associa ions be ween some o he a o emen ioned a iables wi h he composi ion o gu mic obio a. Pa icipan s wi h high alues o BMI, mid-uppe a m ci cum e ence, wais ci cum e ence, and wais - o-hip a io we e ela ed o a diminished alpha di e si y. Oscillospi a and he amily S24-7 ela i e abundances we e in e sely associa ed wi h an h opome ic measu es. BMI and wais and hip ci cum e ences we e ela ed posi i ely o Acidaminococcus, especially mo e in women han in men [47]. One o he p oposed mechanisms is ha physical ac i i y aises ene gy expendi u e ac i a ing lipolysis, so he a mass is diminished i he ene gy consumed is no eimbu sed o wi h a ise in calo ic in ake, main aining a nega i e ene gy balance [ 48 ]. On he con a y, physical inac i i y in con empo a y obesogenic ci cums ances o igina es maladap a ion, cha ac e ized by a posi i e ene gy balance, causing long-las ing disease and becoming a main public heal h p oblem [ 49 ]. Ne e heless, egula physical ac i i y has a deep exp es- sion e ec on ou genome [ 50 ], which has been p e e ed o enhancing ae obic me abolism o main ain ene gy in a si ua ion o ood insu iciency [ 51 , 52 ], occasioning nume ous a o - able adap a ions and educed isk o ch onic diseases [ 53 ]. The iden i ica ion o adap a ions o exe cise is ad ancing ou knowledge o he pa hophysiology o long-las ing diseases and a ying old iews, which migh bene i new he apeu ic app oaches and a ge s [53]. 3. Physical Ac i i y and Gu Mic obio a in Obesi y Li es yle changes a e s ill he mos widely used and ecommended s a egies o achie e weigh educ ion in obesi y, pa icula ly using di e en die a y s a egies and p omo ing physical ac i i y and exe cise [ 54 ]. Recen au ho s conclude ha he e seems o be an in ima e associa ion be ween he gu mic obio a and li es yle p oposing ha an ac i e li es yle may imp o e he quali y o he mic obio a [ 55 ]. In his sense, obesi y is ela ed o mino di e si y and ichness o he in es inal mic obio a, wi h a lowe a io o Bac e oide es- o-Fi micu es [ 29 ]. Indeed, exe cise aining imp o es obesi y s a us by inc easing insulin sensi i i y, educing sys emic in lamma ion, and imp o ing VO 2max [ 56 ]. Thus, acco ding Nu ien s 2021,13, 3999 4 o 15 o da a om ecen epidemiological, physiological, and omics-based s udies, comple ed h ough s udies in animals and cells s udies, i seems plausible ha mic obial communi ies migh be di ec ly o indi ec ly in luenced, among o he en i onmen al ac o s, by physical ac i i y o exe cise [57,58]. Main aining o es o ing mic obial di e si y is essen ial o a oid pe u bed in es inal homeos asis, which is ela ed o dysbiosis. The excessi e p oduc ion o SCFA, due o e men a ion o non-diges ible ood polysaccha ides by in es inal bac e ia, may induce lipogenesis in he li e and accumula ion o iglyce ides in hos adipocy es [ 5 ]. Indeed, hese SCFAs may also be implica ed in al e a ions associa ed wi h insulin esis ance, gi en ha one o he objec i es o hese SCFA induced signals is glucose homeos asis [ 59 ]. This is possible due o glucagon-like pep ide 1 (GLP-1), a ecognized media o ela ed o glucose homeos asis. In gene al e ms, GLP-1 is p oduced in he in es ine and has a c i ical p o agonis in adjus ing he plasma glucose concen a ion [ 59 ]. In e es ingly, a ecen s udy e eals ha ec al adminis a ion o SCFAs inc eases he GLP-1 sec e ion, con i ming a close associa ion be ween GLP-1 and SCFAs [ 60 ]. The e o e, a ecal bac e ia educ ion may p oduce glucose in ole ance h ough a educ ion in he sec e ion o GLP-1 [ 61 ]. Ano he mechanism sugges ed cla i ying he connec ion be ween obesi y and he gu mic obio a is he ole o he ac i a ion o adenosine monophospha e kinase (AMPK). One o he main unc ions o AMPK is he oxida ion o a y acids [ 62 ]. The e o e, i s inhibi ion could cause an inc eased a accumula ion [63]. 4. Physical Ac i i y and Mic obio a: Some Unde lying Mechanisms Physical ac i i y can s imula e a ia ions in he gu mic obio a by nume ous mecha- nisms such as myokines elease, inc eased in es inal ansi , o he sec e ion o neu o ans- mi e s and ho mones [ 64 ]. Howe e , he in e -indi idual a ia ion and gu mic obio a plas ici y ha e hampe ed e o s o iden i y a “heal hy” in es inal mic obio a. Indeed, in ad- di ion o physical ac i i y, many ac o s lead o ins abili y o he gu mic obio a, such as die , sleep pa e n, an ibio ic exposu e, and a ious como bidi ies [ 65 ]. Impo an ly, a heal hy mic obio a is in ol ed in he immune sys em de elopmen , wi h an an i-in lamma o y ole h ough educing his one deace ylases in egula o y T cells by G p o ein-coupled ecep o s [65]. Recen s udies by Cas ellanos e al. epo ed ha ac i e indi iduals who mee he ec- ommenda ions o physical ac i i y and die om he Wo ld Heal h O ganiza ion (WHO) exhibi di e en ela i e abundances o h ee species o he Bac e oides genus: B. uni o mis, B. o a us, and an unclassi ied species [ 66 ]. Indeed, changes in he composi ion o he mic obio a ollowing an ac i e li es yle a e associa ed wi h inc eases in SCFA, such as n-bu y a e, which can modula e hos ene gy balance and lead o inc eased nu ien a ail- abili y [ 67 ]. On he o he hand, a seden a y li es yle is ela ed o a signi ican ly diminished di e si y and a less dense mic obial ne wo k s uc u e [ 66 ]. In his con ex , gu mic obio a di e si y has de eloped as a candida e indica o o o e all hos heal h, he gu mic obio a ne wo k o ac i e people being mo e obus han ha o seden a y people [ 64 ]. Thus, ac i e people, who display a mo e di e se mic obial communi y, appea o be mo e s able, esis pa hogenic in asions, exhibi g ea e esilience, and show unc ional edundancy leading o mo e e icien esou ce u iliza ion han seden a y indi iduals [ 68 ]. Fu he mo e, his phenomenon o inc eased bac e ial di e si y could help o es o e and a oid dysbiosis, especially in se e e si ua ions such as he use o an ibio ics, which his ea men pe se d i es a dec ease o some bac e ial species [ 66 ]. In conco dance wi h hese esul s, B essa e al. showed ha physical ac i i y execu ed a sho doses bu con inuously may ise he heal h-p omo ing bac e ia abundance (Bi idobac e ium spp., Akke mansia muciniphila, Rosebu ia hominis, and Faecalibac e ium p ausni zii) in he gu mic obio a [ 55 ]. Howe e , a seden a y li es yle is in e sely associa ed wi h in es inal mic obio a ichness [ 55 ]. Ke n e al. demons a ed ha exe cise inc eases alpha di e si y and dis u bs he gene al mic obio a composi ion in indi iduals wi h o e weigh and obesi y a e 6 mon hs o in e en ion in a andomized clinical ial (RCT) [ 69 ]. Simila ly, ano he ial e ealed ha bo h mode a e- Nu ien s 2021,13, 3999 5 o 15 in ensi y exe cise and esis ance aining o 8 weeks igge shi s in mic obial di e si y, in pa icula , alpha bac e ia [ 70 ]. Mahdieh e al. epo ed an imp o emen o Bi idobac e ium coun s in 18 women wi h obesi y who we e aining ae obic exe cise (3 sessions pe week, las ing 30–45 min) o 10 weeks [ 71 ]. In addi ion, hey showed how exe cise dec eases in- es inal in lamma ion and modi ies gu mic obio a p o ile in insulin- esis an subjec s [ 72 ]. The e o e, physical ac i i y is sugges ed as a use ul non-pha macologic ins umen o coun e ac pa hological al e a ions o he gu mic obio a in o de o p e en me abolic dis u bances, especially in obesi y. In addi ion, a seden a y li es yle has ma e ialized as a new isk a iable o heal h, which is ela ed o a high incidence o ch onic diseases such as cance ca dio ascula diseases and ype 2 diabe es [ 64 , 67 ], wi h obesi y being he main con ibu o o he de elopmen o hese pa hologies [5]. Some p oposal mechanisms o he in es inal mic obio a and obesi y a e ela ed o p ima y bile acids sa ely con e ed by gu mic obio a o seconda y bile acids ha pe o m h oughou he TGR5 ecep o o s imula e GLP-1 elease imp o ing he mogenesis in adipose issue [ 57 , 73 ] and also by he nuclea a nesoid X ecep o ela ed o ca bohyd a e me abolism [74]. The die a y ibe e men a ion by mic obes, belonging especially o Fi micu es and Bac e oide es, c ea es SCFAs (p opiona e, bu y a e, and ace a e) ha impac he hos me abolism in se e al ways by pe o ming on G p o ein-coupled ecep o s exp essed by en e oendoc ine cells [ 75 , 76 ]. SCFAs could s imula e GLP-1 and pep ide YY libe a ion a ec ing he b ain and panc eas, and ace a e may imp o e a s o age h ough he ac ion o gh elin sec e ion [76,77]. LPS, compounds ound in G am-nega i e bac e ia, a e ela ed o in lamma ion p o- cesses [ 77 ]. In addi ion, succina e, a mic obial-de i ed, could ha e p o-in lamma o y ac ions on LPS-de i ed mac ophages and migh he e o e cause in lamma ion and insulin esis ance in adipose issue [ 78 ]. O he s udies suppo ha succina e could ac i a e he uncoupling p o ein 1 exp ession ha a ec s he adipose issue he mogenesis [79,80] Gu bac e ial-de i ed b anched-chain amino acids ela ed, in cases o high a in ake, o insulin esis ance in bo h oden s and humans [ 57 , 81 ]. Sec e ed p o eins h ough gu bac e ia also egula e endoc ine o pa ac ine ac ion (e.g., G p o ein-coupled ecep o 119) [82]. Finally, physical ac i i y could be a en a i e ea men o p oduce di e en ac ions in speci ic le els, changing he mic obio a composi ion and ac i a ing o e speci ic p o eins, such as uncoupled p o ein 1, o s imula ing he libe a ion o SCFAs. 5. Obesi y, Die In e en ions, Physical Ac i i y/Exe cise, and Thei Impac on Gu Mic obio a Al hough scien is s con inue o make subs an ial p og ess in imp o ing li es yles in o de o dec ease he epidemic o obesi y and i s ela ed o como bidi ies, o cou se, lack o physical ac i i y (s ongly a ec ed by a a ie y o ac o s, p ima ily socioeconomic and li es yle s a us) and high-calo ie die s ac as an impo an pa in he p og ess o me abolic diseases. The i s ecommended ea men o obesi y is a low-calo ie die and egula physical ac i i y. Howe e , hese li es yle in e en ions ha e low o e all compliance and limi ed e ec i eness in people wi h obesi y. In adul s, Mu alidha an e al. [ 31 ] e ealed ha ene gy es ic ion and Medi e anean die wi h physical ac i i y, and beha io al suppo could p o oke a educ ion in nume ous Fi micu es membe s, especially belonging o Lachnospi aceae a e 1-yea o in e en ion in indi iduals wi h obesi y and o e weigh . In addi ion, hey obse ed a selec i e ise in some SCFA p oduce s [ 31 ]. This ype o in e en ion may ha e a bene icial e ec on ca dio ascula diseases, po en ially modula ed by gu mic obio a [ 31 ]. Fu he mo e, Allen e al. showed ha exe cise-induced modula ion o in es inal mic obio a and SCFAs we e ela ed o changes in VO 2max a e 6 weeks o ae obic exe cise in indi iduals wi h obesi y [ 56 ]. In addi ion, hey obse ed ha he e u n o he seden a y s a e was in e sely associa ed wi h he changes ha happened in esponse o exe cise aining [ 56 ]. O e all, hese indings con i m ha physical ac i i y and die a y con ol con ibu e signi ican ly o imp o ing he composi ion o he gu mic obio a. Nu ien s 2021,13, 3999 6 o 15 Mo eo e , i appea s ha exe cise on ecal SCFAs le els is posi i ely co ela ed wi h body composi ion [ 83 ]. One o he possible mechanisms ha could explain his heo y could be ha SCFAs may imp o e skele al muscle insulin sensi i i y and egula e sa ie y [ 84 ], wi h an impac on body composi ion. In addi ion, SCFAs a e also ene gy subs a es o se e al issue ypes, such as adipose issue, colon, and muscle [ 56 ], sugges ing ha SCFAs may imp o e ene gy in ake om he die , ul ima ely leading o inc eased issue de elopmen , including skele al muscle [ 67 ]. Ano he mechanism ha could explain he bene i s o physical ac i i y on he in es inal mic obio a is he shi in gu pH du ing physical ac i i y [ 83 ]. These changes migh p oduce an en i onmen al se ing allowing o iche communi y di e si y. Mo eo e , esis ance aining may cause changes in he gas oin es inal ac , as low issue hypoxia and blood low, d i ing o inc eased abso p ion capaci y and ansi [85]. 5.1. Child en and Adolescen Popula ion In e es ing a ge popula ion s udies a e child en and adolescen s wi h obesi y. In his line, a ecen sys ema ic e iew e alua ed he composi ion o gu mic obio a ela ed o adiposi y in child en and adolescen s, concluding ha he e is an absence o consensus o he composi ion o in es inal mic obio a associa ions wi h adiposi y. Mo eo e , he heal hy gu mic obio a a e ela ed o a die ich in ui s and ege ables wi h mode a e consump ion o animal a and p o ein [ 86 ]. O no e, e en he ma e nal gu mic obio a al e a ions du ing impo an phases o emb yonic, e al, and ea ly pos na al de elopmen could ha e consequences on he gu mic obio a o sp ing, wi h li elong e ec s o suscep ibili y o disease [ 87 ]. A ecen s udy indica ed ha he di e si y and abundance o gu mic obio a in child en wi h obesi y we e signi ican ly mino han hose in no mal-weigh child en [88]. An exe cise p og am combined wi h die a y es ic ions may imp o e gu mic obio a heal h in child en wi h obesi y. Ne e heless, he mos e ec i e aining p og am is no s ill well es ablished, hough i seems ha he combined aining p og am o esis ance and ae obic exe cise could be able o dec ease body a and inc ease gu di e si y [ 34 , 54 ]. Huang e al. epo ed ha a six-week exe cise aining (ae obic and esis ance exe cises) wi h die a y es ic ion no only dec eased bodyweigh bu also inc eased cen al hemodynamic measu es (pe iphe al a e iola esis ance and mic o ascula co ona y pe usion) ha we e ela ed o modi ying gu mic obio a in adolescen s wi h obesi y [89]. In addi ion, a ecen s udy has epo ed ha six weeks o exe cise and he die a y p og am a e use ul ools in o de o inc ease au onomic unc ion and cen al hemodynamics wi h educed a e ial s i ness in adolescen s wi h obesi y [ 90 ]. Mo eo e , Cho e al., wi h a weigh educ ion p og am ha in ol ed die a y al e a ion, augmen ed beha io al modi ica ion and physical ac i i y du ing 2 mon hs in child en wi h obesi y, obse ed signi ican modi ica ions in he gu mic obio a composi ion, and expec ed unc ional p o iles o he gu mic obio a and ichness wi h weigh loss a e li es yle changes [ 91 ]. On he o he hand, Qui oga e al., wi hou nu i ional in e en ion, show h ough ae obic and esis ance combined aining du ing 12 weeks in hi y-nine child en wi h obesi y ha he exis ence o a de imen al mic obio a p o ile in obesi y is al e ed by exe cise in e en ion, emphasizing he alue o exe cise ou ine as an e ec i e non-pha macological he apy in ea ly obesi y [34]. Finally, in child en wi h o e weigh and obesi y, i is desc ibed ha oligo uc ose-en iched inulin p ebio ics modi y he gu mic obio a composi ion and mode a ely dec ease in lamma o y bioma ke s, adiposi y, and body weigh [92]. 5.2. Physical Ac i i y, Die , Mic obio a, and T ea men Physical ac i i y signi ican ly dec eases he Gammap o eobac e ia and P o eobac e ia. Mo eo e , i ended o ise Dialis e ,Blau ia, and Rosebu ia, c ea ing a mic obio a p o ile simila o ha o heal hy child en. T aining p o ocol signi ican ly ep essed he igge ing o he obesi y-associa ed NLRP3 signaling pa hway [ 34 ]. Howe e , he e a e limi ed indings o he gu mic obio a composi ion in obese child en, deno ing ha addi ional analysis es ablished on he unc ion o he in es inal mic obio a in childhood obesi y is necessa y. Nu ien s 2021,13, 3999 7 o 15 A sys ema ic e iew o he ou comes o nine c oss-sec ional s udies and six in e en- ions epo ing he ou comes o die a y a on in es inal mic obio a in humans [ 93 ] showed ha die s wi h excessi e sa u a ed o monounsa u a ed a s ha m ully p edisposed he gu mic obio a while die s high in polyunsa u a ed a seemed o be neu al wi h espec o he gu mic obio a. Simila ly, high-polysaccha ide die in e en ions ha e caused di e en gu mic obio a connec ed wi h se um, inc eased ecal, o u ine concen a ions o SCFAs, imp o emen s o cy okine and me abolome p o iles, and weigh loss [ 94 – 97 ]. Likewise, in e en ions wi h augmen ed physical ac i i y ha e exhibi ed adap i e and ansmissible a ia ions o he in es inal mic obio a connec ed wi h an augmen ed capaci y o he b eak- down o b anched-chain amino acids and lac a e, an augmen ed po en ial o syn hesis o SCFAs, and imp o emen s in insulin sensi i i y and ca dio espi a o y i ness. Lac obacillus,Bi idobac e ium, and Saccha omyces spp. a e gene ally ecognized as sa e (GRAS) p obio ics [ 98 – 100 ], and in he pas yea s, new membe s ha e been included such as F. p ausni zii [ 101 ], A. muciniphila [ 102 ], and nume ous Clos idia spp. [ 103 ]. New da a ha e epo ed ha i is possible ha some p obio ics, A. muciniphila s ains, do no e en equi e colonizing he in es ine o ob ain help ul me abolic e ec s in he hos ela ed o heal h [ 104 , 105 ]. RCTs assessmen o p ebio ics (non-diges ible polysaccha ides) has epo ed ha inulin- ype uc ans ans o med he gu mic obio a composi ion in adul women wi h obesi y, leading o modes changes in hos me abolism [ 106 ]. Finally, he new in eg an o he “bio ics” amily, pos bio ics, means o ela es wi h he pas eu ized e sion o p obio ics o po ions o mic obial s ains holding heal h-p omo ing e ec s [ 107 ]. A pilo ial o pas eu ized A. muciniphila and i s memb ane p o ein Amuc_1100 showed posi i e e ec s on human me abolism indica o s [ 102 , 108 ]. This p o ein eco e s gu ba ie unc ions wi h augmen ed goble cell densi y by oll-like ecep o 2 and mode a ely epea s he bene icial e ec o li e bac e ium A. muciniphila on insulin sensi i i y and ene gy me abolism [102,108]. 6. Pe o mance: Gu Mic obio a P o ile in A hle es P o essional a hle es a e a speci ic popula ion wi h e iden di e ences in mic obio a composi ion when compa ed wi h he non-a hle e popula ion [ 109 ]. Se e al s udies ha e demons a ed he associa ion be ween gu mic obio a and bo h physical ac i i y and ex- e cise [ 110 ]. Di e ences a e ma ked also acco ding o di e en a hle es cha ac e is ics as well as hei body composi ion [ 111 ]. A hle e gu mic obio a shows he highes alpha di- e si y in compa ison wi h obesi y pa ien s being associa ed wi h se e al isk ac o s [ 112 ]. Impo an ly, ca dio espi a o y i ness (a powe ul indica o o a hle ic pe o mance and heal h) has been associa ed o Fi micu es/Bac e oide es a io in heal hy young adul s, and hese associa ions we e independen o die composi ion, demons a ing ha gu mic obio a di e si y depends on he le el o physical i ness o he popula ion [ 113 ]. On he o he hand, a hle es’ cha ac e is ics a e also a ac o ela ed o hei mic obio a com- posi ion [ 109 ]. Speci ically, di e ences a e e iden in ugby a hle es ha show a highe p opo ion Akke mansia genus han a g oup wi h an ele a ed BMI [33]. Mo eo e , he Bac- e oides o P e o ella a io is di e en be ween endu ance (ca dio ascula exe cise pe o med o an ex ended pe iod) aining elde ly subjec s and heal hy con ols [ 114 ]. In e es ingly, bac e ial genus Veillonella was ela ed o exe cise changes in a hle es a e unning he Bos on Ma a hon [ 115 ], sugges ing ha exe cise changes ela ed o mic obio a include enzyma ic p ocesses ela ed o lac a e p oduc ion. Mo eo e , a p o essional cyclis shows a highe abundance in axa ela ed o exe cise loads, such as P e o ella and Me hanob e ibac e smi hii, which could be ela ed o posi i e consequences o exe cise o pe o mance and a hle ic heal h [45]. Finally, Dono an e al. [ 116 ] s udied he mic obio a composi ion acco ding o di e en g oups o spo s and ound di e ences in ela i e abundance ac oss i e species, namely, Polynucleobac e necessa ies,Eubac e ium ec ale,B. ulga us,F. p ausni zii, and Go donibac e massiliensis. In e es ingly, he classi ica ion was based on dynamic (mo e ela ed o aug- men ed ca diac ou pu ) and inac i e componen s (mo e associa ed wi h inc easing he Nu ien s 2021,13, 3999 8 o 15 maximal olun a y con ac ion) [ 116 , 117 ]. They ound ha hose pa icipa ing in high dynamic spo ha e a bigge abundance o Lac obacillus acidophilus,Bi idobac e ium animalis, F. p ausni zii, and P e o ella in e media, while a hle es wi h bo h s a ic componen s and high dynamic we e ela ed o a g ea e Bac e oides caccae abundance. Thus, he au ho s ha e indica ed ha he di e ences in abundance ac oss g oups may be a esul o he speci ic cha ac e is ics o spo s, p incipally ela ed o he p oduc ion o c ea ine, lac a e, and subs an ial muscle u no e [118]. 7. Fu he Pe spec i es The WHO anked physical inac i i y as he ou h p incipal isk elemen o global mo ali y. In con as , egula and adequa e physical ac i i y le els d op he mo ali y a e p oduced by some ch onic diseases. Fo ins ance, physical exe cise bene i s he p e en ion o se e al obesi y- ela ed diso de s such as dyslipidemia, insulin esis ance, and hype ension, educing in ahepa ic lipid [119]. Addi ionally, exe cise may posi i ely con ol gu mic obio a in immune-based and ch onic diseases. In ac , exe cise can p o oke quali a i e and quan i a i e changes in mic obial composi ion in humans [ 120 ]. In addi ion, a de e io a ed mic obio a p o ile may con ibu e o he e iopa hogenesis o obesi y [ 121 ]. Acco dingly, he e is a concep ual amewo k in which s udies on exe cise in he e e sion o hype calo ic die s e ec s and obesi y by modula ing mic obio a a e gaining momen um wi hin he scien i ic commu- ni y. Howe e , unsol ed ques ions emain open conce ning he complex nexus be ween mic obio a, heal h main enance, and obesi y, and e en mo e, he exe cise in ensi y, ype, du a ion, o doses emains a con o e sial issue. Fo example, i is likely he impac o exe cise on he mic obio a would no be he same i i is p ac iced as a habi o main ain weigh and heal h, in ensi ely as a high-le el a hle e, o as a weigh -loss s a egy wi h o wi hou calo ic es ic ion. In consequence, he exe cise e ec s on he mic obio a canno be conside ed globally as he e a e many a iables o conside in his equa ion depending on he ul ima e pu pose o he exe cise. Mo eo e , i is also necessa y o conside ha exe cise p o okes unique mic obio a p o iles acco ding o he hos cha ac e is ics. Fu he mo e, he a ge exe cise popula ion should be conside ed, no only he baseline physical i ness and he p esence o absence o unde lying diseases bu also he age, sex, and me abolic and ho monal s a us o he indi idual. A his poin , i should be no ed whe he women a e pos - o p e-menopausal since i is one o he main con olle s o ci cula ing es ogens in he gu mic obio a [ 122 ]. In consequence, he implied me abolic pa hways could no be he same and he e o e nei he could be hei impac on he mic obio a. Fu he , he close connec ion be ween he b ain and he gu mic obio a ( he “gu –b ain axis”) should also be conside ed. In his ega d, some pieces o e idence show ha he e is an ele a ed ela ionship be ween emo ional and physical s ess h oughou exe cise and modi ica ions in gas oin es inal mic obio a composi ion [ 123 ], bu i is ye unsol ed whe he exe cise modi ies men al heal h, which is sugges ed by modi ica ions in he gu –b ain axis o he obse ed imp o emen in men al heal h due o exe cise-induced changes in he mic obio a. Figu e 1summa izes he main in o ma ion desc ibed in he p esen manusc ip . Nu ien s 2021,13, 3999 9 o 15 Nu ien s 2021, 13, x FOR PEER REVIEW 9 o 15 in he mic obio a. Figu e 1 summa izes he main in o ma ion desc ibed in he p esen manusc ip . Figu e 1. Impac o exe cise on gu mic obio a in obesi y. Abb e ia ions: BCAA, b anched-chain amino acids; FXR, a - nesoid X ecep o ; LPS, lipopolysaccha ide; GLP-1, Glucagon-like pep ide 1; GPCRs, G-p o ein-coupled ecep o s; GPR119, G p o ein-coupled ecep o 119; PYY, Pep ide YY; UCP-1, Uncoupling p o ein 1; TGR5, G-p o ein-coupled bile acid ecep o , TLR2, oll-like ecep o 2. 8. Conclusions In es inal mic obio a ac as a signi ican playe in obesi y p og ession. Physical ac i - i y po en ially bene i s obesi y h ough changes in mic obio a composi ion. Mic obio a, exe cise, and die a y habi s ha e a complex ela ionship. Acco dingly, i is manda o y o e alua e he possible in luence o exe cise and speci ic die s, oods, nu ien s, o supple- men s on mic obial di e si y in he gu . The changes o gu mic obio a s imula ed by physical exe cise depend on he basal physiological s a e and maybe condi ioned by pa- ame e s, such as age o BMI. Fu he in es iga ion is needed o elucida e he unde lying mechanisms. Au ho Con ibu ions: J.A.-V., P.S.-U., F.J.R.-O., A.I.Á.-M., J.O.-A. and J.P.-D. pa icipa ed in he bibliog aphic sea ch, discussion, and w i ing o he manusc ip . All au ho s ha e ead and ag eed o he published e sion o he manusc ip . Funding: This esea ch ecei ed no ex e nal unding. Ins i u ional Re iew Boa d S a emen : No applicable. Figu e 1. Impac o exe cise on gu mic obio a in obesi y. Abb e ia ions: BCAA, b anched-chain amino acids; FXR, a nesoid X ecep o ; LPS, lipopolysaccha ide; GLP-1, Glucagon-like pep ide 1; GPCRs, G-p o ein-coupled ecep o s; GPR119, G p o ein-coupled ecep o 119; PYY, Pep ide YY; UCP-1, Uncoupling p o ein 1; TGR5, G-p o ein-coupled bile acid ecep o , TLR2, oll-like ecep o 2. 8. Conclusions In es inal mic obio a ac as a signi ican playe in obesi y p og ession. Physical ac i - i y po en ially bene i s obesi y h ough changes in mic obio a composi ion. Mic obio a, exe cise, and die a y habi s ha e a complex ela ionship. Acco dingly, i is manda o y o e alua e he possible in luence o exe cise and speci ic die s, oods, nu ien s, o sup- plemen s on mic obial di e si y in he gu . The changes o gu mic obio a s imula ed by physical exe cise depend on he basal physiological s a e and maybe condi ioned by pa ame e s, such as age o BMI. Fu he in es iga ion is needed o elucida e he unde lying mechanisms. Au ho Con ibu ions: J.A.-V., P.S.-U., F.J.R.-O., A.I.Á.-M., J.O.-A. and J.P.-D. pa icipa ed in he bibliog aphic sea ch, discussion, and w i ing o he manusc ip . All au ho s ha e ead and ag eed o he published e sion o he manusc ip . Funding: This esea ch ecei ed no ex e nal unding. Ins i u ional Re iew Boa d S a emen : No applicable. In o med Consen S a emen : No applicable.