Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota

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1 ARTICLE Reeive 16 De 214 Aepte 14 My 215 Pulishe 23 Jun 215 DOI: 1.138/nomms8489 OPEN Gnoerm luium reues oesity in mie y moulting the omposition of the gut miroiot Chih-Jung Chng 1,2,3,4,5,, Chun-Sheng Lin 1,2,3,5,, Chi-Chen Lu 6, Jn Mrtel 1, Yun-Fei Ko 7,8, Dvi M. Ojius 1,9, Shun-Fu Tseng 5, Tsung-Ru Wu 2,3, Yi-Yun Mrgret Chen 4, John D. Young 1,7,8,1 & Hsin-Chih Li 1,2,3,5 Oesity is ssoite with low-gre hroni inflmmtion n intestinl ysiosis. Gnoerm luium is meiinl mushroom use in tritionl Chinese meiine with puttive nti-ieti effets. Here, we show tht wter extrt of Gnoerm luium myelium (WEGL) reues oy weight, inflmmtion n insulin resistne in mie fe high-ft iet (). Our t inite tht WEGL not only reverses -inue gut ysiosis s inite y the erese Firmiutes-to-Bteroietes rtios n enotoxinering Proteoteri levels ut lso mintins intestinl rrier integrity n reues metoli enotoxemi. The nti-oesity n miroiot-moulting effets re trnsmissile vi horizontl fees trnsfer from WEGL-trete mie to -fe mie. We further show tht high moleulr weight polyshries (43 kd) isolte from the WEGL extrt proue similr nti-oesity n miroiot-moulting effets. Our results inite tht G. luium n its high moleulr weight polyshries my e use s preioti gents to prevent gut ysiosis n oesity-relte metoli isorers in oese iniviuls. 1 Center for Moleulr n Clinil Immunology, Chng Gung University, Gueishn, Toyun 3332, Tiwn, ROC. 2 Deprtment of Meil Biotehnology n Lortory Siene, College of Meiine, Chng Gung University, Gueishn, Toyun 3332, Tiwn, ROC. 3 Deprtment of Lortory Meiine, Chng Gung Memoril Hospitl, Linkou, Gueishn, Toyun 3335, Tiwn, ROC. 4 Deprtment of Miroiology n Immunology, Chng Gung University, Gueishn, Toyun 3332, Tiwn, ROC. 5 Reserh Center of Bteril Pthogenesis, Chng Gung University, Gueishn, Toyun 3332, Tiwn, ROC. 6 Deprtment of Respirtory Therpy, Fu Jen Ctholi University, Xinzhung, New Tipei City 2425, Tiwn, ROC. 7 Chng Gung Biotehnology Corportion, Tipei 158, Tiwn, ROC. 8 Biohemil Engineering Reserh Center, Ming Chi University of Tehnology, Tishn, New Tipei City 2431, Tiwn, ROC. 9 Deprtment of Biomeil Sienes, University of the Pifi, Arthur Dugoni Shool of Dentistry, Sn Frniso, Cliforni 9413, USA. 1 Lortory of Cellulr Physiology n Immunology, Rokefeller University, New York, New York 121, USA. These uthors ontriute eqully to this work. Corresponene n requests for mterils shoul e resse to J.D.Y. (emil: ingeyoung@hotmil.om) or to H-C.L. (emil: hli@mil.gu.eu.tw). NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

2 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 Tritionl Chinese Meiine hs long history in Asin ountries ting k severl thousns of yers 1,2. One lss of tritionl remeies ommonly in use onsists of meiinl mushrooms suh s Ophiooryeps sinensis, Antroi innmome n Agrius lzei Murrill, whih ontin wie rnge of immuno-moultory n iotive ompouns 3,4. One of the most intriguing meiinl mushrooms is the Bsiiomyete fungus Gnoerm luium, whih hs een use for enturies to promote helth n longevity 5. Previous stuies hve shown tht triterpenes n polyshries isolte from G. luium inhiit ipoyte ifferentition 6 n proue hypoglyemi effets in ieti mie 7. In ition, proteoglyns isolte from G. luium fruiting oies inue ntiieti, ntihyperlipiemi n ntioxint tivities 8. However, it remine unknown whether G. luium proues ny effet on oy weight n oesity-relte isorers. Oesity is efine s isese onition ssoite with numerous helth prolems n reue life expetny 9. Growing eviene inites tht oesity is losely linke with hroni, low-gre inflmmtion, whih n le to insulin resistne, type 2 ietes, ftty liver isese, riovsulr isese, ostrutive sleep pnoe n ner 1,11. The high prevlene of oesity is urrently mjor thret to puli helth, with B5 million oese people n 1.4 illion overweight iniviuls worlwie 12. Prevention of oesity thus represents mjor hllenge for moern soieties. A reent stuy inites tht hnges in the omposition of the gut miroiot re ssoite with the evelopment of oesity n its ssoite metoli isorers 13. The gut miroiot omprises trillions of teri tht ontriute to nutrient quisition n energy regultion 14,15. An inrese rtio of the mjor phyl Firmiutes/Bteroietes n hnges in severl teril speies n promote the evelopment of oesity in oth ietry n geneti moels of oesity in mie 16,17. Other stuies in oese nimls suggest tht oesity-inue gut ysiosis use y either environmentl or geneti ftors impirs intestinl integrity 18,19. This proess les to the relese of the enotoxin lipopolysrie (LPS) from intestinl Grm-negtive teri into the loostrem 2, in turn, leing to metoli inflmmtion n insulin resistne in oese mie 21 ue to stimultion of Toll-like reeptor 4 (TLR4)-meite inflmmtion 22. Moreover, hroni injetion of LPS in mie les to mil oesity n insulin resistne 21, highlighting possile role for miroiot-erive LPS in oesity-inue inflmmtion. A numer of tretments, inluing ntiiotis n preiotis 18,19, re eing evlute for the mngement of oesity n its relte metoli isorers 23. For exmple, ntiioti tretment lters the gut miroiot, reues loo enotoxemi n improves gluose tolerne in mie lking the leptin gene (o/o mie) or in mie fe with 19. In ition, preiotis re non-igestile, fermentle rohyrtes n fires, whih reue oy weight n exert nti-inflmmtory effets minly y enhning the growth of speifi enefiil teri foun in the gut 24,25. Preiotis not only lter the intestinl miroiot ut lso improve intestinl tight juntion integrity n erese loo enotoxemi use y LPS 18. Preiotis my, therefore, protet nimls ginst oesity-inue inflmmtion. In the present stuy, we exmine whether wter extrt of G. luium myelium (WEGL) n erese oesity in -fe mie. Our results inite tht WEGL reues oesity n inflmmtion in the trete mie. These effets re trnsmissile to -fe mie through horizontl fees trnsplnttion, initing tht the effets of WEGL involve the gut miroiot. Chrteriztion of WEGL showe tht polyshries of moleulr weight 43 kd exerte similr meliortive effets s WEGL. These results implie tht the high moleulr weight polyshries my e the tive omponents of WEGL. Our t thus emonstrte tht WEGL represents potentil preioti gent tht my e use for the tretment of oesity n its omplitions. Results WEGL prevents -inue oesity in mie. Using mouse moel of oesity, we oserve tht feeing for 8 weeks le to signifint inreses in oy n liver weight, epiiyml n suutneous ft umultion, n lipi eposition in ipoytes n heptoytes ompre with ontrol how feeing (Fig. 1 g). While 8% WEGL i not proue ny pprent effets in howfe mie, supplementtion with WEGL erese weight gin n ft umultion in ose-epenent mnner in -fe mie (Fig. 1 g). Men energy intke, stool ft n fees energy i not vry signifintly etween -fe groups (Supplementry Fig. 1), suggesting tht the effets of WEGL on oy weight n oesity prmeters were not ue to reue foo onsumption or energy extrtion. These results imply tht WEGL reues weight gin n ft umultion in -fe mie. WEGL reues inflmmtion in -fe mie. Previous stuies hve shown tht -fe oese mie proue higher levels of pro-inflmmtory ytokines in hepti n ipose tissues, inluing tumour nerosis ftor-lph (TNF-), interleukin-1- et (IL-1), interleukin-6 (IL-6) n plsminogen tivtor inhiitor-1 (PAI-1; ref. 26). In ontrst, proution of the ntiinflmmtory ytokine IL-1 is reue in oese nimls 27.We mesure messenger RNA (mrna) expression of these ytokines fter 8 weeks of feeing with or without WEGL supplementtion. TNF-, IL-1, IL-6 n PAI-1 expression levels were higher in hepti n ipose tissues of -fe mie ompre with tissues of ontrol how-fe mie, wheres IL-1 expression ws reue (Fig. 2 e). Notly, the expression pttern of these ytokines ws ltere in ose-epenent mnner y WEGL tretment, resulting in expression levels loser to tht of how-fe mie thn -fe mie with inresing WEGL ose (Fig. 2 e). Moreover, WEGL reue the levels of serete TNF-, IL-1 n IL-6 proteins in ose-epenent mnner in the serum of mie (Supplementry Fig. 2). Oesity is hrterize y infiltrtion n tivtion of immune ells in hepti n ipose tissues 28. M1 mrophges, whih re reruite y monoyte hemottrtnt protein-1 (MCP-1), re ssoite with hroni, low-gre inflmmtion in ipose tissues of oese nimls 26. As MCP-1 mrna expression erese in the liver n ipose tissues of -fe mie following tretment with WEGL (Supplementry Fig. 3), we exmine the numers of mrophges reruite into hepti n ipose tissues using flow ytometry nlysis. Doule stining of mrophges with nti-f4/8 ntioy omine with either nti-cd11 ntioy (for liver mrophges, lso lle Kupffer ells) or nti-cd11 ntioy (for mrophges in ipose tissues) ws use for these experiments. Higher levels of mrophges were etete in hepti n ipose tissues of mie ompre with how-fe mie (Supplementry Fig. 3,). While mrophge levels inrese following the tretment with 8% WEGL in how-fe mie, these ells were reue in oseepenent mnner y WEGL in hepti n ipose tissues of -fe mie (Supplementry Fig. 3,). Previous stuies inite tht feeing lso proues grul loss of regultory T (Treg) ells ompre with how-fe mie 26. While lso reue Treg levels in our mouse moel, supplementtion with WEGL le to ose-epenent inreses of Treg ells in liver n ipose tissues of mie 2 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

3 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE Boy weight (g) % +2% +4% +8% Boy weight gin (g) Epiiyml ft (g) (week) 3. WEGL 8% 2% 4% 8% +8% +2% +4% +8% Suutneous ft (g) weight (g) WEGL 8% 2% 4% 8% WEGL 8% 2% 4% 8% Frequeny (%) 3 <5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, 5,5 6, 6,5 7, 7,5 8, 8,5 9, 9,5 >1, +8% WEGL +2% WEGL +4% WEGL +8% WEGL WEGL 8% 2% 4% 8% +8% +2% +4% +8% Figure 1 WEGL reues oy weight n ft umultion in -fe mie. - n -fe mie were trete ily with 1 ml of either wter or WEGL t 2, 4 or 8% (w/v) y intrgstri gvge for two months (n ¼ 7 for eh group). Effets of WEGL tretment on oy weight () oy weight gin () epiiyml ft () suutneous ft () n epiiyml ipoyte size (e) re shown. In e, ipoyte size ws estimte using the Imge J softwre (lower pnel). Sle r, 5 mm. weight ws mesure in n ontrol, how-fe mie (f). lipi ontent ws ssesse using oil re O stining (g). Sle r, 3 mm. Dt re expresse s men±s.e.m. Boy weight ifferenes in were nlyse using unpire two-tile Stuent s t-test (Po1, Po1). Grph rs in,, n f mrke with ifferent letters on top represent sttistilly signifint results (Po5) se on Newmn Keuls post ho one-wy ANOVA nlysis, wheres rs lelle with the sme letter orrespon to results tht show no sttistilly signifint ifferenes. In the se where two letters re present on top of the r in, eh letter shoul e ompre seprtely with the letters of other rs to etermine whether the results show sttistilly signifint ifferenes. NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

4 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 TNF-α mrna (Reltive expression) 3. +8% +2% +4% +8% e IL-1β mrna (Reltive expression) % +2% +4% +8% e IL-6 mrna (Reltive expression) % +2% +4% +8% IL-1 mrna (Reltive expression) % +2% +4% +8%... e PAI-1 mrna (Reltive expression) % +2% +4% +8%.. Figure 2 WEGL ereses pro-inflmmtory ytokine expression in the liver n ipose tissues of -fe mie. Animls were trete s in Fig. 1. Reltive expression of TNF- (), IL-1 (), IL-6 (), IL-1 () n PAI-1 (e) in hepti n ipose tissues ws ssesse using qrt PCR n in omprison with the group. Dt re shown s men±s.e.m. Grph rs with ifferent letters on top represent sttistilly signifint results (Po5) se on Newmn Keuls post ho one-wy ANOVA nlysis, wheres rs with the sme letter orrespon to results tht show no sttistilly signifint ifferenes. In the se where two letters re present on top of the rs in,e, eh letter shoul e ompre seprtely with the letters of other rs to etermine whether the results show sttistilly signifint ifferenes. (Supplementry Fig. 3,e). In ition, how-fe mie trete with 8% WEGL showe inrese Treg levels ompre with untrete how-fe mie (Supplementry Fig. 3,e). These results inite tht WEGL reues inflmmtion in -fe mie y reuing mrophge infiltrtion n enhning Treg umultion in hepti n ipose tissues. WEGL reues enotoxemi n insulin resistne in mie. Enotoxemi n TLR4 signlling ontrol the proution of proinflmmtory ytokines in trget tissues n le to hroni inflmmtion n insulin resistne in -fe mie 19. We exmine the effets of WEGL on LPS serum levels (tht is, enotoxemi) n TLR4 protein expression in hepti n ipose tissues. WEGL reue enotoxemi n TLR4 protein expression in -fe mie ompre with lone (Fig. 3 ). Sine TLR4 signlling pthwys inue the proution of proinflmmtory ytokines y moulting the tivity of JNK n NF-kB 29,3, we exmine whether these pthwys re ffete y WEGL supplementtion. As shown in Fig. 3,e, WEGL inhiite JNK phosphoryltion in hepti n ipose tissues of -fe mie. Moreover, the proution of IkB-, whose intertion with NF-kB prevents NF-kB trnslotion n tivtion, ws enhne y WEGL tretment (Fig. 3f,g). Given tht enhne tivtion of JNK n NF-kB pthwys my inue insulin resistne vi phosphoryltion of insulin reeptor sustrte-1 (IRS-1) on serine 37 n ephosphoryltion of Akt 31, we exmine the effets of WEGL on insulin tivity. As shown in Supplementry Fig. 4 e, WEGL tretment reue fsting insulin n gluose levels n erese gluose n insulin resistne in -fe mie. Aoringly, phosphoryltion of serine 37 on IRS-1 ws inhiite y WEGL in hepti n ipose tissues, wheres phosphoryltion of Akt ws enhne y the myelium extrt (Supplementry Fig. 4f i). WEGL therefore reues enotoxemi n prevents insulin resistne in -fe mie. WEGL regultes lipogeni gene expression. Previous stuies hve shown tht the expression of genes involve in lipi 4 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

5 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE Serum enotoxin (EU ml 1 ) WEGL 8%. 2% 4% 8% TLR-4 β-atin WEGL 8% 1 TLR 4 β-atin 2% 4% 8% WEGL 8% 2% 4% 8% P-JNK T-JNK WEGL 8% 2% 4% 8% P-JNK T-JNK WEGL 8% 2% 4% 8% IkB-α IkB-α β-atin β-atin WEGL 8% 2% 4% 8% WEGL 8% 2% 4% 8% Figure 3 WEGL reues serum LPS n TLR4-relte signlling pthwys in mie. Effets of WEGL tretment on serum enotoxin () TLR4 protein proution (,) JNK phosphoryltion (,e) n IkB- proution (f,g) were exmine in the liver n epiiyml ipose tissues of how- n -fe mie s esrie in Fig. 1. Serum enotoxin (EU ml 1 ) ws etermine s men±s.e.m. using the limulus meoyte lyste ssy kit. Representtive immunolots for trget proteins in -g re shown. Moleulr weight mrkers were inite s kiloltons (kd). Protein levels were normlize to internl ontrols (-tin or totl JNK, T-JNK) n the reltive rtio to the group ws lelle on the top of immunolots. Grph rs in with ifferent letters on top represent sttistilly signifint results (Po5) se on Newmn Keuls post ho one-wy ANOVA nlysis, wheres rs lelle with the sme letter orrespon to results tht show no sttistilly signifint ifferenes. Where two letters re present on top of the r, eh letter shoul e ompre seprtely with the letters of other rs to etermine whether the results show sttistilly signifint ifferenes. iosynthesis suh s etyl-coa roxylse-1, ftty i synthse, sterol regultory element-ining protein-1 n peroxisome prolifertor-tivte reeptors-g is enhne in hepti n ipose tissues of -fe mie 32,33. Our results inite tht 8% WEGL i not signifintly ffet the expression of these genes in how-fe mie (Supplementry Fig. 5 ). In ontrst, WEGL reue lipogeni gene expression in ose-epenent mnner in -fe mie (Supplementry Fig. 5 ). Inrese levels of free ftty is (FFA) in the loo of oese nimls re thought to rise from lrger mss of ipose tissue n enhne inflmmtion in -fe mie 34. These irulting ftty is lso inue TLR4 signlling in trget tissues n use insulin resistne 22. We oserve tht WEGL reue serum FFA levels in mie (Supplementry Fig. 5e). WEGL my thus reue ft umultion y inhiiting ipogeni gene expression n eresing serum FFA in -fe mie. WEGL reverses -inue gut ysiosis. The gut miroiot of oese humns n -fe mie is hrterize y n inrese Firmiutes-to-Bteroietes rtio, elevte enotoxinprouing Proteoteri, n reue immuno-homeostti NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

6 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 teril speies 35,36. We exmine the effets of WEGL on gut miroiot omposition y performing pyrosequening-se nlysis of teril 16S rrna (V3 V5 region) in el fees. After removing unqulifie sequenes (see Methos), totl of 691,37 rw res n n verge of 16,461±5,411 res per smple were otine. After seleting the effetive res, totl of 292,952 effetive res ws generte n eh fel smple (n ¼ 7 for eh group) proue n verge of 6,975±2,192 effetive res. Smples with low numer of effetive res (o3,) were not oserve. Rreftion n Shnnon inex nlyses inite tht the sequening epth overe rre new phylotypes n most of the iversity (Supplementry Fig. 6). UniFr-se prinipl oorintes nlysis (PCoA) revele istint lustering of miroiot omposition for eh tretment group (Fig. 4). Multivrite nlysis of vrine of PCoA mtrix sores inite sttistilly signifint seprtion etween the miroiot of n þ 8% WEGL groups (Fig. 4). Signifint seprtions were lso note for, þ 4% WEGL n þ 8% WEGL groups (Fig. 4). On the other hn, the gut miroiot of þ 2% WEGL mie i not signifintly iffer from tht of mie (Fig. 4), onsistent with the mil effets proue y 2% WEGL (Figs 1 3). Notly, txonomi profiling emonstrte tht tretment with 4% n 8% WEGL reue the rtio of Firmiutes to Bteroietes n the Proteoteri phylum in -fe mie to levels similr to tht of how-fe mie (Fig. 4). Here s well, the hnges proue y the 2% WEGL tretment were not oserve (Fig. 4). We use reunny nlysis (RDA) to ientify the speifi teril phylotypes tht were ltere y feeing n WEGL tretment. Compre with how-fe mie, feeing signifintly ltere 29 opertionl txonomi units (OTUs), prouing 44 inrese n 165 erese OTUs (Supplementry Dt 1 n Supplementry Fig. 7). In fe mie, supplementtion with 2, 4 n 8% WEGL, respetively, ltere 44 (24 inrese n 2 erese), 42 (24 inrese n 18 erese) n 56 OTUs (24 inrese n 32 erese; Supplementry Dt 2 n Supplementry Fig. 7 ), resulting in signifint hnges in totl of 91 istint OTUs (Fig. 4). Among the 91 OTUs tht were ltere ompre with -fe mie, 2, 4 n 8% WEGL tretments ltere OTUs in the sme iretion in mie for 18, 17 n 3 OTUs, respetively (Fig. 4e, highlighte with lk strs). These results suggest tht 8% WEGL is the most effetive tretment for moulting the gut miroiot in our moel. Detile nlysis of the 3 OTUs reverse y 8% WEGL inite tht Muispirilum sheleri 37, Esherihi fergusonii (Proteoteri 2 ), Enteroous spp. 38, Ltoous ltis 39, Clostriium lttifermentns (Clostriium XIV) n Osilliter vleriigenes 25, (whih were foun to e enhne y n to positively orrelte with oesity in the previous stuies ite ove) were ll reverse y 8% WEGL (Fig. 4,e). Notly, in omprison with mie, 8% WEGL tretment enhne vriety of teril speies tht negtively orrelte with oesity, inluing Prteroies golsteinii, Bteroies spp., Anerotrunus olihominis, Roseuri hominis, Clostriium PC2 - perent vrition expline 6.85% PC1 - perent vrition expline 29.13% +8% WEGL +2% WEGL +4% WEGL +8% WEGL % WEGL-2 +8% WEGL-4 +8% WEGL-6 +8% WEGL-7 +8% WEGL-5 +8% WEGL-3 +8% WEGL-1 + 8% WEGL-3 + 8% WEGL-7 + 8% WEGL-1 + 8% WEGL-5 + 8% WEGL-6 + 4% WEGL-3 + 4% WEGL-5 + 4% WEGL-7 + 4% WEGL-6 + 4% WEGL-2 + 4% WEGL-4 + 4% WEGL-1 + 8% WEGL-4 + 8% WEGL-1 + 2% WEGL-1 + 2% WEGL-4 + 2% WEGL-3 + 2% WEGL-6 + 2% WEGL-5 + 2% WEGL-7 + 2% WEGL % Bteril tx (Reltive unne in %) 9% 8% 7% 6% 5% % 3% 2% 1% Unlssifie Verruomiroi Teneriutes Proteoteri Firmiutes Deferriteres Bteroietes Atinoteri % WEGL + 2% WEGL + 4% WEGL + 8% WEGL Figure 4 WEGL lters miroiot omposition in -fe mie. Miroiot omposition in fees of how-fe mie trete with or without 8% WEGL n mie trete with 2, 4 or 8% WEGL were nlyse using next genertion sequening (n ¼ 7 for eh group). () Plots shown were generte using the weighte version of the UniFr-se PCoA. () Multivrite nlysis of vrine from PCoA mtrix sores. () Bteril txonomi profiling in the phylum level of intestinl teri from ifferent mouse groups. () Hetmp showing the unne of 91 OTUs signifintly ltere y WEGL in fe mie se on RDA. (e) Represente teril tx informtion (speies, genus, fmily n phylum) of 91 OTUs from re shown. White irles n lk imons inite the OTUs tht inrese or erese in - n þ WEGL-fe groups reltive to the -fe group. Blk strs represent OTUs whose unne in how-fe mie ws ltere y n then reverse y WEGL. OTU txonomy is shown on the right. 6 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

7 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE + 2% WEGL + 4% WEGL + 8% WEGL OTU1 OTU2 OTU6 OTU12 OTU9 OTU8 OTU14 OTU19 OTU84 OTU25 OTU59 OTU71 OTU55 OTU68 OTU57 OTU75 OTU52 OTU97 OTU83 OTU236 OTU99 OTU158 OTU129 OTU111 OTU155 OTU28 OTU261 OTU195 OTU38 OTU36 OTU254 OTU291 OTU35 OTU324 OTU396 OTU433 OTU522 OTU545 OTU567 OTU382 OTU428 OTU47 OTU493 OTU4 OTU499 OTU569 OTU575 OTU686 OTU75 OTU71 OTU716 OTU718 OTU719 OTU735 OTU758 OTU786 OTU13 OTU4 OTU33 OTU17 OTU OTU11 OTU15 OTU26 OTU24 OTU9 OTU49 OTU27 OTU37 OTU36 OTU44 OTU16 OTU146 OTU54 OTU127 OTU174 OTU144 OTU199 OTU17 OTU175 OTU263 OTU265 OTU268 OTU297 OTU373 OTU284 OTU61 OTU615 OTU647 OTU72 OTU745 Figure 4 Continue. 1 3 Quntity of OTU +2% WEGL +4% WEGL +8% WEGL Prteroies golsteinii (T) - Euterium oprostnoligenes (T) HL - Aneerotrunus olihominis (T) Roseuri hominis (T) type strin: A Clostriium sporospheroies (T) DSM_ Clostriium methylpentosum (T) DSM Clostriium lttifermntns (T) G17 - Clostriium sinens (T) ATCC 3574 Speies Genus Fmily Phylum - Muispirillum sheleri (T) HRI I17 - Esherihi fergusonii (T) ATCC Enteroous felis (T) JCM Osilliter vleriigenes (T) Sjm18-2 (=NBRC 11213) - Ltoous ltis (T) NCDO 67T - Stphyloous sprophytius (T) ATCC Prteroies - Bteroies - Clostriium XVIII - Clostriium XIV - Euterium - Anerotrunus - Clostriium XIV - Roseuri - Clostriium IV - Clostriium XIV - Clostriium III - Clostriium IV - Bteroies - Muispirillum - Esherihi - Enteroous - Osilliter - Ltoous - Clostriium XIV - Clostriium XIV - Clostriium IV - Stphyloous - Peniillus - Lhnospiree - Prophyromonee - Bteroiee - Erysipelotrihee - Unlssifie Clostriiles Lhnospiree - Euteriee - Unlssifie Clostriiles - Ruminooee - Lhnospiree - Lhnospiree - Ruminooee Lhnospiree - Ruminooee Lhnospiree - Unlssifie Clostriiles - Lhnospiree - Unlssifie Clostriiles - Lhnospiree - Unlssifie Molliutes - Ruminooee - Lhnospiree - Corioteriee - Ruminooee - Lhnospiree - Ruminooee - Unlssifie Clostriiles - Lhnospiree - Unlssifie Clostriiles - Lhnospiree - Bteroiee - Unlssifie Clostriiles - Ruminooee Unlssifie Clostriiles - Lhnospiree - Lhnospiree Ruminooee Lhnospiree - Deferriteree - Ruminooee - Enteroteree - Lhnospiree - Enterooee Ruminooee - Unlssifie Clostriiles - Ruminooee - Lhnospiree - Streptooee - Ruminooee Lhnospiree - Ruminooee Lhnospiree - Stphylooee - Lhnospiree - Ruminooee - Lhnospiree Unlssifie Clostriiles - Lhnospiree Lhnospiree - Ruminooee - Peniillee 1 More unnt in group n +WEGL groups reltive to group Less unnt in group n +WEGL groups reltive to group OTU in group hnge y ws reverse y WEGL - Firmiutes Bteroietes Firmiutes - Unlssifie teri Firmiutes - Teneriutes Firmiutes - Atinoteri - Unlssifie teri Firmiutes - Unlssifie teri Firmiutes - Bteroietes Firmiutes - Unlssifie teri Firmiutes - Deferriteres - Firmiutes - Proteoteri - Firmiutes Firmiutes - Unlssifie teri Firmiutes - Unlssifie teri Firmiutes - Unlssifie teri Firmiutes methylpentosum (Clostriium IV), Clostriium XIV n XVIII n Euterium oprostnoligenes (Fig. 4,e n Supplementry Dt 2; note tht these speies were initilly reue y ompre with how feeing). Bteril speies inluing E. oprostnoligenes, C. methylpentosum, P. golsteinii, Bteroies spp., A. olihominis, R. hominis n Clostriium XIV n XVIII were lso enrihe in the þ 8% WEGL tretment ompre with the how iet (Supplementry Dt 3 n Supplementry Fig. 7e). Moreover, mny teril speies inrese in the 8% WEGL group ut were not ltere y, initing tht WEGL my enrih speifi teril speies (Fig. 4e n Supplementry Dt 2). Colletively, these results show tht WEGL moultes the gut miroiot of -fe mie, resulting in miroiot omposition similr to tht of how-fe mie. WEGL mintins intestinl integrity in mie. Given tht intestinl ysiosis in -fe nimls my ffet gut permeility n susequently le to relese of teril LPS into the irultion 19, we exmine whether WEGL moultes gut integrity. While feeing reue expression of the tight juntion omponents, zonul oluens-1 (ZO-1) n oluin, these effets were reverse y WEGL supplementtion (Supplementry Fig. 8). These finings suggest tht WEGL my improve intestinl rrier integrity in -fe mie. WEGL fel trnsplnts reue oesity. Reent stuies hve shown tht the ility of the gut miroiot to moulte oesity n e trnsferre to other nimls 13. To etermine whether the NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

8 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 gut miroiot of WEGL-trete nimls my improve the onition of -fe mie, we trnsferre the miroiot of WEGL-trete mie to -fe mie, followe y exmintion of oesity-relte trits. Anlysis of the ohort of onor mie inite tht WEGL tretment reue oy weight n the Firmiutes-to-Bteroietes rtio in the gut miroiot of fe mie (Supplementry Fig. 9,), similr to the results shown ove (Figs 1 n 4). Our results further showe tht horizontl fel trnsfer from mie fe with how (-), þ 8% WEGL (8% WEGL ()-), or þ 8% WEGL (8% WEGL ()-) reue oy weight, epiiyml n suutneous ft umultion n liver weight ompre with fel trnsfer from -fe mie (-; Fig. 5 ). Fel trnsfer from the þ 8% WEGL group proue the most roust effets on weight gin n ft umultion (Fig. 5 ). Expression of pro-inflmmtory ytokines n lipogeni genes ws lso reue in hepti n ipose tissues of mie fter trnsfer of fees erive from WEGL-trete nimls (Fig. 6 n Supplementry Fig. 1). Furthermore, the mrna n protein expression levels of tight juntion proteins in the ileum segment were lso inrese following the trnsfer of fees from WEGL-trete mie (Fig. 6e g). Trnsfer of fees from 8% WEGL-how-fe mie to mie lso proue sttistilly signifint hnges in TNF- expression (Fig. 6), lipogeni genes (Supplementry Fig. 1) n ileum tight juntions (Fig. 6e g), ompre with fel trnsfer from how-fe mie. These results suggest tht the weight-lowering effets of WEGL in -fe mie my e ue to moultion of the gut miroiot. WEGL fel trnsplnts moulte gut miroiot omposition. In orer to onfirm tht WEGL moultes the gut miroiot, we exmine the omposition of intestinl teri following fel trnsfer from 8% WEGL-trete mie. In seprte sequening nlysis, totl of 1,56,611 rw res n n verge of 52,831±6,766 res per smple were otine. Susequently, totl of 458,93 effetive res ws generte n eh fel smple (n ¼ 5 for eh group) proue 22,95±3,39 effetive res. Uner this sequening epth, rre phylotypes n most iversity were lso overe (Supplementry Fig. 11). In omprison with mie tht reeive fees from -fe mie, reipient -fe mie (n ¼ 5 for eh group) showe istint miroiot fter fel trnsplnttion from -, þ 8% WEGLor þ 8% WEGL-fe mie (Fig. 7,). Fel trnsfer from mie proue Firmiutes to Bteroietes rtios n Boy weight (g) % WEGL () 8% WEGL( ) Epiiyml ft (g) (week) 8% WEGL () 8% WEGL () Suutneous ft (g) % WEGL () 8% WEGL () weight(g) 8% WEGL () 8% WEGL () Figure 5 Oesity n ft umultion re reverse y fel trnsplnttion from WEGL-trete mie to -fe mie. Eight-week-ol -fe mie were olonize with fees from ifferent mouse groups for 8 weeks, followe y mesurement of oy weight () epiiyml ft () suutneous ft () n liver weight (). Eh group onsiste of five mie. Boy weight ifferenes in were nlyse using unpire two-tile Stuent s t-test (Po5, Po1, Po1). Grph rs in with ifferent letters on top represent sttistilly signifint results (Po5) se on Newmn Keuls post ho one-wy ANOVA nlysis, wheres t lelle with the sme letter orrespon to results tht show no sttistilly signifint ifferenes. 8 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

9 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE TNF-α mrna (Reltive expression) 8% WEGL () 8% WEGL () IL-β mrna (Reltive expression) 8% WEGL () 8% WEGL () IL-6 mrna (Reltive expression) 8% WEGL () 8% WEGL () MCP-1 mrna (Reltive expression) 8% GL () 8% WEGL () Oluin mrna (Reltive expression) ZO-1 mrna (Reltive expression) 3. 8% WEGL () 8% WEGL () 8% WEGL () 8% WEGL () ZO-1 17 Oluin 7 β-atin 8% WEGL () 8% WEGL () Figure 6 Anlysis of pro-inflmmtory ytokines n intestinl tight juntions following fel trnsplnttion from WEGL-trete mie. Eight-weekol mie were olonize with fees from the inite mouse groups for 8 weeks. In omprison with the - group, reltive mrna expression levels of TNF- () IL-1 () IL-6() n MCP-1 () in hepti n ipose tissues s well s oluin (e) n ZO-1 (f) in ileum, were ssesse using qrt PCR. Representtive ileum immunolots for oluin, ZO-1 n -tin in eh group. (g) Moleulr weight mrkers were inite s kd. Eh group onsiste of five mie. Grph rs in f with ifferent letters on top represent sttistilly signifint results (Po5) se on Newmn Keuls post ho one-wy ANOVA nlysis, wheres rs lelle with the sme letter orrespon to results with no sttistilly signifint ifferenes. NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

10 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 Proteoteri n Deferriteres phyl levels tht i not iffer from those of -fe mie (Fig. 7, ompre with Fig. 4). In ontrst, fees trnsfer from -, þ 8% WEGL n þ 8% WEGL-fe mie proue vlues similr to those of how-fe or WEGL-trete mie (Fig. 7, ompre with Fig. 4). RDA nlysis ientifie totl of 155 OTUs tht were signifintly ltere y fel trnsplnt from - (126 OTUs), þ 8% WEGL- (71 OTUs) n þ 8% WEGL-fe groups (75 OTUs) ompre with - mie (Supplementry Dt 4 n Supplementry Fig. 12). Among these, M. sheleri, E. fergusonii, L. ltis, C. sinens n O. vleriigenes, whih were enhne y feeing (Fig. 4), were ll reverse y fel trnsfer from -, þ 8% WEGL- n þ 8% WEGL-fe mie (Fig. 7,e). In ition, Clostriium oletum, Bteroies e, Euterium olihum n Coproillus teniformis were ltere fter fel trnsplnttion from the sme three groups of mie (Fig. 7,e, these teri were not ientifie in the WEGL tretment experiments shown in Fig. 4). Of note, while the -inue reution of P. golsteinii (Fig. 4,e) ws oserve in - mie, this speies ws inue y fel trnsplnttion from the other three groups of mie (Fig. 7,e). Interestingly, Akkermnsi muiniphil, potentilly enefiil teril speies, ws only ientifie in -fe mie tht reeive fees from þ 8% WEGLtrete mie (Fig. 7,e). These results inite tht WEGL restores the gut miroiot of mie to omposition similr to those of how-fe mie. WEGL high moleulr weight polyshries reue oesity. To ientify the tive ingreients of WEGL responsile for the nti-oesity effets, we frtionte the myelium extrt into four frtions (G1, G2, G3 n G4) on the sis of their moleulr weights (Tle 1). As shown in Fig. 8 e, frtion G1, whih.3 PCoA - PC1 vs PC PC2 - per ent vrition expline 14% % WEGL() 8% WEGL() PC1 - per ent vrition expline 13.21% % WEGL () - 3 8% WEGL () - 4 8% WEGL () - 1 8% WEGL () - 5 8% WEGL () - 1 8% WEGL () - 2 8% WEGL () - 4 8% WEGL () - 5 8% WEGL () % WEGL () % Bteril tx (reltive unne in %) 9% 8% 7% 6% 5% % 3% 2% 1% Unlssifie Verruomiroi Teneriutes Proteoteri Firmiutes Deferriteres Bteroietes Atinoteri % % WEGL() 8% WEGL() Figure 7 Anlysis of gut miroiot following fel trnsplnttion. Fel trnsplnttion from -, - n / þ 8% WEGL-fe mie ws performe n relevnt miroiot nlysis ws one s esrie in the Methos. () The plots shown were generte using the weighte version of UniFr-se PCoA. () Multivrite nlysis of vrine from PCoA mtrix sores. () Bteril txonomi nlysis of intestinl terium from eh mouse groups. () Hetmp showing the unne of 155 OTUs signifintly ltere y, þ 8% WEGL n þ 8% WEGL trnsplnte mie se on RDA nlysis. (e) Represente teril tx informtion (speies, genus, fmily n phylum) of 155 OTUs from re shown. White irles n lk imons inite the OTUs tht inrese or erese ompre with reipient mie. 1 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

11 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE 8% WEGL () OTU1 OTU6 OTU28 OTU19 OTU25 OTU41 OTU92 OTU49 OTU73 OTU26 OTU69 OTU47 OTU191 OTU98 OTU68 OTU158 OTU143 OTU251 OTU195 OTU137 OTU188 OTU67 OTU185 OTU183 OTU181 OTU229 OTU273 OTU176 OTU182 OTU15 OTU29 OTU286 OTU243 OTU287 OTU237 OTU21 OTU19 OTU234 OTU187 OTU246 OTU349 OTU353 OTU362 OTU224 OTU27 OTU328 OTU326 OTU428 OTU288 OTU359 OTU381 OTU426 OTU477 OTU356 OTU396 OTU445 OTU463 OTU58 OTU278 OTU372 OTU525 OTU493 OTU597 OTU6 OTU4 OTU451 OTU497 OTU613 OTU643 OTU65 OTU58 OTU689 OTU694 OTU687 OTU1375 OTU61 OTU637 OTU845 OTU93 OTU12 OTU779 OTU832 OTU119 OTU164 OTU1336 OTU1489 OTU14 OTU12 OTU5 OTU16 OTU21 OTU2 OTU39 OTU51 OTU197 OTU61 OTU7 OTU86 OTU53 OTU88 OTU125 OTU136 OTU233 OTU113 OTU232 OTU196 OTU11 OTU17 OTU38 OTU382 OTU281 OTU479 OTU33 OTU439 OTU296 OTU9 OTU342 OTU567 OTU513 OTU594 OTU649 OTU531 OTU674 OTU116 OTU417 OTU199 OTU167 OTU5472 OTU55 OTU761 OTU166 OTU1415 OTU1743 OTU177 OTU255 OTU263 OTU2618 OTU2681 OTU5177 OTU5795 OTU646 OTU6674 OTU722 OTU82 OTU94 OTU95 OTU918 OTU997 OTU1129 OTU12531 OTU18546 OTU1876 OTU217 OTU23694 OTU237 8% WEGL () -> 8% WEGL () 8% WEGL () Speies Genus Fmily Phylum - Prteroies golsteinii (T) - Prteroies Prophyromonee Bteroietes - Bmesiell - Clostriium XIV - Lhnospiree - Firmiutes - Prophyromonee - Bteroietes - Akkermnsi muiniphil (T) Mu - Akkermnsi - Verruomiroiee - Verruomiroi - Unlssifie Clostriiles Firmiutes - Flvonifrtor plutii (T) CCUG 2893 ATCC Flvonifrtor - Ruminooee - Prophyromonee - Bteroietes - Lhnospiree Firmiutes - Bmesiell - Ruminooee - Prophyromonee - Bteroietes - Lhnospiree Firmiutes - Bmesiell intestinihominis (T) YIT Bmesiell - Ruminooee - Prophyromonee - Bteroietes - Clostriium XIV - Ruminooee - Lhnospiree Unlssifie Clostriiles - Ruminooee - Unlssifie Clostriiles - Lhnospiree Firmiutes - Unlssifie teri Firmiutes - Ruminooee - Stphyloous sprophytius (T) ATCC Stphyloous - Stphylooee - Unlssifie teri - Lhnospiree - Unlssifie Clostriiles Lhnospiree - Ruminooee Firmiutes Lhnospiree - Unlssifie Clostriiles - Ruminooee - Unlssifie Clostriiles - Unlssifie Bteroiles - Bteroietes - Clostriium XIV - Clostriium XIV - Unlssifie Clostriiles - Lhnospiree - Unlssifie Clostriiles Lhnospiree Ruminooee - Lhnospiree Firmiutes - Unlssifie Clostriiles - Ruminooee - Lhnospiree - Prophyromonee - Unlssifie teri Firmiutes - Bteroietes Ruminooee - Clostriium XIV - Bmesiell Lhnospiree - Unlssifie Clostriiles - Ruminooee - Lhnospiree - Unlssifie Clostriiles - Prophyromonee Firmiutes - Unlssifie teri - Bteroietes - Clostriium XIV - Lhnospiree - Clostriium XIV - Ruminooee - Unlssifie Clostriiles - Lhnospiree - Ruminooee - Lhnospiree Firmiutes - Unlssifie teri - Unlssifie Bteroiles - Bteroietes Lhnospiree Ruminooee - Clostriium lttifermntns (T) G17 - Clostriium XIV Lhnospiree - Ruminooee Firmiutes - Clostriium XIV - Unlssifie Clostriiles - Lhnospiree - Roseuri - Ruminooee Lhnospiree - Esherihi fergusonii (T) ATCC Esherihi - Unlssifie Clostriiles - Lhnospiree - Enteroteriee - Proteoteri - Muispirillum sheleri (T) HRI I17 - Muispirillum - Lhnospiree - Ruminooee - Deferriteree Firmiutes - Deferriteres - Ltoous ltis (T) NCDO 67T - Ltoous - Streptooee - Ruminooee - Clostriium XIV - Lhnospiree - Euterium olihum (T) - Erysipelotrihee inerte seis - Erysipelotrihee - Rosseuri intestinlis (T) L Roseuri - Lhnospiree - Clostriium sinens (T) ATCC Clostriium XIV - Ruminooee - Lhnospiree - Osilliter vleriigenes (T) Sjm18-2 (=NBRC 11213) - Osilliter - Ruminooee - Coproillus teniformis (T) JCM 164 Clostriium XIV - Clostriium XIV - Corproillus Lhnospiree - Erysipelotrihee - Clostriium XIV - Ruminooee Lhnospiree - Unlssifie Clostriiles Lhnospiree Firmiutes - Roseuri - Atopostipes suilolis (T) PPC79 - Atopostipes - Cmoteriee - Clostriium XIV - Esherihi/Shigell Lhnospiree - Enteroteriee - Proteoteri Lhnospiree Firmiutes - Clostriium XIV - Esherihi/Shigell - Enteroteriee - Proteoteri - Clostriium XIV Lhnospiree - Clostriium XIV - Clostriium snsu strito Ruminooee Lhnospiree - Unlssifie Clostriiles - Ruminooee - Clostriiee 1 Firmiutes - Euterium oprostnoligenes (T) HL - Eueterium - Ruminooee - Euteriee Ruminooee - Bteroies e (T) ATCC 43185T - Bteroies - Bteroiee - Bteroietes - Clostriium oietum (T) DSM Clostriium XVIII - Ruminooee - Erysipelotrihee Firmiutes - Ruminooee Bteroies Bteroiee Bteroietes - Stphyloous - Stphylooee - Firmiute - Corioteriee - Atinoteri - Esherihi/Shigell - Enteroteriee - Proteoteri - Unlssifie Clostriiles Firmiutes - Roseuri Lhnospiree Clostriium XIV 1 3 Quntity of OTU More unnt in, 8% WEGL (), n 8% WEGL () groups reltive to group Less unnt in, 8% WEGL (), n 8% WEGL () groups reltive to group Figure 7 Continue. onsiste of polyshries with moleulr weight 43 kd (Tle 1) n monoshrie omposition omprising 47.5% mnnose, 26.3% gluose n 16.9% gltose (Tle 2), proue signifint nti-oesity effets on oy weight, liver weight n epiiyml n suutneous ft in -fe mie. Notly, the extent of nti-oesity effets oserve ws similr to tht NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

12 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 Tle 1 Moleulr weight nlysis of polyshrie sufrtions isolte from WEGL myelium. Sufrtion Component Moleulr weight (MW) Perentge (%) G1 Polyshrie 43 kd 33.7 G2 Polyshrie 1 3 kd 15.6 G3 Polyshrie o1 kd 4. G4 Mono-, i-, oligoshrie Unetermine 46.8 Polyshries were nlyse from 1-ml solution of 2% WEGL (w/v). Tle 2 Monoshrie omposition of WEGL-G1 sufrtion (43 kd). Mn Gl Gl GlN Ar GlN Rh Fu Conentrtion ND (mg l 1 ) Perentge (%) ND 2.9 Ar, rinose; Fu, fuose; Gl, gltose; GlN, gltosmine; Gl, gluose; GlN, gluosmine; Mn, mnnose; ND, not etete; Rh, rhmnose. proue y the whole WEGL myelium extrt (Fig. 8 e). In ontrst, frtion G2 showe moest nti-oesity effets, wheres no signifint effet ws oserve for frtions G3 n G4 (Fig. 8 e). No signifint hnge in men energy intke, stool ft or energy extrtion ws note following tretment with the polyshrie frtions (Supplementry Fig. 13). These results suggest tht the nti-oesity effets of WEGL myelium my e ue minly to its high moleulr weight polyshrie frtion. Disussion Although previous stuies hve shown tht G. luium lowers serum gluose n proues enefiil effets on type 2 ietes mellitus in murine moels 6,41,42, the effets of this fungus on the gut miroiot, inflmmtion n oesity h not een investigte. Our stuy shows tht G. luium myelium prevents ietry-inue oesity n llevites inflmmtion y moulting the omposition of the gut miroiot n mintining intestinl rrier integrity. Our results thus revel tht WEGL moultes the intestinl miroiot previously reporte to orrelte with oesity 43, ut lso ientify the high moleulr weight polyshries (43 kd) s the mjor iotive ingreients responsile for these effets. Our oservtions tht WEGL proues signifint hnges in the gut miroiot n the nti-oesity effets of WEGL re trnsferrle through fel trnsplnttion support the onept tht oesity is ssoite with n ltere gut miroiot. These finings re onsistent with the results of reent stuy y Riur et l. 13 Using twins isornt for oesity s moel, these uthors oserve tht trnsfer of the gut miroiot of oese iniviuls to -fe mie onveye lrger weight gin n higher levels of oesity-ssoite metoli isorers thn fel trnsfer from the iniviul s len twin. Our results suggest tht the gut miroiot n e moulte y ietry intervention or fel trnsfer, n tht the WEGL myelium extrt my e use s preiotis to proue speifi gut miroiot ssoite with reue weight gin, inflmmtion n insulin resistne in oese iniviuls. The urrent moel of -inue hroni inflmmtion n oesity-relte isorers is expline lrgely y ysiosis of the gut miroiot n inrese levels of LPS in the loo, onition lle metoli enotoxemi 19. The intestinl lumen is reservoir of LPS from Grm-negtive teri tht inlue Esherihi spp. 2 In stte of intestinl ysiosis s seen in -fe nimls, the intestinl tue my grully eome leky, llowing the LPS of Grm-negtive teri to enter the enterohepti irultion. Low onentrtions of LPS in loo my use systemi n trgete inflmmtion in -fe mie n oese humns through tivtion of TLR4 signlling in vrious ells 22. Our results inite tht WEGL supplementtion improves gut rrier integrity, reues enotoxemi, ereses TLR4 signlling n ereses inflmmtion in oese mie fe with. The enefiil effets inue y WEGL tretment my therefore e ttriute to speifi ltertions in the gut miroiot (for exmple, reution of Esherihi spp. suh s E. fergusonii) n to mintenne of gut rrier integrity. Mrophges foun within ipose tissues exhiit two ifferent tivtion profiles onsisting of the M1 n M2 types 44. LPS-inue M1 mrophges umulte roun ying ipoytes n heptoytes n serete pro-inflmmtory ytokines, proviing mehnism to explin how oesity my propgte inflmmtion 45. We oserve tht WEGL tretment reues the numer of mrophges n ereses MCP-1 expression in hepti n ipose tissues of -fe mie (Supplementry Fig. 3 ). Furthermore, n inrese of IL-1 expression (Fig. 2) n Treg ells in liver n ipose tissues (Supplementry Fig. 3,e) ws lso oserve in WEGL-trete mie. In ition to mrophges n Treg ells, other immune ells suh s NKT n B ells my lso ontriute to the ntioesity effets oserve here. The gut miroiot of oese humns n nimls is ssoite with erese levels of intestinl Bteroietes n inrese levels of Firmiutes, initing tht these mjor phyl my ply role in oesity-relte inflmmtion 16,49. Aoringly, preiotis feeing with the plnt hemiellulose ompoun rinoxyln reverses the Bteroies-to-Firmiutes rtio n reues oesity 5. We oserve tht 8% WEGL supplementtion in -fe mie restore the Firmiutes to Bteroietes rtio to tht oserve in how-fe mie (Fig. 4). Intriguingly, the proioti Bifioterium spp., whih were previously reporte to reue oesity 51,52, were not etete in the present stuy. This oservtion suggests tht WEGL my proue nti-oesity effets y ltering the Firmiutes-to-Bteroietes rtio s well s moifying the levels of other speifi teril speies (Supplementry Dt 2 n 3). A previous stuy showe tht hitin-glun fires moulte Clostriium luster XIV (Roseuri spp.) in the gut miroiot of -fe mie 53. Bteri elonging to Clostriium lusters XIV, XVIII n IV, whih lk prominent toxins n virulene ftors, were foun erlier to moulte host ftty i metolism, inue Treg ell tivity n ttenute olitis 54. Furthermore, Euterium spp. inue y preioti oligoshries proue enefiil effets on niml hosts 55, highlighting the potentil proioti effet of these speies. Our results emonstrte tht WEGL supplementtion enhnes teril levels of Clostriium lusters IV, XVIII n XIV (Roseuri spp.), n Euterium spp. in -fe oese mie (Fig. 4,e n Supplementry Dt 2). These results inite tht the effets of WEGL my e t lest prtilly ue to n inrese in the popultions of these enefiil speies. WEGL feeing lso erese severl teril speies ssoite with inflmmtion n oesity. For instne, E. fergusonii, whih is ssoite with -inue inflmmtion 2, ws reue following WEGL tretment (Fig. 4,e n Supplementry Dt 12 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

13 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE Boy weight (g) Epiiyml ft (g) weight (g) % +G1 +G (weeks) +8% +G1 +8% +G1 +G2 +G3 +G4 +8% +G2 +G3 +G4 +G3 +G4 +8% +8% +G1 +G2 +G3 +G4 +G1 +G2 +G3 +G4.. +G1 +G2 +G3 +G4 Boy weight gin (g) Suutneous ft (g) % +G1 +G2 +G3 +G4 +8% +G1 +G2 +G3 +G4 +8% +G1 +G2 +G3 +G4 +8% +G1 +G2 +G3 +G4 Figure 8 Effet of WEGL polyshrie frtions on oy weight n ft umultion in -fe mie. Mie fe with how or were trete ily with 1 ml of polyshrie sufrtions (G1, G2, G3, G4), 8% WEGL or wter y intrgstri gvge for 2 months (n ¼ 5 for eh group). Effets of polyshrie sufrtions on oy weight () oy weight gin () epiiyml ft () suutneous ft () n liver weight (e). Boy weight ifferenes in were nlyse using unpire two-tile Stuent s t-test (Po1, Po1). Grph rs in e lelle with ifferent letters on top represent sttistilly signifint results (Po5) se on Newmn Keuls post ho one-wy ANOVA nlysis, wheres rs with the sme letter orrespon to results tht show no sttistilly signifint ifferenes. In the se where two letters re present on top of the rs in e, eh letter shoul e ompre seprtely with the letters of the other rs to etermine whether the results show sttistilly signifint ifferenes. 2). Osilliter spp. were lso reporte to inrese in -fe mie ompre with how-fe mie, n these teri showe negtive reltionship with the expression of intestinl tight juntion proteins. Consistent with these oservtions, the 8% WEGL tretment reverse the perentge of Osilliter spp. in the gut miroiot of -fe mie to perentge similr to tht seen in how-fe mie (Fig. 4,e n Supplementry Dt 1 n 2). In ition, Muispirillum spp. elonging to Deferriteres, whih re known to olonize the muus lyer, inrese in -fe mie ompre with how-fe mie 56. In ontrst, Muispirillum spp. were reue y WEGL in mie in the present stuy (Fig. 4,e n Supplementry Dt 2). Therefore, WEGL my prevent -inue oesity y moulting the omposition of the gut miroiot in multiple wys 57. Nonetheless, the hypothesis tht WEGL my lso iretly ffet pro-inflmmtory signlling pthwys suh s TLR2, whih lso ontrols iposity n insulin resistne 58, nnot e rule out. In ition to moultion of the miroiot omposition, our in vivo experiments emonstrte tht the ministrtion of WEGL lso reues expression of genes involve in ftty i synthesis n reues insulin resistne in -fe mie. These results suggest tht the effets of WEGL my e ue to moultion of lipogeni gene expression. Moreover, previous stuy emonstrte tht over-proution of pro-inflmmtory ytokines suh s TNF-, IL-1, IL-6 n MCP-1 in oese nimls my e responsile for the evelopment of hroni inflmmtion n insulin resistne, ue t lest in prt to IRS-1 phosphoryltion (on serine 37; ref. 31). In the present stuy, WEGL tretment inue the e-phosporyltion of IRS-1 n NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

14 ARTICLE NATURE COMMUNICATIONS DOI: 1.138/nomms8489 enhne phosphoryltion of Akt, leing to improve insulin sensitivity. Thus, WEGL my not only regulte expression of lipogeni genes, ut lso ffet signlling pthwys involve in insulin resistne. Previous stuies hve highlighte the importne of shorthin ftty is (SCFAs) suh s ette, propionte n utyrte in meliortion of hroni inflmmtory iseses n promotion of olonoyte helth 59. SCFAs were reporte to suppress proution of pro-inflmmtory ytokines, enhne IL-1 expression n tivte Treg ells, leing to meliortion of olitis 6. SCFAs re proue from fermenttion of polyshries n some other preiotis y gut teri suh s Bteroies spp. 5 As the perentge of Bteroies ws enhne y tretment of mie with 8% WEGL, it is possile tht the mount of SCFAs my lso inrese in this se. It remins to e etermine whether SCFAs re ffete or not y WEGL n whether these moleules ontriute to the ntiinflmmtory effet of WEGL. Notly, our results show tht high moleulr weight polyshries (43 kd) isolte from WEGL proue signifint nti-oesity effets in -fe mie. Conerning the possile mehnism of tion of polyshries from WEGL, previous stuies suggest tht intestinl teri possess istint polyshrie preferenes n tht these moleules my fvour the growth of speifi teril speies in the gut miroiot 61. Colletively, our results suggest tht oth WEGL n its high moleulr weight polyshries my e use s preiotis to reue oy weight gin, hroni inflmmtion n insulin resistne in oese iniviuls. Methos Murine n fungl strins. Animl experiments were pprove n performe in orne with the guielines of Institutionl Animl Cre n Use Committee of Chng Gung University (IACUC; Approvl No. CGU11-117). Mie of the C57BL/ 6NCrlBltw geneti linege were purhse from Biolso (Tiwn) n kept uner ontrolle light onitions (12 h light rk yle), with free ess to foo n wter. Eight-week-ol mle mie were rnomly istriute into six groups ontining five to seven nimls eh (see the legen of Figs 1,4 6,8). Mie were house in groups of three or four nimls per ge, n were fe with either stnr how iet (13.5% of energy from ft; LDiet 51; LDiet, USA) or high-ft iet (6% of energy from ft; TestDiet 58Y1; TestDiet, USA). The G. luium strin initilly isolte n hrterize t Chng Gung Biotehnology n the wter extrt of ulture myelium were proesse s esrie efore 62. Briefly, the wter extrt ws prepre y mixing g of rie G. luium myelium in 1 l of wter efore gittion t 15 r.p.m. for 3 min t 121 C. The solution ws oole to room temperture (22 C), followe y entrifugtion t 5,894g for 3 min t 4 C using Sorvll RC 3C Plus entrifuge (Thermo Fisher Sientifi, USA). The superntnt ws onentrte using Buhi R22 Rotvpor vuum onentrtor (Buhi, Switzerln) t 65 C to otin finl volume of 2 l. The extrt ws sterilize t 121 C for 2 min, followe y storge t 4 C in rk glss ottles. The myelium onsiste of o5% rue fire; 41% polyshries; rue proteins t g per 1 g; rue ft t 2.41 g per 1 g; rohyrtes t g per 1 g; mino is t 5.2 g per 1 g; n soium t mg per 1 g. Clories were mesure t 345 kl per 1 g. Eh group of mie ws fe for 2 months with how iet or, plus ily ministrtion of 1 ml of either wter or WEGL t 2, 4 or 8% (w/v) y intrgstri gvge. Men energy intke ws ssesse y onverting the mount of foo onsume into lories using the informtion provie y the mnufturer (LDiet 51 n TestDiet 58Y1). Preprtion of WEGL polyshrie sufrtions. WEGL polyshrie frtions were provie y Chng Gung Biotehnology. Briefly, 1 ml of WEGL extrt ws mixe with 6 ml of 95% ethnol (v/v) efore inution for 16 h t 4 C. The solution ws entrifuge t 4,5g for 2 min t 4 C (Sorvll RC 3C Plus entrifuge; Thermo Fisher Sientifi, USA). The first superntnt ws ente n 1 ml of 7% ol ethnol ws e to proue pellet. The solution ws entrifuge s ove n the seon superntnt ws ente. This opertion ws repete three times. The first n seon superntnts were poole to otin volume of 1,5 ml (frtion G4). The preipitte pellet ontining rue polyshries ws mixe with 1, ml of istille wter n the mteril ws issolve ompletely. The solution of rue polyshries ws onentrte to finl volume of 7 ml using n R22 vuum onentrtor (Bühi, Switzerln) t 65 C to remove resiul lohol. Distille wter ws e into the rue polyshrie solution to otin finl volume of 2, ml. The solution ws filtere using the Spetrum KrosFlo system with.2 mm hollow fire (1,5 m 2, PES; Spetrum Lortories, USA). The trnsmemrne pressure ws set t 15 p.s.i. A totl of 1,8 ml of istille wter ws e uring filtrtion of the rue polyshrie solution. The retentive filtrte (65 ml) ws preserve (G1-1). The solutions were filtrte using 3 kd ssette memrne (Minimte TFF Cpsule; Pll, USA). A totl of 6 ml of istille wter ws e uring filtrtion. The retentive filtrte (95 ml) ws gthere (G1-2). The G1-1 n the G1-2 filtrtes were omine to otin volume of 1,6 ml (G1). The permete filtrte ws filtrte with 1 kd ssette memrne. A totl of 6 ml of istille wter ws e uring filtrtion. The retentive filtrte (97 ml) (G2) n 3,6 ml of the permete filtrte (G3) were otine. The G1, G2, G3 n G4 solutions were onentrte to finl volume of 1 ml using the vuum onentrtor. Fel trnsplnttion. Fel trnsplnt ws performe se on n estlishe protool 63. Briefly, 8-week-ol mle onor mie (n ¼ 5 per iet group) were fe with, þ 8% WEGL, or þ 8% WEGL for 3 months. After 4 weeks of feeing, stools were ollete ily for the susequent 2 months uner lminr flow hoo in sterile onitions. Stools from onor mie of eh iet group were poole n 1 mg ws resuspene in 1 ml of sterile sline. The solution ws vigorously mixe for 1 s using enhtop vortex (Vortex-Genie 2, Sientifi Inustries, USA; spee 9), efore entrifugtion t 8g for 3 min. The superntnt ws ollete n use s trnsplnt mteril s esrie elow. Fresh trnsplnt mteril ws prepre on the sme y of trnsplnttion within 1 min efore orl gvge to prevent hnges in teril omposition. Eight-week-ol mle reipient mie (n ¼ 5 for eh trnsplnt group) were fe with n inoulte ily with fresh trnsplnt mteril (1 ml for eh mouse) y orl gvge for 2 months, efore eing kille for susequent nlysis. Anlysis of oy weight n gut miroiot of the onor mie (Supplementry Fig. 9,) inite tht the 4-weeklong iet tretments use for this ohort of mie proue hnges similr to those of the 2-month-long tretments (Figs 1 n 4). Antioies. Antioies ginst IkB- (nuler ftor of kpp light polypeptie gene enhner in B ells inhiitor lph; 1:1,; 9242L), JNK (-Jun N-terminl; 1:1,; 9252L), phosphorylte JNK (1:1,; 4668S), phosphorylte IRS-1 (insulin reeptor sustrte-1; phosphoryltion on serine 37; 1:1,; 2381S), IRS-1 (1:1,; 2382L), Akt (1:1,; 4691L), phosphorylte Akt (phosphoryltion on serine 473; 1:1,; 6L) n TLR4 (1:1,; 2219) were purhse from Cell Signling Tehnology (USA). Antioies ginst zonul oluens-1 (ZO-1; 1:25; 61 7,3) n oluin (1:25; 71 1,5) were otine from Invitrogen (USA). Seonry ntioies (nti-rit IgG, H þ L; 1:1, n 1:2, for primry ntioies from Cell Signling Tehnology n Invitrogen, respetively; ) were purhse from Jkson ImmunoReserh (USA). Antioy ginst -tin (1:2,; NB6-51) n seonry ntioy nti-mouse IgG (1:2,; s-25) were purhse from Novus Biologils (USA) n Snt Cruz Biotehnology (USA), respetively. FITC-onjugte nti-f4/8 (1:1; ; ebiosiene, USA), PE-onjugte nti-cd11 (1:1; ; BD Phrmingen, USA), nti-cd11 (1:1; 5571; BD Phrmingen), PE-onjugte nti-cd4 (1:1; 55738; BD Phrmingen), PerCp-Cy5.5-onjugte nti-cd25 (1:1; 55171; BD Phrmingen) n Alex Flour 488-onjugte nti-foxp3 (1:1; 563; BD Phrmingen) ntioies were lso use. Determintion of energy n ft in fees. Mesurements were me se on protool reporte previously 64. The energy ensity ws etermine using n iti om lorimeter (Gllenkmp, UK). Totl fel lipis were extrte s esrie previously 65. Briefly, rie fel smples were homogenize one with heptne/iethylether/ethnol (1:1:1, vol/vol) n twie with heptne/iethylether/ ethnol/wter (1:1:1:1, vol/vol). Superntnts were ollete in glss vils tht h een weighe eforehn. Totl lipi mount in eh superntnt ws mesure grvimetrilly fter solvent evportion n ws expresse s perentge of the weight of the strting fel smple. Oil re O stining. Frozen liver setions (6-mm thik) were stine with Oil Re O (Sigm, USA) for 2 min, n then ounter-stine with hemtoxylin for 1 min. Setions were exmine uner light mirosopy. A totl of 2 tissue setions were nlyse for eh niml. Orl gluose tolerne test. Overnight-fste mie were given gluose y orl gvge (3 g kg 1, 66% solution), n mesurement of homeostti moel ssessment-insulin resistne ws performe s esrie efore 2. Bloo gluose ws etermine with gluose meter (Rohe Dignostis, Switzerln) using loo ollete from the tip of the til vein. Biohemil nlyses. Serum LPS quntifition ws performe using ommeril kit se on the use of Limulus meoyte extrt (Ll kit; Cmrex Bio Siene, USA). Smples were ilute 1:2 n hete for 1 min t 7 C. Serum insulin onentrtions were etermine in 5 ml of serum using ommeril ELISA 14 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

15 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE kit (Meroi, Sween) se on the mnufturer s instrutions. Serum FFA were etermine using ommeril etetion kit (Biovision, USA). Quntittive rel-time reverse-trnsription PCR. Totl RNA ws isolte using totl tissue RNA isoltion kit (Genei, Tiwn). Equl mounts of totl RNA were use to synthesize DNA with the Qunt II fst RT kit (Tools, Tiwn). Quntittive rel-time reverse-trnsription PCR (qrt PCR) ws performe in triplite using SYBR Green, 384-well pltes n the LightCyler 48 Rel-Time PCR System (Rohe Dignostis). Eh well ws loe with totl of 1 ml ontining ml of DNA, 1 ml of trget primers, ml of wter n 5 ml of Kp SYBR Fst Mster Mix. Hot-strt PCR ws performe for 5 yles, with eh yle onsisting of enturtion for 15 s t 94 C, nneling for 3 s t 6 C n elongtion for 3 s t 72 C. The Rohe LightCyler softwre (version., Rohe Dignostis) ws use for t nlysis. Reltive quntifition ws one using the 2 DDCT metho 66. Expression ws normlize ginst the housekeeping gene glyerlehye 3-phosphte ehyrogense. Men expression levels of how-fe mie were set s 1%. The primers use re shown in Supplementry Tle 1. Western lotting. One hunre mg of ipose, liver or intestine tissue were homogenize in ommeril Pro-Prep Protein Extrtion Solution (Intron Biotehnology, South Kore). Totl protein lystes were frtionte on 1% soium oeyl sulfte polyrylmie gel n eletro-lotte onto polyvinyliene ifluorie memrnes (Immoilon TM-P; Millipore, USA). Memrnes were loke with 5% non-ft milk for 1 h t room temperture in TBST uffer (Tris 1 mm, NCl 15 mm, ph 7.6,.1% Tween 2) n proe with primry ntioies overnight t 4 C. Memrnes were then inute with horserish peroxise-onjugte seonry ntioy. The ilutions of primry n seonry ntioies were esrie in the Antioy setion ove. Protein ns were evelope using enhne hemiluminesene (Millipore). The originl immunolots were provie in Supplementry Fig. 14. Morphometry nlysis of epiiyml ipose tissues. Freshly isolte epiiyml ipose tissues from wil-type or WEGL-trete mie were fixe overnight in 1% formlin, followe y ehyrtion, emeing in prffin, n setioning. Setions of 8 mm were stine with hemtoxylin n eosin, n ell size ws nlyse using the Imge J softwre (Ntionl Institutes of Helth, USA). Flow ytometry nlysis. Epiiyml ipose n hepti tissues were rinse in sline, mine into fine piees n igeste with ollgense (Sigm, USA) in Kres Henseleit HEPES uffer (Sigm, USA; ph 7.4) supplemente with 2 mg ml 1 of BSA n 2 mm gluose. Inution ws performe t 37 C in shker for 45 min. The smples were psse through mesh n frtionte y rief entrifugtion (1,g). The pellets or the floting ells were ollete to otin the stroml vsulr frtion or ipoytes in ipose tissues, respetively. Cells in the stroml vsulr frtion n liver frtions were lyse in Phrm Lyse uffer for 3 min t 4 C n resuspene in Phrmingen stin uffer (Beton Dikinson, USA). Cells were inute with the ommeril ntioy 2.4G2, whih rets ginst the FgII n FgIII murine reeptors (Beton Dikinson, USA) for 1 min n then with primry ntioies or the mthing ontrol isotypes for 3 min t 4 C. The ells were rinse twie n resuspene in Phrmingen stin uffer. Flow ytometry nlysis ws performe using FACSCliur (Beton Dikinson, USA). Dt nlysis ws performe using the Kluz flow ytometry nlysis softwre (Bekmn Coulter, USA). Mrophges were ientifie either s F4/8 n CD11 oule-positive ells in ipose tissues or s F4/8 n CD11 oule-positive in the liver. CD4, CD25 n trnsription ftor Foxp3 were nlyse for Treg ells. Cytokine mesurements. IL-1, IL-6 n TNF- protein levels were mesure using ommeril ELISA kits (R&D Systems, USA). Gut miroiot nlysis. Stool smples were snp-frozen in liqui nitrogen efore storge t 8 C. DNA ws extrte using fel DNA isoltion kit (MoBio Lortories, USA). For eh el stool smple, the 16S rrna gene omprising V3 V5 regions ws mplifie using omposite forwr primer n reverse primer ontining unique 1-se roe to tg eh PCR prout. For eh smple, 5 ml PCR mix ws prepre ontining 25 ng DNA templte, 5 KAPA HiFi Buffer, 1 mm KAPA NTP Mix, 1 U ml 1 KAPA HiFi DNA Polymerse (KAPA Biosystems, USA) n.3 mm of omposite primer pirs. The PCR retion onitions onsiste of 95 C for 3 min, followe y yles of 98 C for 2 s, 45 C for 15 s n 72 C for 15 s, n finl extension of 72 C for 1 min. The omposite primer pirs onsiste of the forwr primer (5 -GCCTTGCCAGCC CGCTCACTCCTACGGGAGGCAGCAG-3 ) omposite of 454 primer B (unerline) n the universl teril primer 338F (itlis) n the reverse primer (5 -GCCTCCCTCGCGCCATCAGNNNNNNNNNNCCGTCAATTCMTT TGAGTTT-3 ) omposite of 454 primer A (unerline), unique 1-se roe (NNNNNNNNNN) n the ro-rnge teril primer 97R (itlis). Replite PCRs were poole n mplions were purifie using the QiQuik PCR Purifition Kit (Qigen, USA). PCR prouts were sequene on 454 FLX pyrosequener pltform oring to 454 Rohe reommene proeures. Highqulity res for ioinformtis nlysis were selete n ll of the effetive res from ll smples were lustere into OTUs se on 97% sequene similrity oring to 454 SOP 67. Briefly, qulity ontrol riteri for seleting rw res of high qulity inlue removl of sequenes tht lke V3 V5 primers or roe sequene (roe sequene poorly mthe or ws not ientifie) s well s sequenes tht ontine short vrile region (o9 p) or unetermine ses (42 ses) in the V3 V5 vrile region. De-noising riteri omprise (1) using 5-p sliing winow to reue sequening error n (2) n verge qulity sore of 35 within tht winow for sequene trimming. All high-qulity sequenes were ligne using the nerest lignment spe termintion multi-ligner in SILVAomptile tse lignment. Res tht i not lign to the ntiipte region of the referene lignment were remove. Chimer sequenes ientifie using the UCHIME lgorithm 68 were remove. All res were lssifie using Byesin lssifier with homeme RDP tse. Res tht oul not e lssifie t the kingom level were remove. Alph iversity nlysis inluing rreftion nlysis n Shnnon inex were lulte using QIIME 69. Fst UniFr PCoA ws performe with the phylogeneti tree onstrute y inserting the representtive of eh OTU lso generte using QIIME 69. Aoring to pulishe sttistil methos 7, the sttistil signifine of the seprtion mong niml groups in PCoA sores plots ws ssesse y multivrite nlysis of vrine test with ifferenes in physiologil n iohemil vlues for sttistil signifine. Normlly istriute t were nlyse y nlysis of vrine (ANOVA) using Tukey s post ho test (SPSS, USA). The reltive unne of eh OTU (log 1 - trnsforme) ws use to onstrut RDA moels n OTUs tht were ifferent etween niml groups were ssesse with Cnoo for Winows 4.5 (Miroomputer Power, USA) oring to the mnufturer s instrutions. Sttistil signifine ws ssesse using the Monte Crlo Permuttion Proeure with 499 rnom permuttions. Determintion of teri y quntittive rel-time PCR. Using teri-speifi primers esrie in Supplementry Tle 1, unne of Firmiutes, Bteroietes n totl teri in fel stool from eh iet group t initive time point ws etermine y 2 DDCT metho-se quntittive rel-time PCR 66. The reltive unne of Firmiutes n Bteroietes ws normlize to totl teri for lultion of Firmiutes-to-Bteroietes rtio. Sttistil nlysis. Dt otine from three replite experiments re shown s mens±s.e.m. Differenes in oy weight were ssesse using the unpire twotile Stuent s t-test. Dt sets tht involve more thn two groups were ssesse y one-wy ANOVA followe y Newmn Keuls post ho tests (see the legen of Figs 1 3,5,6,8). Next genertion sequening nlysis ws ssesse using Tukey s honest signifint ifferene post ho tests. A P vlue of 5 ws onsiere sttistilly signifint. In the figures, the t with ifferent supersript letters re signifintly ifferent se on post ho ANOVA sttistil nlysis. SPSS version 17. ws use. Referenes 1. Stone, R. Biohemistry. 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Novel hypoglyemi effets of Gnoerm luium wter-extrt in oese/ieti ( þ / þ ) mie. Phytomeiine 16, (29). 43. Zho, L. The gut miroiot n oesity: from orreltion to uslity. Nt. Rev. Miroiol. 11, (213). 44. Fujisk, S. et l. Regultory mehnisms for ipose tissue M1 n M2 mrophges in iet-inue oese mie. Dietes 58, (29). 45. Cesr, R. et l. Gut-erive lipopolyshrie ugments ipose mrophge umultion ut is not essentil for impire gluose or insulin tolerne in mie. Gut 61, (212). 46. Lynh, L. et l. invrint NKT ells protet ginst iet-inue oesity n metoli isorer through regultory ytokine proution. Immunity 37, (212). 47. Winer, D. A. et l. B ells promote insulin resistne through moultion of T ells n proution of pthogeni IgG ntioies. Nt. Me. 17, (211). 48. Strissel, K. J. et l. T-ell reruitment n Th1 polriztion in ipose tissue uring iet-inue oesity in C57BL/6 mie. Oesity (Silver Spring) 18, (21). 49. Turnugh, P. J. et l. A ore gut miroiome in oese n len twins. Nture 457, (29). 5. Neyrink, A. M. et l. Preioti effets of whet rinoxyln relte to the inrese in Bifioteri, Roseuri n Bteroies/Prevotell in iet-inue oese mie. PLoS ONE 6, e2944 (211). 51. Prnell, J. A. & Reimer, R. A. Preioti fier moultion of the gut miroiot improves risk ftors for oesity n the metoli synrome. Gut Miroes 3, (212). 52. Everr, A. et l. Cross-tlk etween Akkermnsi muiniphil n intestinl epithelium ontrols iet-inue oesity. Pro. Ntl A. Si. USA 11, (213). 53. Neyrink, A. M. et l. Dietry moultion of lostriil luster XIV gut teri (Roseuri spp.) y hitin-glun fier improves host metoli ltertions inue y high-ft iet in mie. J. Nutr. Biohem. 23, (212). 54. Atrshi, K. et l. Treg inution y rtionlly selete mixture of Clostrii strins from the humn miroiot. Nture 5, (213). 55. Roerfroi, M. et l. Preioti effets: metoli n helth enefits. Br. J. Nutr. 14(Suppl 2): S1 63 (21). 56. Rvussin, Y. et l. Responses of gut miroiot to iet omposition n weight loss in len n oese mie. Oesity (Silver Spring) 2, (212). 57. Lin, C. S. et l. Impt of the gut miroiot, preiotis, n proiotis on humn helth n isese. Biome. J. 37, (214). 58. Criilli, A. M. et l. Gut miroiot is key moultor of insulin resistne in TLR 2 knokout mie. PLoS Biol. 9, e11212 (211). 59. Sonnenurg, E. D. et l. Speifiity of polyshrie use in intestinl Bteroies speies etermines iet-inue miroiot ltertions. Cell 141, (21). 6. Smith, P. M. et l. The miroil metolites, short-hin ftty is, regulte oloni Treg ell homeostsis. Siene 341, (213). 61. Koroptkin, N. M., Cmeron, E. A. & Mrtens, E. C. How glyn metolism shpes the humn gut miroiot. Nt. Rev. Miroiol. 1, (212). 62. Chng, C. J. et l. Gnoerm luium stimultes NK ell ytotoxiity y inuing NKG2D/NCR tivtion n seretion of perforin n grnulysin. Innte Immun. 2, (214). 63. Boroy, T. J., Prmsothy, S. & Agrwl, G. Fel miroiot trnsplnttion: initions, methos, eviene, n future iretions. Curr. Gstroenterol. Rep. 15, 337 (213). 64. Kom, Y. et l. Mehnisti omprison etween gstri ypss vs. uoenl swith with sleeve gstretomy in rt moels. PLoS ONE 8, e72896 (213). 65. Rossi, J. et l. Alimentry trt innervtion efiits n ysfuntion in mie lking GDNF fmily reeptor lph2. J. Clin. Invest. 112, (23). 66. Livk, K. J. & Shmittgen, T. D. Anlysis of reltive gene expression t using rel-time quntittive PCR n the 2 -DDCT Metho. Methos 25, 2 8 (21). 67. Shloss, P. D. et l. Introuing mothur: open-soure, pltform-inepenent, ommunity-supporte softwre for esriing n ompring miroil ommunities. Appl. Environ. Miroiol. 75, (29). 68. Egr, R. C., Hs, B. J., Clemente, J. C., Quine, C. & Knight, R. UCHIME improves sensitivity n spee of himer etetion. Bioinformtis 27, (211). 69. Cporso, J. G. et l. QIIME llows nlysis of high-throughput ommunity sequening t. Nt. Methos 7, (21). 7. Wng, J. et l. Moultion of gut miroiot uring proioti-meite ttenution of metoli synrome in high ft iet-fe mie. ISME J. 9, 1 15 (214). Aknowlegements We thnk Dr Li-Mn Hung for her vie onerning the orl gluose tolerne test n insulin resistne monitoring. This work ws supporte y grnt MOST B MY3 n MOST B MY3 from the Ministry of Siene n Tehnology of Tiwn n grnt CMRPD1B53 n CMRPD1C782 from Chng Gung Memoril Hospitl, Linkou, Tiwn. 16 NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

17 NATURE COMMUNICATIONS DOI: 1.138/nomms8489 ARTICLE Author ontriutions C.-J.C. n C.-S.L. oneive the projet, ontriute to experimentl esigns, performe experiments, interprete the results, generte figures n wrote the mnusript; Y.-Y.M.C., J.D.Y. n H.-C.L. oneive n supervise the projet, interprete the results n wrote the mnusript; Y.-F.K. provie the extrt n polyshrie sufrtions of G. luium; C.-C.L., S.-F.T. n T.-R.W. performe the experiments. J.M., D.M.O. n J.D.Y. interprete the results n wrote the mnusript. All uthors isusse the results n pprove the mnusript. Aitionl informtion Aession oes:miroiot sequening t were eposite into NCBI s Sequene Re Arhive tse uner ession oe SRP5786. Supplementry Informtion ompnies this pper t ntureommunitions Competing finnil interests: YFK is Presient of Chng Gung Biotehnology; JDY is Chirmn of the Bor of Chng Gung Biotehnology. The other uthors elre no ompeting finnil interests. Reprints n permission informtion is ville online t reprintsnpermissions/ How to ite this rtile: Chng, C.-J. et l. Gnoerm luium reues oesity in mie y moulting the omposition of the gut miroiot. Nt. Commun. 6:7489 oi: 1.138/nomms8489 (215). This work is liense uner Cretive Commons Attriution 4. Interntionl Liense. The imges or other thir prty mteril in this rtile re inlue in the rtile s Cretive Commons liense, unless inite otherwise in the reit line; if the mteril is not inlue uner the Cretive Commons liense, users will nee to otin permission from the liense holer to reproue the mteril. To view opy of this liense, visit NATURE COMMUNICATIONS 6:7489 DOI: 1.138/nomms & 215 Mmilln Pulishers Limite. All rights reserve.

18 DOI: 1.138/nomms1613 OPEN Corrrigenum: Gnoerm luium reues oesity in mie y moulting the omposition of the gut miroiot Chih-Jung Chng, Chun-Sheng Lin, Chi-Chen Lu, Jn Mrtel, Yun-Fei Ko, Dvi M. Ojius, Shun-Fu Tseng, Tsung-Ru Wu, Yi-Yun Mrgret Chen, John D. Young & Hsin-Chih Li Nture Communitions 6:7489 oi: 1.138/nomms8489 (215); Pulishe 23 Jun 215; Upte 11 Jul 217 The imge in Fig. 1e of this Artile showing the þ 8% group ws invertently uplite from the þ 8% group. The orret version of the figure ppers elow. Open Aess This rtile is liense uner Cretive Commons Attriution 4. Interntionl Liense, whih permits use, shring, pttion, istriution n reproution in ny meium or formt, s long s you give pproprite reit to the originl uthor(s) n the soure, provie link to the Cretive Commons liense, n inite if hnges were me. The imges or other thir prty mteril in this rtile re inlue in the rtile s Cretive Commons liense, unless inite otherwise in reit line to the mteril. If mteril is not inlue in the rtile s Cretive Commons liense n your intene use is not permitte y sttutory regultion or exees the permitte use, you will nee to otin permission iretly from the opyright holer. To view opy of this liense, visit r The Author(s) 217 NATURE COMMUNICATIONS 8:1613 DOI: 1.138/nomms

19 CORRRIGENDUM NATURE COMMUNICATIONS DOI: 1.138/nomms1613 Boy weight (g) Epiiyml ft (g) e WEGL 8% 2% 4% 8% +8% +2% +8% +2% +4% +8% % +8% 8 (Week) Boy weight gin (g) Suutneous ft (g) f weight (g) WEGL WEGL 8%. 2% 4% 8% 8% 2% 4% 8% g Frequeny (%) <5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, 5,5 Cell size (µm 2 ) 6, 6,5 7, 7,5 8, 8,5 9, 9,5 >1, +8% +8%WEGL + 2% WEGL + 4%WEGL + 8%WEGL WEGL 8% 2% 4% 8% +2% +4% +8% Figure 1 2 NATURE COMMUNICATIONS 8:1613 DOI: 1.138/nomms1613

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