Intestinal microbiota and energy balance pro s and con s

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Dirk Hller Chir of Nutrition nd Immunology School of Life Sciences

1 Technicl University of Munich Nutrition nd Immunology Intestinl microiot nd energy lnce pro s nd con s Prof. Dr. Dirk Hller Chir of Nutrition nd Immunology School of Life Sciences Weihenstephn (WZW) Reserch Center for Nutrition nd Food Sciences (ZIEL) ZIEL - Microiome Core Fcility

2 WHO 11 Worldwide prevlence of oesity in popultions ge ove in 8

Wht re the common mechnisms of chronic immunemedited nd

Inflmmtory Bowel Diseses Irritle Bowel Syndrome, Colorectl

Dietes Alzheimer s Disese Asthm Atopic Dermtitis

3 Wht re the common mechnisms of chronic immunemedited nd metolic disorders role of microes? Inflmmtory Bowel Diseses Irritle Bowel Syndrome, Colorectl Cncer Immune-medited diseses Multiple Sclerosis Type 3 Dietes Alzheimer s Disese Asthm Atopic Dermtitis Metoliclly-driven diseses Type 1 dietes Crdiovsculr Disese, Type dietes, Oesity Renz,, Hller 1 Nture Immunology

Community structure nd ctivity of the intestinl microiot is tightly linked to immune nd metolic functions Gut s centrl orgn o Control of rrier integrity o Control of immune nd

4 Community structure nd ctivity of the intestinl microiot is tightly linked to immune nd metolic functions Gut s centrl orgn o Control of rrier integrity o Control of immune nd inflmmtory processes o Energy extrction nd control of metolism Stomch CFU/ml Duodenum CFU/ml Jejunum CFU/ml Ileum < 1 8 CFU/ml Colon 1 1 CFU/ml Diversity nd Density

5 Functionl interctions etween the gut microiot nd host metolism Body Mss Index (BMI) Oesity > 3 kg/m Tremroli nd Bäckhed 1 Nture

6 Puttive mechnisms for the effect of the intestinl microiot on metolic functions of the host Cox nd Blser 13 Cell Metolism

7 Weight chnges ffect microil composition the first steps Stomch CFU/ml Duodenum CFU/ml Jejunum CFU/ml Ileum < 1 8 CFU/ml Colon 1 1 CFU/ml Diversity nd Density Ley,, Gordon 6 Nture

8 Cloric lod chnges microil composition nd contriutes to incresed energy hrvest in oese volunteers o Weight mintining diet (WMD) clculted s (kg) X o Experimentl diet 1/ (EXD1) representing either or 3 kcl/d with similr mcronutrient composition (% protein, 16% ft, 6% crohydrtes) o Volunteers include 1 len (BMI<5; Averge 3) nd 9 oese (BMI>3; Averge ) Jumpertz,, Krkoff 11 Am J Clin Nutr

9 Cloric lod chnges microil composition nd contriutes to incresed energy hrvest in oese volunteers Reduced energy loss in feces ssocited with % chnges in Fermicutes nd Bcteroidetes ~15 kcl per dy Jumpertz,, Krkoff 11 Am J Clin Nutr

10 Trnsfer of stool microiot from twins discordent for oesity into germfree mice mirrow humn weight gin Ridur,, Gordon 13 Science

11 Erly life exposure to low dose concentrtions of ntiiotics re ssocited chnges in ody composition Age w + 7 w Ax Associted with induction of lipogenesis in liver Cho,, Blser 1 Nture

12 High ft diet is ssocited with incresed LPS plsm concentrtion nd loss of glucose tolernce Weight gin positively ssocited endotoxin in lood Glucose tolernce negtively ssocited endotoxin in lood Inflmmtion meditors positively ssocited endotoxin in lood Cni et l. 7 Dietologi (Cni et l. 7 Dietes)

13 lood glucose [mg/dl] permeility of proximl colon [µm h -1 ] lood glucose [mg/dl] permeility of distl colon[µm h -1 ] lood glucose [mg/dl] len mss [g] TER of proximl colon [ cm ] ft mss [g] TER of distl Colon [ cm ] AUC [mg*min/dl] ody mss [g] lood glucose [mg/dl] ody mss [g] lood glucose [mg/dl] ody mss [g] lood glucose [mg/dl] len mss [g] ft mss [g] AUC [mg*min/dl] G H I AKR/J pcd BL/6J pcd 3 AKR/J phfd ** 3 35 ** BL/6J phfd * ge [weeks] ge [weeks] time fter glucose gvge 16 [min] time fter glucose gvge [min] pcd pcd J phfd K phfd pcd 15 1 pcd phfd phfd D E F 8 AKR/J BL/6J SWR/J AKR/J BL/6J SWR/J AKR/J BL/6J AKR/JSWR/JBL/6J SWR/J G H I ** ge [weeks] ge [weeks] ge [weeks] D E F however these effects re not reproducile nd thus pcd pcd pcd phfd phfd 35 phfd question the role 8 of the hypothesis 8 Metolic endotoxemi 5 15 A 5 B 5 C 5 AKR/J pcd BL/6J pcd SWR/J pcd AKR/J BL/6J SWR/J AKR/J BL/6J SWR/J AKR/J BL/6J SWR/J AKR/J phfd BL/6J phfd SWR/J phfd L pcd AKR/J pcd phfd 5 AKR/J phfd M pcd phfd BL/6J pcd BL/6J phfd * ** ge [weeks] time fter glucose gvge [min] pcd phfd AKR/J BL/6J SWR/J * SWR/J pcd SWR/J phfd SWR/J pcd SWR/J phfd 5 AKR/J BL/6J 5 SWR/J AKR/J BL/6J SWR/J5 J time fter glucose gvge [min] 15 pcd 15 pcd K time fter glucose gvge [min] Collortive project with Profs Klingenspor nd Dniel (in preprtion) time fter glucose gvge [min]

fold chnge to CD tio Occludin/ß-Actin) TNF mrna old chnge TNF to CD (fold mrna of CD) io Occludin/ß-Actin) (fold of CD) fold chnge to CD io E-Cdherin/ß-Actin) IFNg mrna old chnge IFNg to CD (fold of

E-Cdherin/ß-Actin) IFNg mrna old chnge IFNg to CD (fold mrna of CD) E-Cdherin/ß-Actin) (fold of CD) TNF mrna (fold of CD) TNF mrna (fold of CD) endotoxin TER concentrtion [ cm ] [EU/mL] IFNg mrna

sl glucose [ cm ] [mg/dl] lood glucose [mg/dl] permeility of fluorescein [µm h -1 ] AUC [mg*min/dl] AUC [mg*min/dl] sl ody glucose mss [g] [mg/dl] lood ft mss glucose [g] [mg/dl] cum.

energy ] c c D FD 8 FD 75 FD 78 cf 1 [min] c c 1 1 c 5 5 however these effects re not reproducile nd thus 1 3 1 3 - time 1 of intervention 3 [wks] - time of intervention [wks] 1 3 question time of

14 fold chnge to CD tio Occludin/ß-Actin) TNF mrna old chnge TNF to CD (fold mrna of CD) io Occludin/ß-Actin) (fold of CD) fold chnge to CD io E-Cdherin/ß-Actin) IFNg mrna old chnge IFNg to CD (fold of mrna CD) E-Cdherin/ß-Actin) (fold of CD) fold chnge to CD tio Occlidin/ß-Actin) TNF mrna old chnge TNF to CD (fold mrna of CD) io Occlidin/ß-Actin) (fold of CD) rtion fold chnge to CD io E-Cdherin/ß-Actin) IFNg mrna old chnge IFNg to CD (fold mrna of CD) E-Cdherin/ß-Actin) (fold of CD) TNF mrna (fold of CD) TNF mrna (fold of CD) endotoxin TER concentrtion [ cm ] [EU/mL] IFNg mrna (fold of CD) IFNg mrna (fold of CD) permeility of fluorescein [µm h -1 ] TNF mrna (fold of CD) TNF mrna (fold of CD) endotoxin concentrtion [EU/mL] IFNg mrna (fold of CD) IFNg mrna (fold of CD) TER sl glucose [ cm ] [mg/dl] lood glucose [mg/dl] permeility of fluorescein [µm h -1 ] AUC [mg*min/dl] AUC [mg*min/dl] sl ody glucose mss [g] [mg/dl] lood ft mss glucose [g] [mg/dl] cum. AUC energy [mg*min/dl] intke [kj] cum. energy ody m ft ms cum. energy ] c c D FD 8 FD 75 FD 78 cf 1 [min] c c 1 1 c 5 5 however these effects re not reproducile nd thus time 1 of intervention 3 [wks] - time of intervention [wks] 1 3 question time of the intervention role [wks] of the hypothesis Metolic time endotoxemi of intervention [wks] F D E F 35 c CD A c B C DG CD HFD 8 c HFD 75 HFD 78 cf c c CD 1 HFD 8 HFD 3 75 HFD 78 cf time of intervention [wks] CD * # HFD 8 HFD 75 HFD 78 cf c time time fter of intervention glucose gvge [wks][min] c CD HFD 8 HFD 75 HFD 78 cf 1 3 time of intervention [wks] 15 CD CD c CD 35 CD HFD 8 HFD 8 HFD 8 HFD 78cf HFD HFD 8 * # c HFD 75 1 HFD 75 HFD 78cf HFD 75 3 HFD 78cf c HFD 78 * $ cf A ileum 16 B colon CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf Jejunum distl Ileum Jejunum proximl Colon distl distl Ileum Colon proximl Colon distl Colon time fter glucose gvge [min] Jejunum distl Ileum proximl Colon distl Colon J G 5 I 5 C G CD HFD HFD 78cf 1 HFD CD HFD 8 HFD 75 HFD 78 cf 5 CD HFD 8 HFD 75 HFD 78 cf 5 5 CD. HFD 8 CD HFD 75 CD HFD 78 cf CD JejunumHFD 8 distl HFD Ileum 75 HFD proximl 78 cf Colon distl Colon I 3 1 PEG E Plce grph here: 1 1 Doule-click, or Drg grph from the 5 5nvigtor. Jejunum distl Ileum CDproximl HFD Colon 8 HFD distl 75 Colon. HFD 78 cf E-Cdherin1. 1. Collortive project with Profs Klingenspor nd 1. Dniel (in preprtion) CD CD HFD HFD 8 8 HFD HFD HFD HFD 78 cf 78 cf CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf CD CD HFD HFD 8 8 HFD HFD HFD HFD 78 cf 78 cf * $ H H E Occludin ß-Actin HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf F J J CD CD HFD HFD 8 8 HFD HFD HFD HFD 78 cf 78 cf CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf 5 D 3 H F c CD HFD 8 HFD 75 HFD 78cf CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 HFD 75 HFD 78 cf CD HFD 8 CD HFD 75 CD HFD 78 cf CD CD HFD HFD 8 8 HFD HFD HFD HFD 78 cf 78 cf

15 Does high ft diet nd oesity contriute to gut ssocited inflmmtion? Nutrition s n etiologic risk fctor for developing IBD o o A recent met-nlysis of 19 studies with 169 CD nd 13 UC ptients identified high dietry intke of totl fts nd met s risk fctor (Hou et l. Am. J. Gstroenterol. 11) High ody mss index (BMI) ws not ssocited with the incidence of UC nd CD in prospective cohort (EPIC) of 3,7 prticipnts (Cln et l. Am. J. Gstroenterol. 13) Nutrition in niml models mechnistic understnding o Dietry ft drives pthoiont selection (Bilophil wdsworthi) in experimentl colitis (Devkot et l. Nture 1) o Chnges in gut microiot control inflmmtion nd gut permeility in oese mice (Cni et l. Dietes 7, Gut 9)

HFD ccelerte the development of smll intestinl inflmmtion in mouse model

Histopthologicl Score [-1] 7 6 5 3 1 WT control diet WT high-ft diet TNF

ARE/WT high-ft diet c 8w 1w 16w 8w 1w 16w WT TNF ΔARE/WT control HFD

control diet TNF ARE/WT high ft diet * * ** * * 1w 6 8 1 1 1 16 ge

16 HFD ccelerte the development of smll intestinl inflmmtion in mouse model of Crohn s disese Ilel Histopthology Colonic Histopthology Histopthologicl Score [-1] WT control diet WT high-ft diet TNF ARE/WT control diet TNF ARE/WT high-ft diet Histopthologicl Score [-1] WT control diet WT high-ft diet TNF ARE/WT control diet TNF ARE/WT high-ft diet c 8w 1w 16w 8w 1w 16w WT TNF ΔARE/WT control HFD Disese Activity Index [-1] Disese Activity Index TNF ARE/WT control diet TNF ARE/WT high ft diet * * ** * * 1w ge (weeks) Gruer,, Hller 13 PLOS ONE

17 Metolic fingerprints in response to HFD in plsm nd ilel tissue Gruer,, Hller 13 PLOS ONE

High-ft diet impirs gut rrier function in norml

ARE WT High-ft diet - - - - + + + + β-actin

diet TNF ΔARE/WT Control diet TNF ΔARE/WT

LPS concentrtion [EU/ml] 3,,5, 1,5 1,,5, WT TNF

18 High-ft diet impirs gut rrier function in norml nd the disese-susceptile host Genotype WT ARE ARE WT High-ft diet β-actin Portl vein LPS E-Cdherin Occludin WT Control diet TNF ΔARE/WT Control diet TNF ΔARE/WT High-ft diet E-Cdherin Occludin WT High-ft diet LPS concentrtion [EU/ml] 3,,5, 1,5 1,,5, WT TNF ARE/WT control Control diet high High-ft diet Gruer,, Hller 13 PLOS ONE

19 High ft diet triggers epithelil chemokine expression nd dendritic cell recruitment into the smll intestine CCL CD11c + DC fold of control (normlized to GAPDH) 1 WT 8 TNF ARE/WT 6 % positive cells 5 WT TNF ARE/WT c Control control diet High-ft high diet control Control diet high ft High-ft diet Gruer,, Hller 13 PLOS ONE

20 High ft diet modultes cteri-medited epithelil cell ctivtion nd dendritic cell (DC) recruitment CCL secretion Mode K cell culture Recruitment of BM-DCs towrds Mode K conditioned medi CCL concentrtion [pg/ml] unstim TNF ng/ml whole cecl lyste * cecl wter control diet high-ft diet chemotctic index unstim TNF ng/ml whole cecl lyste * control diet high-ft diet cecl wter Gruer,, Hller 13 PLOS ONE

21 H is to lo g ic l s c o r e o f d is t l ile u m [m x. 1 ] P o rt l v e in e n d o to x in [E U /m L ] H is to lo g ic l s c o re o f te rm in l ile u m [m x. 1 ] Histopthology Mternl oesity ccelertes disese ctivity in mouse model for Crohn s disese F F1 8 8 w e e k s 1 w e e k s Mternl control diet 6 ** Mternl HFD WT owt ARE oare WT owt ARE oare 5 r =.5 p =. 3 r =.9 1 p = P l s m T N F [p g /m L ] P l s m T N F [p g /m L ] Hemmerling,, Hller 1 PLOS ONE; Hemmerling,, Hller (in preprtion)

22 Fecl Microiot Trnsplnttion (FMT) in chronic diseses Smits,, Nieuwdorp 13 Gstroenterology

23 Fecl trnsplnttion in type- dietes s proof-ofconcept for the clinicl relevnce of intestinl cteri Vriese,, Nieuwdrop 1 Gstroenterology

24 Proiotic intervention to reduce weight in humn intervention studies met-nlysis

25 Conclusion o Diet ffects microil composition nd ctivity in the gut o Chnges in microil composition modulte energy homeostsis The propositions re: Trnsfer of stool microiot into germfree mice mimick weight gin in humns Efficiency to extrct energy from the diet increses with oesity ssocited chnges in short chin ftty cids Oesity nd/or HFD ntgonize intestinl rrier functions nd provoke metolic endotoxemi FMT is effective in modulting systemic insulin resistnce ut not weight; the contriution of proiotics remin inconclusive o HFD ccelertes erly life disese ctivity of IBD relted intestinl inflmmtion independent of the oese phenotype

Acknowledgment Fleming Institute, Greece George Kollis U Alert Richrd Fedork, Thoms Lee Chpel

Boekshoten Erlngen Benno Weigmnn Munich Hnnelore Dniel, Klus-Peter Jnssen, Mthis Heikenwälder

Schmöller, Sigrid Kisling, Griele Hörmnnsperger Ev Rth, Irin Sv-Piroddi, Tigo Nunes, Olivi

Bznell, Elen Loner Annemrie Schmidt, Jelen Clsn, Amir Metwly, Hongsup Yoon, Srh Just, Ndine

26 Acknowledgment Fleming Institute, Greece George Kollis U Alert Richrd Fedork, Thoms Lee Chpel Hill R. Blfour Srtor Brcelon Julin Pnes Wgeningen Michel Müller, Mrk v. Boekshoten Erlngen Benno Weigmnn Munich Hnnelore Dniel, Klus-Peter Jnssen, Mthis Heikenwälder Funding EU, DFG, BMBF Nutrition nd Immunology, TUM Thoms Clvel, Ilis Lgkouvrdos, Ingrid Schmöller, Sigrid Kisling, Griele Hörmnnsperger Ev Rth, Irin Sv-Piroddi, Tigo Nunes, Olivi Korer, Emnuel Berger, Jn Hemmerling Monik Schueck, Sören Ocvirk, Vlentin Schüppel, Monik Bznell, Elen Loner Annemrie Schmidt, Jelen Clsn, Amir Metwly, Hongsup Yoon, Srh Just, Ndine Wldschmitt Nico Gehrdt, Silvi Pitriu, Melnie Klein, Sndr Hennig, Simone Dxuer, Alexndr Buse, Croline Ziegler

* * * * * liver kidney ileum. Supplementary Fig.S1

* * * * * liver kidney ileum. Supplementary Fig.S1 Supplementry Fig.S1 liver kidney ileum Fig.S1. Orlly delivered Fexrmine is intestinlly-restricted Mice received vehicle or Fexrmine (100mg/kg) vi per os (PO) or intrperitonel (IP) injection for 5 dys (n=3/group).