Dysbiosis versus Pathobiont selection in Chronic Intestinal Inflammation

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1 Technische Universität München Dysbiosis versus Pathobiont selection in Chronic Intestinal Inflammation Prof. Dr. Dirk Haller Chair of Nutrition and Immunology School of Life Sciences Weihenstephan (WZW) ZIEL Institute for Food & Health (Director) Chair of Nutrition and Immunology ZIEL Institute for Food & Health

2 Gene-environment interaction in chronic immune pathologies what is the role of the gut microbiota? Environment Microbiome Gut Immune system Incidence (%) Multiple Sclerosis Crohn s disease Type 1 Diabetes Asthma Genes Renz,, Haller 2011 Nat. Immunol. Bach 2002 N. Engl. J. Med.

3 Inflammatory bowel diseases as a paradigm for microbe-host interaction Crohn s disease (CD) Stomach CFU/ml Duodenum CFU/ml Jejunum CFU/ml Ileum < 10 8 CFU/ml Colon CFU/ml Ulcerative colitis (UC) Density

4 Microbial factors link a defective mucosal interface with the chronic activation of adaptive immune functions Microbial factors IEC Loss of barrier function (CDH1, MUC19) Failure to maintain epithelial cell homeostasis (XBP1; ORMDL3) specifically targeting Paneth cells in CD Health Loss of innate mechanisms for microbial clearance (NOD2, ATG16L1, ATG5) Treg IL-10 Th17 IL-23 Th1/17 Disease Shift towards aggressive immune responses and loss of tolerance (TNFS15, IL-10RB, IL-23R) Persistance of pathogenic antigen

5 Identification of microbial risk patterns in patients with IBD new technologies but still wishful thinking Diversity Phylum Class Order Family Genus Species Strain Proteobacteria Clostridiales Faecalibacterium prausnitzii lbd subset Normal Frank,, Pace 2007 PNAS Gevers,, Xavier 2014 Cell Host Microbe

6 Changes in community structure of IBD patients is independent of disease activity iron replacement therapy 3 months Lee, Clavel,, Fedorak, Haller (submission in preparation)

7 What are the characteristic features of a dysbiotic microbiota in IBD? Dysbiosis = Changes in bacterial community structure associated with adverse effects in the host Disease Pathogenic traits Community Mutualistic traits Health

8 Background - available mouse models in IBD research Germ-free Nonpathogenic? microbiota Colitis models IL-10 KO HLA-B27 TG CD45RB Ileitis models hi SCID N-Cadherin DN TNF ARE IKK IEC SAMP1/Yit Fc Caspase-8 DSS IEC XBP-1 X ATG16L1 IEC Normal gut Inflammation

9 TNF ARE mice as a model for Crohn s disease-like ileitis WT TNF ARE o Heterozygous deletion of the adenosin-uracil rich element in the TNF transcript (Kontoyannis et al o TNF IEC (Roulis et al. 2011) o Ileitis (>>proximal colitis) o Spontaneous development o Transmural inflammation o Extraintestinal manifestation (Arthritis)

10 Disease activity is reflected by immune activation and is clustering in three categories Schaubeck,, Haller 2015 Gut

11 Dysbiotic microbial communities cause transmissive Crohn s disease-like ileitis Schaubeck,, Haller 2015 Gut

12 Phylotype analysis identified Hungatella sp. in health- and disease-related microbial ecosystems Analysis of Operational Taxonomic Units: Sequencial abundance Schaubeck,, Haller 2015 Gut

13 Conclusion I o Distinct bacterial community structures cause Crohn s disease-like ileal inflammation Dysbiosis Disease course [Question] what are the triggers that initiate the divergence of bacterial communities towards a dysbiotic configuration?

14 Conclusion I o Loss of Paneth cell function develops subsequently to the onset of inflammation Schaubeck,, Haller 2015 Gut

15 Conclusion II o Loss of Paneth cell function develops subsequently to the onset of inflammation Schaubeck,, Haller 2015 Gut

16 What are the characteristic features of a dysbiotic microbiota in IBD Pathobiont = Bacterial (Microbial) phylotypes with aggressive features relevant for the disease susceptibility of the host Disease Pathogenic traits Community Mutualistic traits Health

17 Absence of cell wall lipoproteins in Enterococcus faecalis abolish pathobiont-driven colitis in IL-10-/- mice Partial inhibition of colitis Enterococcal polysaccharide antigen Reduced mucus penetration Inhibition of colitis Cell surface lipoproteins Loss of innate immune activation Schillde et al Cell Host Microbe; Steck et al Gastroenterology; Öcvirk et al PLOS Pathogens ;

18 Fecal Microbiota Transplantation (FMT) as a tool to treat chronic diseases who might benefit? Moayyedi et al Gastroenterology UC patients in remission o 24 % (FMT) o 5% (Placebo) Smits,, Nieuwdorp 2013 Gastroenterology

19 Conclusion III o Dysbiotic bacterial communities are able to cause disease ativation, but what drives bacterial dysbiosis o Innate triggers are sufficient to reactivate the disease in the immunologically primed host [Question] what are the clinical consequences for the implementation in IBD? o Donor selection in FMT o Combination therapies adressing luminal changes (FMT) and immune targets (Biologicals, Immunosuppressive drugs a.o.)

20 Technische Universität München Cleveland University Fabio Cominelli U Alberta Richard Fedorak Chapel Hill R. Balfour Sartor Barcelona Julian Panes Norwich and Wageningen Michael Müller, Mark v. Boekshoten Paris Matthieu Allez Munich Hannelore Daniel, Klaus-Peter Janssen, Mathias Heikenwälder, Philippe Schmitt-Kopplin Nutrition and Immunology, TUM Thomas Clavel, Ilias Lagkouvardos, Ingrid Schmöller, Sigrid Kisling, Gabriele Hörmannsperger, Ludovica Butto, Irina Sava-Piroddi, Eva Rath, Olivia Kober, Emanuel Berger, Elena Lobner, Soo Ham, Sevana Khaloian, Monika Schaubeck, Valentina Schüppel, Monika Bazanella, Isabella Lengfelder, Jelena Calasan, Amira Metwaly, Hongsup Yoon, Sarah Just, Nico Gebhardt, Silvia Pitariu, Melanie Klein, Sandra Hennig, Thomas Korbica, Eda Öztürk, Simone Daxauer, Alexandra Buse, Caroline Ziegler DFG Chair of Nutrition and Immunology ZIEL Institute for Food & Health