Maturation of the Gut Microbiome: Potential for Prevention of Type 1 Diabetes

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1 Maturation of the Gut Microbiome: Potential for Prevention of Type 1 Diabetes Mikael Knip Children s Hospital, University of Helsinki and Helsinki University Hospital

2 PATHOGENESIS OF TYPE 1 DIABETES Healthy Beta-cell autoimmunity Clinical disease Insulin secretory capacity, % IAA ICA GADA II. Trigger IV. Driving antigen ZnT8A IA-2A 2 months - >20 years Modyfying factors FPIR Age IGT Clinical diabetes III. I. Beta-cell autoimmunity Genetic susceptibility Knip et al. Diabetes 2005; 54, Suppl. 2: S125-S136

3 IAA AND GADA AS THE FIRST APPEARING AUTOANTIBODY IN THE DIPP STUDY Knip et al. Semin Immunopathol 2017; 39:

4 Incidence of T1D/100,000 children <15 years of age Finland Estonia Russian Karelia Kondrashova et al. Ann Med 2005;37: 67-72

5 FREQUENCY OF IMMUNE-MEDIATED DISEASES AND PHENOMENA IN FINNISH AND RUSSIAN KARELIAN CHILDREN Incidence of Prevalenve of Prevalence of thyroid Prevalence of birch T1D, / celiac disease, % autoimmunity, % IgE, % TGAB TPOAb 11 x 5,6 x4,7 x5,7 x6,6 x5,5 2 Kondrashova et al. Ann Med 2005;37: 67-72; Kondrashova et al. Ann Med 2008;40: ; Kondrashova et al. J Clin Endocrinol Metab 2008;93: ; Seiskari et al. Clin Exp Immunol 2007;48:47-52

6 DIABIMMUNE Study Birth Cohort Recruitment of the newborn infants between Sep 2008 and May 2010 Follow-up for the first 3 years of their life Monitored prospectively for infections, vaccinations, use of antibiotics (ABX), early feeding and introduction of solid foods, etc. Figures by Tommi Vatanen

7 STOOL SAMPLE SEQUENCING Vatanen et al. Cell 2016; 165:

8 PRINCIPAL COORDINATE ANALYSIS PLOTS OF 16S SAMPLES BY COUNTRY (left) AND AGE (right) Vatanen et al. Cell 2016; 165:

9 GEOGRAPHICAL AREA I: Phylum level composition Bacteroidetes Actinobacteria Vatanen et al. Cell 2016; 165:

10 GEOGRAPHICAL AREA II: Genus- and species-- level differences Vatanen et al. Cell 2016; 165:

11 STRAIN LEVEL DIVERSITY (left) AND STABILITY (right) IN Bacterioides AND Bifidobacterium SPECIES Vatanen et al. Cell 2016; 165:

12 ABUNDANCE OF HUMAN MILK OLIGOSACCHARIDE (HMO) UTILIZATION GENES ACROSS THE THREE COUNTRIES OVER THE FIRST YEAR Vatanen et al. Cell 2016; 165:

13 LIPID A BIOSYNTHESIS PATHWAY NORMALIZED READ COUNTS (RPKM) PER SAMPLE Vatanen et al. Cell 2016; 165:

14 GEOGRAPHICAL AREA III: Differences in LPS producers Vatanen et al. Cell 2016; 165:

15 STRUCTURES OF LPS MOLECULES ISOLATED FROM E. Coli (A) AND B. Dorei (B) Vatanen et al. Cell 2016; 165:

16 LPS-INDUCED IMMUNE EDUCATION Vatanen et al. Cell 2016; 165:

17 INDUCTION OF ENDOTOCXIN TOLERANCE IN NOD MICE BY E. coli-derived LPS Vatanen et al. Cell 2016; 165:

18 INHIBITION OF E. coli-driven ENDOTOXIN TOLERANCE INDUCTION IN HUMAN MONOCYTES BY B. dorei LPS Vatanen et al. Cell 2016; 165:

19 EFFECT OF E. coli OR B. dorei DERIVED LPS ON DIABETES INCIDENC IN NOD MICE Vatanen et al. Cell 2016; 165:

20 SUMMARY Vatanen et al. Cell 2016; 165:

21 DECREASED DIVERSITY OF GUT MICROBIOTA AMONG PROGRESSORS DIPP 2011 Giongo et al. ISME J 2010; 5: 82-91

22 16S rrna mining suggests case/control functional differences Brown et al. PLoS One 2011;6:e25792

23 TRIGR PILOT AND FINDIA STUDY COHORT de Goffau et al., Diabetes 2013;62:

24 RELATION BETWEEN THE NUMBER OF AUTOANTIBODIES AND COMPOSITION THE GUT MICROBIOME (PRINCIPAL COMPONENT 1) 0.9 (+) or ( ) sign indicates a positive or negative correlation with Principal component 1. Absence of MW-U indicates a Spearman s Rho test was used. PC 1: 46 % Autoantibody positivity Variable % P Number of autoantibodies (0-4) na (-) IA2A positivity MW-U na (-) *Faecalibacterium prausnitzii (+) *Roseburia faecis (+) *Gemmiger formicilis (+) *Eubacterium desmolans (+) Bifidobacterium adolescentis (+) Clostridium clostridioforme (+) Clostridium clariflavum (+) Clostridium bolteae (+) Ruminococcus albus (+) Ruminococcus callidus (+) * Producers of butyrate Producers of acetate and lactate Degraders of complex polysaccharides de Goffau et al. Diabetes 2013;62:

25 DEARTH OF BIFIDOBACTERIUM ADOLESCENTIS AND PSEUDOCATENULATUM AMONG CHILDREN WITH SIGNS OF BETA-CELL AUTOIMMUNITY de Goffau et al. Diabetes 2013;62:

26 Autoantibody-positivity and disease progression is associated with cooccurrence of high abundance of Bacteroidetes and Saccharomycetes and low abundance of Firmicutes pfirmicutes cclostridia oclostridiales fruminococcac eae Ruminococcus pascomycota csaccharomycetes osaccharomycetales fsaccharomycetaceae Saccharomyces pbacteroidetes cbacteroidia obacteroidales fbacteroidaceae Bacteroides Honkanen et al., submitted for publication

27 Dunne et al. Clin Exp Immunol 2014; 177: 30-37

28 THE BETA-CELL AUTOIMMUNITY COHORT IN THE DIABIMMUNE STUDY: 11 CASES AND 22 MATCHED CONTROLS Kostic et al. Cell Host Microbe 2015; 17:

29 Relative abundance (log2) Blautia* Lachnospiriceae Rikenellaceae* Ruminococcus* Veillonellaceae Streptococcus* Microbial abundance Relative overabundance of pathobionts* (=> capacity to behave like pathogens) Relative underabundance of beneficial bacteria Seroconverters in between Kostic et al., Cell Host Microbe 2015;17:

30 R E A S E D DECREASED DIVERSITY AMONG THE PROGRESSORS Kostic et al. Cell Host Microbe 2015; 17:

31 Altered gene content and activity prior to T1D diagnosis T1D-associated reduced functional gene content Shift towards passive transporting-in of nutrients instead of active synthesis Change typical of auxotrophs thriving in inflammatory environments (dead tissue => easy access to nutrients) Multiple sugar transport system (M00216) Tyrosine biosynthesis (M00025) Phenylalanine biosynthesis (M00024) Aromatic amino acid metabolism Heme biosynthesis (M00121) Kostic et al. Cell Host Microbe 2015; 17:

32 INTESTINAL MICROBIOTA AND MICROBIOME IN RELA- TION TO THE DEVELOPMENT OF TYPE 1 DIABETES Children who progress to clinical type 1 diabetes are characterized by a reduced bacterial diversity which seems to emerge after seroconversion to autoantibody positivity Progression to clinical disease is associated with a reduced functional gene content in the gut microbiome Are there possibilities to modify the intestinal microbiota to prevent or delay progression to overt type 1 diabetes in children at risk?

33 ROLE OF THE INTESTINAL MICROBIOTA IN THE DEVELOPMENT OF TYPE 1 DIABETES (T1D) Fetal life T1D Genetic disease susceptibility Step 1 Poor immune education by the gut microbiota Infancy Step 2 Aquired susceptibility to immune-mediated diseases Dysbiosis; decreased microbial diversity Early childhood Young children Seroconversion to autoantibody positivity Clinical disease

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35 Annual incidence of T1D and relative abundance of Bifidobacterium longum in the in the infant gut in three countries Russian Karelia Estonia Finland Annual rate of type 1 diabetes /100,000 children < 15 years Mean relative abundance of Bifidobacterium longum

36 B. infantis Breast milk human oligosaccharides (HMO) + Stool ph Short-chain fatty acids in the gut B. infantis Bifidobacterium Antigen presenting cells Insulin T cell Stability of intestinal microbiota Colonisation resistance against other microbes Preserved intestinal barrier Immunlogical education Pancreatic β- cell survival

37 EFFECT OF ACETATE- AND BUTYRATE-YIELDING DIETS ON THE INCIDENCE OF AU- TOIMMUNE DIABETES IN NOD MICE NP; normal protein diet HAMS; high-amylose maize starch HAMSB; butyrylated high amylose starch HAMSA; acetylated high amylose starch ##P = (HAMSA+HAMSB vs HAMS) ***P = (HAMSA+HAMSB vs NP) #P = (HAMSA vs HAMS) **P = (HAMSA vs NP) *P = (HAMSB vs NP) NS = non-significant Marino et al. Nat Immunol 2017; 18:

38 EFFECT OF ACETATE- AND BUTYRATE-YELDING DIETS ON REGULATORY T CELLS IN THE SPLEEN IN NOD MICE Marino et al. Nat Immunol 2017; 18:

39 EFFECT OF ACETATE- AND BUTYRATE-YELDING DIETS ON THE DISTRIBUTION OF OTUs STOOL SAMPLES FROM NOD MICE Marino et al. Nat Immunol 2017; 18:

40 CONCLUSIONS There is still a lot to learn about the role of the intestinal microbiota in the development of type 1 diabetes Is the time mature for interventions aimed at modulation of the intestinal microbiota for the prevention of type 1 diabetes? The first human intervention trial based on early supplemention with a specific probiotic (Bifidobacterium longum subsp. infantis) is in the late planning phase Other option: an acetate- and butyrate-yielding diet?

41 COLLABORATORS Primary National International Research Group - Taina Härkönen - DIPP Study Group - Natalya Dorshakova - Eeva Jason - Anu-Maaria Hämäläinen - Hermie Harmsen - Anna Parkkola - Heikki Höyty - Matej Oersic - Petra Pöllänen - Jorma Ilonen - Vallo Tillman - Terhi Ruohtila - Harri Lähdesmäki - Raivo Uibo - Samppa Ryhänen - Riitta Lahesmaa - Ramnik Xavier - Jenni Selvenius - Olli Simell - Tommi Vatanen - Kirsi Salonen - Jorma Toppari - DIABIMMUNE Study - Heli Siljander - Outi Vaarala Group - Riitta Veijola - Suvi Virtanen

42 FUNDING EU 7th Framework (grant number ) Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research Juvenile Diabetes Research Foundation Academy of Finland Sigrid Juselius Foundation

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