Diet, microbiota and the immune system: A gut feeling about type 1 diabetes. Dr. Eliana Mariño Monash University Melbourne, Australia

Transcription

1 Diet, microbiota and the immune system: A gut feeling about type 1 diabetes Dr. Eliana Mariño Monash University Melbourne, Australia

2 Diet, gut microbiota and Western lifestyle diseases Asthma Fatty liver - Salt - Articial sweetners - Food emuldifiers IBD Type 1 diabetes Food allergies From Maslowski and Mackay Nat. Immunol 211

3 The role of dietary metabolites in inflammatory diseases Gut Cancer Obesity Diet and Microbiota Metabolic Sindrome T1D Kidney

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6 Type 1 Diabetes Blood sugar regulation lost Loss of insulin production and Hyperglyceamia Insulin producing beta cells destroyed Immune attack - autoimmune disease Controlled with exogenous insulin Diabetic complications are a major issue Insulin labelling Insulin labelling - pancreas T1D subject (x4) (x4) Images: thnx to Pete Campbell & Tom Kay SVI Melbourne

7 Epidemiology of T1D Findland Sweeden UK USA Australia Mexico China Venezuela Diabetic Medicine Volume 23, Issue 8, pages , 26 JUN 26 DOI: /j x

8 Diet and Inflammatory Disease Increase in diabetes and inflammatory diseases = popularity of Western-style diets Diet ( fibre fat) Developing countries diets ( fibre) = inflammatory disease Mediterranean diet = cardiovascular disease, asthma

9 Gut microbiota and Short-Chain Fatty Acids (SCFAs) SCFAs are produced by the gut microbiota from fermentation of dietary fibre Most common are: Dietary fibre bacteria acetate butyrate propionate SCFAs are absorbed across the gut epithelium They pass through the portal vein to the liver the primary site of metabolism

10 Hypothesis Diet alters gut microbiota and reduced production of microbial SCFAs affect immune tolerance that increase T1D susceptibility Aim To study the cellular and molecular mechanisms by which diet and SCFAs influence the course of autoimmune diabetes

11 a b diet increase levels of acetate b (% ) cdiabetes-free Prop Marino et al. Fig. 2 Acetate (mm) Propionate (mm) Butyrate (mm) Feces 1 HAM S **** 8 6 A B 4 **** 2 * Prop In plasma from NOD mice Age (weeks) Cecal content Hepatic portal blood NOD 5 week-old NOD 15 week-old NOD diabetic Butyrate (mm) Acetate (mm) Propionate (mm) ** **** SCFAs protect from T1D *** Acetate (mm) Butyrate (mm) Propionate (mm) B ##, *** * * Prop +B ##, *** Acetate (mm) #, **, *, 15 NP, Butyrate (mm) Propionate (mm) Peripheral blood * ** -fed NOD 15 week-old NP * score (%) 1 75 Prop 5

12 Protective bacteria Non-protective bacteria

13 Acetate markedly reduces auto-reactive effector T cell numbers in NOD8.3 mice

14 Diet controls peripheral Treg numbers Spleen: C57BL/6 mice a c % Foxp3 + [gated on CD4 + ] Spleen ** #### NP Marino et al. Fig. 5 ## #### 2. Number of Foxp3 + Treg cells (x1 6 ) ## *** ** NP CD4+CD25+FoxP3+ (x1^6) b Diabetes-free (%) 1 d Barastoc ****, P<.1 *, P=.1 High Fat diet (HFD) High Fibre diet Weeks post injections HFD/HF ****,## **, P=.83 HFD/Barastoc **** ## NP

15 HDAC inhibition/ epigenetic mechanisms Foxp3 Single cell PCR

16 Diet (particularly acetate) changes MHC I and co-stimulatory molecules on B cells (and DCs) Control diet Acetate diet Butyrate diet

17 Effector T cells don t proliferate when transferred to fed mice NOD8.3 TCR Tg CD8+ cells transferred to NOD on different diets autoantigen (IGRP) recognised by transgenic TCR Pancreatic LN Mesenteric LN

18 SCFAs improve barrier function LPS in serum IL-22 (gut homeostasis) in serum

19 Microbiota shaped by different diets differs markedly contributes to disease susceptibility/protection Mice on different diets chow a Dramtic changes in microbiota composition Germ free Mice on the same chow diet Unknown Bacteroides Bacteroidaceae B. acidifaciens Chow Unknown microbiome Parabacteroides Porphyromonadaceae B Unknown Unknown Genus Unknown Family Unknown Unknown shaped Genus Unknown Family Clostrid microbiome Unknown Lactobacillus Lactobacillaceae Lacto NP Unknown Unknown GenusUnknown Unknown Family shaped Unknown Anaeroplasma Anaeroplasmataceae microbiome Anae High fat b Butyrate High fat shaped microbiome c Bacteroides 1 Acetate Lactobacillus ( % ) 8

20 Unknown Lactobacillus Lactobacillaceae Lactobacillales Anaeroplasmataceae SCFA acetate change abundance of Bacteroidetes phyla in NOD mice associated with T1D protection c Bacilli Firmicutes Unknown Unknown GenusUnknown order Alphaproteobacteria Proteobacteria Unknown Family Unknown Anaeroplasma Anaeroplasmatales Mollicutes Tenericutes 1 bacillus Anaeroplasma Unclassified Oscillospira ( % ) Diabetes-free NP.FT.FT.FT.FT * Eubacterium Clostridium Ruminococcus Age (weeks) Dehalobacterium

21 Summary Summary of mechanisms Improvements to gut homeostasis/integrity Effects on Treg biology Effects on co-stimulatory molecules on B cells/dcs Decreased autoimmune T effector numbers Changes in gut microbiota composition

22 AhR ARNT Western lifestyle diet Hygiene? Antibiotic use? Microbiota composition Metabolites and disease HDAC inhibition Asthma Fatty liver acetate propionate butyrate Omega-3 fatty acids Transcription factors IL-22 CYP1 enzymes Metabolite sensing by GPCRs IBD Type 1 diabetes Food allergies Tan et al Annual Review Immunol 217 Dysbiosis Leaky gut LPS distribution Cell shape/ motility Ga Gg Gb PI3K b-arrestin2 Cardiovascular Inflammasome activation MAP kinases PKC mtor TAK NF-kB Inhibition of inflammatory cytokines Neural conditions

23 Acknowledgements Prof Charles Mackay James Richards Keiran McLeod Yu Anne Yap