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gut microbiomes AND Type 2 diabetes.pptx
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- 2. Microbial community inhabitingthe human intestine
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- 6. Microbes are OMNIPRESENT Millionsof microbes per square inch of our body If we weigh DNA in human body, 54% microbial and 46% human
- 7. Microbiome differs throughoutthe GI tract
- 8. COMPOSITION Insights Into theRole of the Microbiome in Obesity and Type 2 Diabetes Annick V. Hartstra, Kristien E.C. Bouter, Fredrik Bäckhed and Max Nieuwdorp Diabetes Care 2015 Jan; 38(1): 159-165
- 9. CTORS AFFECTING GUTMICROBIOME • Prenatal events • Host genetic make up • Delivery methods • Infant feeding • Duration of lactation • Complementary foods • Geographical location • Environmental factors • Antibiotic use • Dietary pattern Pollution Pharmaceuticals Microbial exposures Psychological status Diet Stress Commensals Pathobionts Host genetics
- 10. SYMBIOSIS • Shelter • Nutrition •Growth TO MICROORGANISM TO THE HOST • Stimulates immune function • Produces antimicrobial substances
- 11. Dysbiosis “Abnormal microbial colonizationof the intestine where changes in quantity and quality of flora become pathological and harmful” Change in bacterial composition Decreased abundance and diversity
- 13. Dysbiosis ⬇ Short chainfatty acid production ⬇GLP1 secretion ⬆ Low-grade inflammation Diabetes mellitus pathogenesis Contributing factors Western diets Antibiotics Microbial exposure 📩 📩 📩
- 15. AT A GLANCE Wombto Tomb
- 17. EXTERNAL INFLUENCES HEALTHINTERNAL HOST PROPERTIES Diet Prebiotics Probiotics Antibiotic usage Illness Lifestyle Living environment Density Diversity Activity Ageing Genetics Stress Physiologic processes Digestive tract: Anatomy Digestive tract: Physiology DISEASES
- 19. • the elucidationof the molecular mechanistic pathway • on the role of gut microbiota in the gut-brain axis is not • moving forward as expected. • This is because the elucidation of the molecular mechanistic pathway of gut microbiota in the gutbrain axis depends on precise high throughput identifi cation of the microbial organisms constituting gut microbiota. Although there were some techniques utilized to identify microbial organisms constituting gut microbiota, current technological • advances make the high-throughput identifi cation of individual • microbial components of gut microbiota possible. • Especially, the advent of next-generation sequencing (NGS) has enabled • the metagenomic and meta-transcriptomic analysis for high • throughput identification of microbial organisms constituting • gut microbiota
- 20. • Human gutmicrobiome is dominated by four phyla: • Firmicutes • Bacteroidetes • Proteobacteria • Actinobacteria
- 21. ROLE IN HEALTH •Regulation of digestive processes including GI motility, secretion,absorption and blood flow • Regulation of food intake & glucose metabolism • Modulation of the gut-associated immune system • Synchronization of physical and emotional states impacting on the GI tract.
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- 23. IDENTIFYING THE MICROBIOME TOOLS: •Initially culture based- < 1% culturable • Gene Sequencing Based- Next Generation Sequencing Biomarker sequencing (16S rRNA gene) Metagenomics/transcriptomics • Protein Based: LCMS Metaproteomics/Metabolomics The Human Intestinal Microbiome in Health and Disease Susan V. Lynch, Ph.D., and Oluf Pedersen, M.D., D.M.Sc N Engl J Med 2016;375:2369-79
- 24. Gut Microbiome AndDiseases ENVIRONMENTAL FACTORS CHANGES IN *Microbial composition *Metabolism *Functional gene transcription Altered Host exposure and response to antigens INCREASED DISEASE RISK
- 25. Gut Microbiota asa Target in the Pathogenesis of Metabolic Disorders: A New Approach to Novel Therapeutic Agents Ejtahed H-S et al. 2016 Horm Metab Res
- 26. Obesity • Impaired energyhomeostasis Significantly lower • Akkermansia muciniphyla • Faecalibacterium prausnitzii • Bacteroides/Prevotella group • Candida spp., and Saccharomyces spp.
- 27. • Regulation offasting-induced adipose factor (FIAF) expression • FIAF - protein produced by enterocyte • Inhibits lipoprotein lipase (LPL) • Unbalanced gut microbiota suppress FIAF • Increase LPL activity and triglyceride accumulation in adipose tissue
- 28. MECHANISM • Increased systemiclipopolysaccharide • Changes in bile acid metabolism • Alterations in short chain fatty acid (SCFA) production • Alterations in gut hormone secretion • Changes in circulating branched chain amino acids
- 29. Mechanisms Linking theGut Microbiome and Glucose Metabolism Kristina M. Utzschneider, Mario Kratz, Chris J. Damman, and Meredith Hullarg J Clin Endocrinol Metab 101: 1445–1454, 2016
- 30. The “Leaky Gut”Hypothesis and Endotoxemia • LPS- endotoxin- gram negative bacteria • Stimulate inflammation via TLR-4 and TGF beta activation ------ sepsis • Higher systemic LPS / LPS binding protein • Low-grade, chronic inflammation • Obesity, Metabolic syndrome and T2DM.
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- 32. QUALITATIVE • Highly conservedinner region – Lipid A • Subtle changes such as Differential phosphorylation • Increase in affinity of LPS to TLR 4 Receptors
- 33. • LPS canbe taken up by gut epithelial cells • Incorporated into chylomicrons in the small intestine after a high-fat meal. • Lps contains a lipid moiety Taken up by enterocytes and transported to the golgi apparatus , where chylomicrons are also formed
- 34. GUT MICROBIOME &PERMEABILITY • Probiotics (Streptococcus thermophilus/ Lactobacillus acidophilus) • Prevented increases in permeability induced by TNF or gamma IFN • In mouse models, high-fat feeding leads to dramatic changes in the gut microbiota, glucose intolerance, insulin resistance, increased plasma LPS, intestinal permeability, inflammation, and oxidative stress.
- 36. GUT MICROBIOME &BILE ACID METABOLISM Gut microbial composition can alter the amount and type of secondary bile acids Bacterial enzymes and genes involved in the deconjugation (bile salt hydrolase), dehydroxylation and epimerization of bile acids are distributed across many genera Reduced abundance of Gut microbial bsh genes observed in individuals with t2dm compared to healthy controls
- 37. Effects of BileAcid Metabolites on Glucose Homeostasis
- 38. • Farnesoid Xreceptor is expressed in the ileum, liver, and pancreas • ILEUM: • FGF-19-affects glucose tolerance through mechanisms that are largely independent of insulin . • Activation of TGR5 leads to production of GLP-1
- 39. Pancreas: • Insulin transportand secretion • Protect islets against lipotoxicity • LIVER: • Improves insulin sensitivity via shp-and sterol regulatory element binding protein-1c (srebp-1c)-dependent mechanisms
- 40. Role of ShortChain Fatty Acids (SCFAs) • Bacteria in the colon ferment nondigestible carbohydrates into SCFAs, with acetate, butyrate, and propionate • Interplay between dietary fiber content, microbiota and SCFAs • SCFAs are also produced during amino acid catabolism by gut bacteria • 17–38% of the SCFA produced in the cecum and sigmoid/rectum from proteins
- 41. SCFA - Functions Butyrate: energy source for colonocytes Propionate: substrates for lipogenesis and gluconeogenesis Acetate: substrate for peripheral cholesterol synthesis Stimulate fatty acid oxidation Inhibit de novo lipogenesis Signalling molecules by activating AMP kinase and free fatty acid receptors 2 and 3 Regulate secretion of gut hormones-GLP-1& anorectic hormone peptide YY (PYY)
- 42. • Butyrate hasreceived increased focus as a potential beneficial intermediary. • Butyrate producing bacteria are less abundant in subjects with T2DM • Butyrate supplementation improves insulin sensitivity
- 44. SCFA + SCFAreceptors L cells GLP 1 and Peptide YY Promote satiety Glucose mediated insulin secretion
- 45. Microbial Synthesis ofAmino Acids • Branched chain amino acids contribute to Obesity and Insulin resistance. • Certain species of gut bacteria can synthesize Branched chain aminoacid s. ISOLEUCINE, LEUCINE, VALINE, TYROSINE & PHENYLALANINE
- 46. Flora in Diabetes •Decrease in: • Bifidobacterium • Faecalibacterium prausnitzii • Firmicutes-related bacteria • (Eubacterium rectale and Blautia coccoides)
- 47. T1DM and GutMicrobiome
- 48. MECHANISMS… • Increased intestinalpermeability • Alteration of microvilli • Leakiness of tight junctions • Increased expression of HLA D related DP subregion • Intercellular adhesion molecule-1-villi/crypt • Enhanced antigen presentation
- 49. Ongoing cohort studies… •DiPP = Diabetes Prediction and Prevention Project • DIABIMMUNE = Pathogenesis of Type 1 Diabetes – Testing the Hygiene Hypothesis • TEDDY = The Environmental Determinants of Diabetes in the Young study • ENDIA = Environmental Determinants of Islet Autoimmunity Clin Exp Immunol. 2014 Jul; 177(1): 30–37. The intestinal microbiome in type 1 diabetes J L Dunne et al.
- 50. Differences PROPERTY SEROCONVERTED SUBJECTS HIGH-RISK CONTROL SUBJECTS Dominantphylum Bacteroidetes Firmicutes SCFA producers Succinate, acetate Butyrate Bacterial diversity Low High Functional diversity Low High Genus differences Bacteroides Bifidobacterium Clostridium Faecalibacterium Veillonella Lactobacillus Community stability Low High De Goffau MC, Luopajärvi K, Knip M, et al. Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes. 2013;62:1238–1244.
- 51. • Variation inGut Microbiota • 57% by Dietary change • 12% by Genetic change • PREBIOTICS • Dietary Change • PROBIOTICS
- 52. PREBIOTICS • A prebioticis an ingredient that its fermentation leads to beneficial changes in the gut microbiota • Short chain inulin-type fructans, oligofructose or wheat-derived arabinoxylan oligosaccharides, lactulose, lactitol, galacto-oligosaccharides, fructo- oligosaccharides, inulin, isomalto-oligosaccharides, polydextrose, resistant starch and gums • Rise in Bifidobacterium spp.
- 53. PREBIOTICS • Trophic effecton the intestine & redistribution of occludin and zonula occludens • Prebiotic treatment changes 102 gut bacterial taxa, & abundance of 25 taxa • Increase in proglucagon-GLP2 Expression • Increase in L-cells in the intestine • Akkermansia muciniphila was increased by approximately 100-fold (inversely correlates with body weight) • Increase in SCFA levels
- 54. PROBIOTICS • Live microorganismsthat their administration In adequate amounts causes health benefits on the host • Lactobacillus, bifidobacterium, saccharomyces,enterococcus, streptococcus, pediococcus, leuconostoc and bacillus
- 55. PREBIOTIC PROBIOTIC 1.Growth of beneficial bacteria 2.Improved insulin sensitivity 3.Decrease in Systemic markers of inflammation
- 56. Fecal microbiota transplantation(FMT) • Transfers intestinal bacteria from a healthy donor into a patient • Important “physiologic” factor in the prevention & treatment of metabolic dysregulation • Improving the obesity, insulin resistance, & metabolic syndrome Vrieze A et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143: 913.e7–916.e7
- 57. Metformin & GutBrain Axis • Activates GLP-1 receptors • Increase protein kinase A (PKA) activity • Intestinal vagal afferents • NMDA receptors - nucleus of the solitary tract (NTS) • Onward signalling to the efferent Fibres of the hepatic vagal nerve • Reduction in hepatic glucose production.
- 58. Metformin & GutMicrobiome • Metformin - Decrease in the bacterial diversity of microbiome. • Marked increase in Akkermansia muciniphila • Increase in mucin-producing goblet cells & endocannabinoids Reduce inflammation Modify gut peptide secretion Improve the thickness of the gut mucus barrier ACARBOSE…. Metformin and the gastrointestinal tract Laura J. McCreight & Clifford J. Bailey & Ewan R. Pearson Diabetologia (2016) 59:426–435
- 59. CHALLENGES… • Majority ofmicrobiome not cultivable • Long term prospective cohort studies to define causative process • Use of intestinal biopsy and genomic sequencing rather than fecal samples
- 60. • Gut microbiotais an “invisible organ” of the human body • Vital for normal metabolism and immuno-modulation • The number and diversity of microbes differ across the gastrointestinal tract from the mouth to the anus, and is most abundant in the intestine.
- 61. Anti diabetic drugs •1. Therapeutic efficacy and potential side effects--influenced by resident microbiota • 2. Antidiabetic drugs alter GM composition
- 62. microbial shift increasingSCFAs concentration enhanced the presence of Bifidobacterium Mlongum and reduced LPS levels.
- 63. • 1. VOGLIBOSE=decreased Firmicutes to Bacteroidetes ratio • Lactobacillus, Faecalibacterium, • and Dialister up-regulation Butyricicoccus, Phascolarctobacterium, and Ruminococcus Reduction • 2. Increase in SCFA • 3.Decrease in LPS
- 64. • sitagliptin andvildagliptin, modulate GM. • they restore the GM composition increasing the abundance of Bacteroidetes • liraglutide administration promoted the • expression of SCFA producing bacteria. • SGLT2 inhibitors-no change in GM
- 65. METFORMIN • therapeutic effectsare mediated by the GM • strengthening of tight junction • there are indeed specific microbiotic clusters able to • predict the efficacy of metformin therapy in diabetic • Patients • an increased presence of Prevotella copri appears • to limit the ability of reducing glycated hemoglobin • (HbA1c) • Similarly, an increased presence of Streptococcus parasanguinis before starting antidiabetic • treatment is predictive of metformin-associated side-effects • associated with a higher production of SCFAs
- 66. • the differentefficacy achieved by a given nutritional intervention in different enterotypes confirms the hypothesis that • everyone should be offered a personalized strategy,‘tailor-made’ according to the composition of her/his • microbiota.
- 67. Effects of exercise HIGHINTENSITY • dysbiosis • “exerciseinduced gastrointestinal syndrome” impacts on its composition, MODERATE INTENSITY • Increasing Akkermansia muciniphila • and Oscillospira • Increase in SCFAs and lactic acid-production
- 68. PRE VS PROBIOTICS DOTHEY IMPROVE GLYCEMIC CONTROL? • Lactobacillus and Bifidobacterium strains, can also improve lipid profile and reduce fasting glycaemia • Akkermansia muciniphila CAN regenerate • the intestinal barrier, reduce inflammation, and improve metabolic processes. • this strategy only can be adjuvant and not curative itself.
- 69. PRE BIOTICS • Complexcarbohydrates, polyphenols, and polyunsaturated Fas • increase stool consistency and can be fermented to SCFAs. • For example, oligo-fructose has • shown positive effects on glucose homeostasis, inflammation,leptin sensitivity, GLP-1 production, • Berberine, resveratrol,alliin, capsaicin, betacyanin, and cranberry proanthocyanins have also shown antidiabetic effects
- 70. Diabetes and fecalmicrobiota transplantation (FMT) • the transfer of stools from a healthy donor into another subject’s gastrointestinal • tract, aiming to change the recipient’s GM • gaining health benefit • Currently successful for for recurrent and • refractory Clostridium Difficile Infection (CDI)
- 71. • FMT maynot only improve insulin • Sensitivity • alter the natural course of type I • diabetes by modulating autoimmunity.
- 72. • success ofmicrobial modulation • depends on the tested strains, on its composition • and diversity, on the patients pre-existing microbial diversity • and his genetic fingerprint. However, there are • some risks related to FMT that should be taken into • account. Major concerns regard the transfer of infectious • disease or the promotion of dysbiotic status which • could promote the development of disorders linked to • GM
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