Microbiome Diabetes Obesity. Ruchi Mathur MD FRCPC Cedars Sinai Medical Center Sept 2016

Transcription

1 Microbiome Diabetes Obesity Ruchi Mathur MD FRCPC Cedars Sinai Medical Center Sept 2016

2 Maybe next time. Type 1 diabetes Microbiome, Brain, Gut Bariatrics Nutrition beyond emulsifiers

3 Chronic Complications of Diabetes

4 Currently there are 30 million people in the US with diabetes An additional 80 million Americans have pre-diabetes that s over 35% of the adult US population Diabetes affects over 380 million people world wide In the US (2015) Total (direct and indirect) costs for diabetes-related illness and care: $320 billion Source: International Diabetes Federation

5 Natural History of Type 2 Diabetes Plasma Glucose Postmeal glucose 126 mg/dl Fasting glucose Relative -Cell Function Insulin resistance Insulin secretion Years of Diabetes TYPE 2 DIABETES... A PROGRESSIVE DISEASE Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota.

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7 Alpha-Glucosidase Inhibitors Precose (Acarbose) Glyset (Miglitol) Amylin Analog Symlin (Pramlintide) Combination Products (13) Glipizide/Metformin Glyburide/Metformin Pioglitazone/Glimepiride Pioglitazone/Metformin Repaglinide/Metformin Rosiglitazone/Glimepiride Rosiglitazone/Metformin Saxagliptin/Metformin Sitagliptin/Simvastatin Sitagliptin/Metformin Linagliptin/Metformin Alogliptin/Metformin Alogliptin/Pioglitazone Currently Available Agents (U.S) Dipeptidyl peptidase-4 inhibitor (5) Onglyza (Saxagliptin) Januvia (Sitagliptin) Galvus (Vildagliptin) Tradjenta (Linagliptin) Nisina (Alogliptin) Dapaglflozin GLP1-Agonist Victoza (Liraglutide) Byetta (Exenatide) Bydureon Meglitinides Starlix (Nateglinide) Prandin (Repaglinide) Sulfonylurea (5) Chlorpropamide Amaryl (Glimepiride) Glucotrol (Glipizide) Diabeta (Glyburide), Glynase Biguanides Metformin Riomet Glumetza TZD Avandia(Rosiglitazone) Actos (Pioglitazone) Insulin (14) Novolog (Aspart) Novolog 70/30 Levemir (Detemir) Lantus (Glargine) Apidra (Glulisine) Humulin N, Novolin N Humulin70/30, Novolin 70/30 Humalog (Lispro) Humalog50/50, 75/25 Humulin R, Novolin R Tujeo Degludec SGLT2 inhibitors Canagliflozin/Invokana Dapagliflozin/Fargixa Empagliflozin/Jardiance Other Cycloset (bromocriptine) Welchol Tolazamide

8 Alpha-Glucosidase Inhibitors Precose (Acarbose) Glyset (Miglitol) Amylin Analog Symlin (Pramlintide) Combination Products (13) Glipizide/Metformin Glyburide/Metformin Pioglitazone/Glimepiride Pioglitazone/Metformin Repaglinide/Metformin Rosiglitazone/Glimepiride Rosiglitazone/Metformin Saxagliptin/Metformin Sitagliptin/Simvastatin Sitagliptin/Metformin Linagliptin/Metformin Alogliptin/Metformin Alogliptin/Pioglitazone Currently Available Agents (U.S) Dipeptidyl peptidase-4 inhibitor (5) Onglyza (Saxagliptin) Januvia (Sitagliptin) Galvus (Vildagliptin) Tradjenta (Linagliptin) Nisina (Alogliptin) Dapaglflozin GLP1-Agonist Victoza (Liraglutide) Byetta (Exenatide) Bydureon Meglitinides Starlix (Nateglinide) Prandin (Repaglinide) Sulfonylurea (5) Chlorpropamide Amaryl (Glimepiride) Glucotrol (Glipizide) Diabeta (Glyburide), Glynase Biguanides Metformin Riomet Glumetza TZD Avandia(Rosiglitazone) Actos (Pioglitazone) Insulin (14) Novolog (Aspart) Novolog 70/30 Levemir (Detemir) Lantus (Glargine) Apidra (Glulisine) Humulin N, Novolin N Humulin70/30, Novolin 70/30 Humalog (Lispro) Humalog50/50, 75/25 Humulin R, Novolin R Tujeo Degludec SGLT2 inhibitors Canagliflozin/Invokana Dapagliflozin/Fargixa Empagliflozin/Jardiance Other Cycloset (bromocriptine) Welchol Tolazamide

9 Prevalence of Obesity and Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0% Diabetes No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% CDC s Division of Diabetes Translation. United States Surveillance System available at

10 Why Would We Evolve This Way? An Evolutionary Perspective: When Weight Gain was a Good Thing Think thrifty gene hypothesis Enhanced nutrition = Enhanced survival Enhanced storage = Enhanced survival

11 Environmental Genetics Cultural GI MICROBES OBESITY (600 million) DIABETES (380 million) Psychological Social Meds Psychiatric

12 Conventionalization and Energy Uptake CONV-R: Conventionally acquired microbiota (conventionally raised) CONV D: Colonized with cecal content from conventional donor mice Backhed et al Proc Natl Acad Sci USA 101 (44) 2004

13 2004 by National Academy of Sciences Bäckhed F et al. PNAS 2004;101:

14 FMT from adult female twin pairs discordant for obesity into germ-free mice Increased total body weight and fat mass Phenotype is transmissible Science 2013 Sept 341 (6150)

15 How do our microbes help us with energy harvest? Intestinal health: Enhanced capillary density and villus integrity. Effects on transit. Bile acids: Influencing the ratio of enterohepatic circulation and effects on FXR and TGR5 signaling pathways Mediation of inflammation resulting in insulin resistance (Cani 2008) Suppression of fasting induced adipocyte factor resulting in increased lipoprotein lipase and cellular uptake of FFA and TG accumulation in adipocytes (Backhed 2004) Degradation of undigested dietary fiber to SCFA (acetate, propionate and butyrate) which become substrates for lipogenesis and gluconeogesis (Backhed 2006) Influence via SCFA on the secretion of GLP-1 and PYY

16 What are the postulated microbial factors involved in developing diabetes and obesity? 1) An overall decrease in richness and diversity

17 Le chatelier Nature vol 500 Aug 2013

18 What are the postulated microbial factors involved in developing diabetes and obesity? 1) An overall decrease in richness and diversity 2) Ratio of Firmicutes to Bacteroidetes

19 Germ Free -Low body weight -Increased oral intake + = Add Fecal Flora (Bacteroidetes>Firmicutes) Gain weight with reduced oral intake Germ Free -Low body weight -Increased oral intake + = Add Fecal Flora from Obese mice (Firmicutes>Bacteroidetes) Far greater weight gain Turnbaugh Nature 444, (21 December 2006)

20 Ob/Ob mice have lower levels of Bacteroidetes and higher Firmicutes than wildtype Ley et al Proc Natl Acad Sci 2005;102(31) Obese humans also have lower levels of Bacteroidetes than lean subjects. Bacteroidetes levels increased with weight loss (despite type of diet) Ley et al Nature 2006; 444(7122) RYGB results in lower Firmicutes and higher Bacteroidetes then prior to surgery Li et al Gut 2011; 60(9) 1214 Similar results were seen in rats post RYGB compared to sham Liou et al Sci Transl Med 2013; 5(178) More recently this has been called into question

21 Composition of stool in obese subjects compared to non-obese showed no difference in bacterial numbers or percentage of total fecal bacteria present as Bacteroidetes when on a weight maintenance diet Hold 2002, Eckberg 2005 There were no overall changes in the percentage of Firmicutes in the stool when on a weight loss diet, although within the phylum there were reductions in butyrate producers Duncan 2008

22 Schwiertz et al noted that the ratio of Firmicutes and Bacteroidetes changed in favor of Bacteroidetes in overweight (P=0.001) and obese (P=0.005) subjects.which contradicts the expected Schwiertz A et al Obesity ,

23 What are the postulated microbial factors involved in developing diabetes and obesity? 1) An over all decrease in richness and diversity 2) Ratio of Firmicutes to Bacteroidetes 3) The role of infant microbial exposure and colonization

24 We know that diet-induced maternal obesity can often result in offspring that are growth restricted These offspring often overcompensate and become hyperinsulinemic with elevated leptins and insulin resistance These effects are magnified with high fat feeding The fundamental link (?epigenetic?) between maternal and infant obesity is unclear We now know that the placenta, amniotic fluid and cord blood all exhibit microbial colonization and that meconium itself is not sterile Could maternal colonization in pregnancy influence fetal and infant development of obesity and insulin resistance?

25 91 pregnant women of varying prepregnancy BMIs and gestational diabetes status and their infants Gut microbiota changed dramatically from first (T1) to third (T3) trimesters: Expansion of diversity between mothers in T3 Overall increase in phylae Proteobacteria and Actinobacteria Koren et al Cell 2012 Aug 3;150(3)

26 When transferred to germ-free mice: T3 microbiota induced greater adiposity and insulin insensitivity compared to T1?Adaptive Koren et al Cell 2012 Aug 3;150(3)

27 436 mother-child dyads followed for 7 years Prenatal ab use by questionnaire administered in the late 3 rd trimester Delivery mode documented Z scoreobesity BMIs > 95 %tile Muller et al Int J Obes (Lond) April ; 39(4):

28 Compared with children not exposed to antibiotics during the second or third trimester, those exposed had 84% higher risk of obesity, after multivariable adjustment Second or third trimester antibiotic exposure was also positively associated with BMI, waist circumference and % body fat

29 What are the postulated microbial factors involved in developing diabetes and obesity? 1) An over all decrease in richness and diversity 2) Ratio of Firmicutes to Bacteroidetes 3) The role of infant microbial exposure 4) Dietary influences on the microbiome

30 Rice Cereal Solids Table food Adult diet Microbial species Breast milk 2011 by National Academy of Sciences Koenig J E et al. PNAS 2011;108:

31 Carboxymethylcellulose or polysorbate-80 added to the drinking water of mice for 12 weeks Hypothesis: Emulsifiers disrupt mucosal/microbial interactions and promote inflammation that can lead to metabolic syndrome Both are FDA approved as food additives Effects reported were seen in young (4 weeks) as well as older (4 months) mice Chassaing Nature 519, March 2015

32 Emulsifier-induced low-grade inflammation and metabolic syndrome parameters require the presence of gut microbes Administration of emulsifiers to germ-free mice resulted no significant changes in metabolic syndrome parameters including: Body mass Fat Mass Food intake Fasting glucose levels Chassaing Nature 519, March 2015

33 C57BL/6 mice Group 1: Control (saline gavage) Group 2: Polysorbate 80 1% NS gavage 4 weeks In addition P-80 fed mice showed: Increased levels of bioactive LPS Increase myeloperoxidase enzyme activity Reduction in acetate, propionate and butyrate concentrations in fecal samples Singh RK et al SOJ Microbiol Infect Dis (1)

34 What are the postulated microbial factors involved in developing diabetes and obesity? 1) An over all decrease in richness and diversity 2) Ratio of Firmicutes to Bacteroidetes 3) The role of infant microbial exposure 4) Dietary influences on the microbiome 5) Enhanced presence of methanogens

35 Methanogen Model - Syntropic Effect Host Indigestible Substrate Host Indigestible Substrate Methanobrevibacter smithii H 2 Intoxicates self H 2 H 2 H 2 H 2 CH 4 Digestible Substrates for Host = Syntroph = Methanogen Digestible Substrates for Host

36 Mathur et al. Research Journal of Endocrinology and Metabolism 2014,

37 Methane in Obese Patients N=58 No Methane on breath (n=46) Positive Methane on breath (n=12) P-value Age (yrs) Height (in) Weight (lbs) BMI P= All Subjects No Methane Positive Methane Basseri et al. Gastroenterology & Hepatology 2012, 8:22-8

38 BMI Methane in Non-obese Patients Multivariate analysis controlling for age, sex, diabetes, Anti-depressant and other confounding variable (P<0.001) Normal Breath test N=792 Positive Hydrogen Breath Test Methane Only Methane and Hydrogen Positive Mathur et al. JCEM 2013, 98:E

39 Insulin Sensitivity (SI) estimated using Modified MinMod for OGTT analysis in methane eradicated subjects: Mathur et al. Obesity 2016, 24:

40 Zhang et al PNAS 2009, 106(7):

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42 What are the postulated microbial factors involved in developing diabetes and obesity 1) An over all decrease in richness and diversity 2) Ratio of Firmicutes to Bacteroidetes 3) The role of infant microbial exposure 4) Dietary influences on the microbiome 5) Enhanced presence of methanogens 6) Antibiotics

43 Percent body fat: STAT and Control STAT= Subtherapeutic antibiotic treatment (Infant pigs) The use of STAT promotes absolute growth and improved feed efficiency and the ability to convert food calories into body mass The effects were see across animal species- chickens, pigs and cattle The younger in life the agents were started- the profound the effects on both growth and efficiency Blaser, M. (2011), "Disappearing microbiota and human metabolic health", in Finlay, B. (ed.), Microbiota: Agents for Health and Disease, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at

44 Percent body fat: STAT and Control (mice) Blaser, M. (2011), "Disappearing microbiota and human metabolic health", in Finlay, B. (ed.), Microbiota: Agents for Health and Disease, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at

45 All children with annual visits at ages 0 to 23 months, as well 1 or more visits at ages 24 to 59 months, were enrolled. The cohort comprised 64,580 children from the Philadelphia area Bailey et al JAMA Pediatr. 2014;168(11):

46 Bailey et al JAMA Pediatr. 2014;168(11):

47 Retrospective cohort study using data collected prospectively in the scope of routine care from 1995 to 2013 (UK) Scott FI et al Gastroenterology 2016;151:

48 Nested case control study using a large populationbased database from the UK. The cases were defined as those with incident diagnosis of diabetes For every case, four eligible controls matched on age, sex, practice-site, and duration of follow-up before index-date were selected using incidence-density sampling Exposure of interest was antibiotic therapy 1 year before index-date Boursi et al European Journal of Endocrinology (2015) 172,

49 diabetics controls OR 1.15 for 2-5 courses and 1.37 for > 5 courses of quinolones

50 Higher adjusted risk for type 2 diabetes among individuals with recurrent exposures to: penicillin cephalosporins macrolides quinolones Risk increases with number of exposures There was no increase in adjusted risk for exposure to antiviral or antifungal medications

51 Retrospective longitudinal study in US >35 weeks gestational age Normative birth parameters No chronic illness, no steroids Pediatric follow up Specifically looking at systemic antibiotic exposure in the first 6 months Outcomes were measured up to 7 years Gerber et al JAMA (12)

52 Exposure to antibiotics within the first 6 months of life compared with no exposure was not associated with a statistically significant difference in weight gain through age 7 years This was true in singleton exposure as well as discordant twin exposure Adiposity not measured

53 What are the postulated microbial factors involved in developing diabetes and obesity 1) An over all decrease in richness and diversity 2) Ratio of Firmicutes to Bacteroidetes 3) The role of infant microbial exposure 4) Dietary influences on the microbiome 5) Enhanced presence of methanogens 6) Antibiotics

54 Final thoughts Diabetes and obesity are pandemics- intimately linked in part by the thread of insulin and insulin resistance The numbers continue to rise despite awareness and interventions Multiple factors contribute to these diseases of which the microbiome is one (newly noted) player Our microbiome developed with us throughout evolution and assists us in energy harvest and thus in survival The mechanisms by which the microbiome affect our metabolism are multiple

55 Perturbations and manipulations of the microbiome can effect our metabolic balance...it goes beyond F:B and includes many other microbial players including Archaea The effect of the microbiome on metabolism can occur as early as in utero (?epigenetics) There is a well honed precedence in animals showing manipulations via antibiotics can cause weight gain and fat accumulation There is a growing body of human literature showing the same findings Details about all these proposed mechanisms remain elusive

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