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Meghan JardineMS, MBA, RDN, LD, CDEAssociate Director of Diabetes Nutrition EducationPhysicians Committee for Responsible MedicineDallas, TX

Disclosure to Participants• Notice of Requirements For Successful Completion

– Please refer to learning goals and objectives– Learners must attend the full activity and complete the evaluation in order to claim continuing

education credit/hours

• Conflict of Interest (COI) and Financial Relationship Disclosures:– Meghan Jardine, MS, MBA, RDN, LD, CDE – No COI/Financial Relationship to disclose

• Non-Endorsement of Products:– Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products

displayed in conjunction with this educational activity

• Off-Label Use:– Participants will be notified by speakers to any product used for a purpose other than for which it was

approved by the Food and Drug Administration.

Gut Check! The Microbiota’s Role in Obesity and Diabetes• Overview of the human microbiota• Diseases associated with dysbiosis• Nutrition and lifestyle

The Microbiota• Microbial population living in a specific environment• Symbiotic relationship with the host • The human microbiome has evolved

Mullard A, Nature 2008 May 29;453:578-80.Gut Microbiota Worldwatch http://www.gutmicrobiotawatch.org/gut-microbiota-info/

The Microbiota (cont.)

• At least 1,000 different known species• Weight = 2 to 3 kg• 1/3 is common to most humans• 2/3 is unique to each individual• The microbiome – the combined genetic

make up

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The Microbiota Composition/Activity Depends on:• Nutrition• Exercise• Stress• Genetics• Smoking• Pollution

• Travel• Geography• Circadian

disorganization• Medications

Conlon et al. Nutrients. 2015;7:17-44.

Core Functions of the Microbiome• Digest and absorb nutrients• Synthesize of vitamins and amino acids• Prevent pathogenic colonization• Regulate immune function• The metabolites released depends on nutrition• Modulate of GI hormone release• Regulate mood and behavior

Kristensen et al. Genome Med. 2016;8:52.Brown et al. Nutrients. 2012;4:1095-1119.

The Development of the Microbiota• Vaginal delivery vs. C-section

• 1996 1 in 5• 2011 1 in 3

• Breast milk• Formula fed babies lack bifidobacteria• Species stabilized by age of three• Communities evolve throughout the lifecycle

Mullard A, Nature 2008 May 29;453:578-80.Gut Microbiota Worldwatch http://www.gutmicrobiotawatch.org/gut-microbiota-info/Moreno-Indias I, et al. Front Microbiol. 2014;5:1-10.Blaser, Martin. Missing Microbes. New York: Henry Holt and Company, LLC. 2014. Print.

Hygiene • Our microbiota trains the immune system• Healthy tissues might be attacked:Nerves (MS) Intestines (Crohn’s disease, Celiac)Pancreas (T1D)Systemic (Rheumatoid arthritis, Lupus)

Gut Check: Exploring Your Microbiome (Coursera):https://www.coursera.org/learn/microbiome Allin, et al. Gut microbiota in patients with type 2 diabetes mellitus. http://www.ncbi.nlm.nih.gov/pubmed/25416725

Antibiotic Use• 5-day course of antibiotics modifies

microbiota• Antibiotics and obesityBabiesAdults

• Environmental exposure to antibiotics

Gut Check: Exploring Your Microbiome (Coursera):https://www.coursera.org/learn/microbiome Allin, et al. Gut microbiota in patients with type 2 diabetes mellitus. Moreno-Indias I, et al. Front Microbiol. 2014;5:1-10Riley, et al. Front Public Health. 2013;1:69

Obesity Prevalence 2010Antibiotic Rx per 1,000 persons

Ventola LC The antibiotic resistance crisis. P&T. 2015;40:277-283CDC Data and Statistics: https://www.cdc.gov/diabetes/data/center/slides.html

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Infectious Diseases have EvolvedHistorical Diseases:• Cholera• Pneumonia• Scarlet fever• Diptheria• Whooping cough• Tuberculosis• Smallpox

Modern Day Diseases:• Obesity• Diarrhea• Diabetes• Atherosclerosis• Nonalcoholic fatty liver disease • Colitis/Crohn’s Disease• Autism• Asthma• Eczema• Multiple sclerosis• Alzheimer’s disease

Gut Microbiota Watch: http://www.gutmicrobiotawatch.org/the-gut-microbiota-you-and-your-100-trillion-friends/Blaser, JB (2014) Missing Microbes. Henry Holt and Company, New York

Major Divisions/Phyla• Firmicutes (60%)– gram positive: largest

comprising 200 genera• Bacteroidetes (15%) – gram negative: 20

genera• Actinobacteria (15%) – gram positive• Proteobacteria (1%) – gram negative

Esteve E, et al. Curr Opin Clin Nutr Metab Care. 2011;14:483-490Shen J, et al. Mol Aspects Med. 2013;34:39-58Tilg H, J Clin Invest. 2011;121:2126-2132Bibiloni R, et al. Ann Nestle Eng. 2009;67:39-47

Bacteria Associated with T2DMIncrease in T2DM Decrease in T2DM

Firmicutes XBacteriodetes XRoseburia XEubacterium hali XFacalibacterium prauznitzii XLactobacillus grasseri XStreptococcus mutans XE. coli X

Hartstra et al. Diabetes Care.38:159-165

Obese/T2DM Microbiome Lean/Healthy Microbiome

↑Firmicutes to Bacteriodetes ratio ↓Firmicutes to Bacteriodetes ratio

Low gene count High gene count

↑Gut permeability ↓Gut permeability

↑ LPS/inflamma on ↓ LPS/anti-inflammation

↓ FA oxidation ↑FIAF/AMPK activity

↑ lipogenesis ↓ lipogenesis

↓ Butyrate production ↑Butyrate produc on

↓ Incretin secretion ↑Incretin secretion

Dysbiosis vs. Healthy Microbiome

Esteve E, et al. Curr Opin Clin Nutr MetabCare. 2011;14:483-490Tilg H, J Clin Invest. 2011;121:2126-2132Bibiloni R, et al. Ann Nestle Eng. 2009;67:39-47

Immune System and Microbiota• 70-90% of immune system is in the

intestines.• Activated immune system leads

inflammation:– Metabolic syndrome (DM, CAD, NAFLD)– Aging (dementia, cancer)

Conlon, et al. Nutrients 2015;Hakanson et al. Nutrients. 2011;3:637-682.Boulange et al. Genome Medicine. 2016;8:42

Gut Barrier DysfunctionHypothesis:

• High-fat diet leads to ↑ gut barrier permeability due ↑ bile secretion– Antimicrobial effects– ↑gram negative bacteria (Enterobacteriaceae, Bacteroides)– Strong detergent

• Allows Bacteria and lipopolysaccharide (LPS) to enter the host (Bacteroides)

• Triggers inflammatory responses• Healthy bacteria – improves gut barrier, stabilizes the

immune response; reduces inflammationCani AE, et al. Best Practice & Research Clinical Gastroenterology. 2013;27:73-83Picture: http://sanjosefuncmed.com/wp-content/uploads/2013/05/tight-junction-intestinal-permeabili ty.gif

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LipogenesisOxidative Stress

↑ fatty acid storage in adipocytes

↑ LPS and insulin resistance

↓FA oxidationd/t ↓ AMPK activity

HFD ↑ gut permeability

Proposed Mechanisms for Insulin Resistance and Obesity

Monosaccharides and SCFA

• ↑ Energy Harvest• ↑ FA storage• ↓ Mitochondrial activity• ↑ Endotoxemia (Insulin Resistance)

Type 1 Diabetes• Incidence increasing worldwide• Current evidence is not sufficient to determine if dysbiosis

causes T1DM• Dysbiosis in T1DM:

– Low genetic diversity– Less butyrate producing bacteria– Higher ratio of phyla Bacteriodetes to Firmicutes– Reduced Lactobacillus spp.– Increased intestinal permeability

• Hypothesis: microbial antigens promote T-cells involved in β-cell destruction in genetically susceptible individuals

Brown et al. Nutrients. 2012;4:1095-1119.Knip et al. Nature. 2016;12:154-167. Atkinson, Diabetologia. 2012;55:2868-2877

Factors Associated with Type 1 DiabetesReduced Risk

• Breast feeding• Vaginal delivery• “dirty environment”• Bacterial and parasitic

infection

Increased Risk• Virus Infection• C-section• Hygiene• Stress• Low Vitamin D• Cow’s milk• Gluten

Antvorski et al. Diabetologia. 2014;57:1770-1780Bibbo et al. Ann Med. 2017;49:11-22.

Gut Microbiota• ↓Firmicutes/Bacteriodetes• ↑Bacteroides• ↑Clostridium cluster XIVa• ↑Candida

• ↓Lactobacillus• ↓Bifidobacterium• ↓Prevotella• ↓Butyrate producers

Gut Permeability

Dysbiosis

VirusesParasitesCow’s milkGlutenOthers

Release of pro-inflammatory cytokines

Development of B-cells autoimmunity

T1D Onset• Insulitis• B-cell destruction

T1D Mediated by Microbiota (proposed)

Bibbo et al. Ann Med. 2017;49:11-22.

Microbiota and Aging• Changes in taste, smell, chewing ability

changes nutrient intake:– Higher consumption of sugar, fat– Reduction in vegetables and fruit

• LT care patients have reduced gene diversity• Normal aging: reduced diversity, immunosenescence

Jeffery, et al. Nutrients. 2013;5:234-252.Claesson et al. Nature. 2012;488:178-184

Low Healthy Food Diversity Index Score

• Low gene count• Reduced functionality• Higher Bacteriodes,

Alistipes• Lower Prevotella

Jeffery, et al. Nutrients. 2013;5:234-252.Drescher, et al. J Nutr. 2006;137:647-651.Claesson et al. Nature. 2012;488:178-184

• Increased frailty• Inflammation• Less SCFA production

Associated with

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Microbiota of Semi-SupercentenariansBiagi, et al.• 105-109 year olds • High degree of diversity• Allows for opportunistic bacteria• Harbors symbiotic and health associated

bacteria (Akkermansia, Bifidobacterium, Christensenellaceae)

Biagi et al. Curr Biol 2016;26:1480-1485

Interventions to Improve Microbiota

• Prebiotics• Probiotics• Nutrition• Stress Management • Exercise

What is a Prebiotic?

Dietary fiber: 1. Not digested or absorbed in small intestine2. Fermented by the microbiota3. Stimulate growth of health-promoting species of: Lactobacillus Bifidobacterium Other important species (Ruminococcus bromii, Rosburia

intestinalis, Eubacterium rectale, Faecalibactrium prausnitzii)Krumbeck Cur Opin Gastroenterol. 2016;32:110-119.Slavin J. Nutrients. 2013;5:1417-1435

Prebiotics 100 g prebiotics produces 30 g bacteria Need 5 to 8 g per day Improve gut barrier integrity Increase SCFA production Enhance the absorption of Ca+, Mg, and Fe+ Inter-individual variability in microbial responses.

Slavin J. Nutrients. 2013;5:1417-1435Cani PD, et al. Current Pharmaceutical Design. 2009;15:1546-1558

Prebiotics

BLOOD:↓ LPS levels↓ Inflammation↑ GLP-1 and PYY↓Ghrelin

↑Insulin sensitivity↓Steatosis/lipogenesis

↑fatty acid oxidation

Modulate Gut Microbiota:↑Satiety↓ Food intake

Cani PD, et al. Current Pharmaceutical Design. 2009;15:1546-1558

↑Bifidobacterium and Lactobacillus

Prebiotics• Breast milk• Jerusalem artichoke• Chicory root• Raw dandelion greens• Leeks• Onions• Garlic• Asparagus

• Whole grains• Beans• Green bananas• Wheat• Oats• Soybeans• Psyllium husk

(Metamucil®)

Jardine MA, OTCE. 2015;35:10-14.

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Probiotic Definition: Pro = “for” Bios = “life” Live micro-organisms Colonize Provide health benefits

Bermudez-Brito M, et al. Ann Nutr Metab. 2012;61:160-174

Probiotics

Kills pathogens

SCFA

ReducespHImproves

gut barrier

function

Immune function

↑ Diet Quality

Probiotic Benefits

Kechagia, et al. ISRN Nutr. 2013Beena Divya, et al. Eng Life Sci. 2012;12:377-390

Food Sources of Probiotics• Plant-Based Sources:

– Sauerkraut– Kimchi– Tempeh– Soy sauce– Miso– Water kefir– Sour dough bread– Kombucha

• Dairy-based Sources– Yogurt– Kefir Bermudez-Brito M, et al. Ann Nutr Metab. 2012;61:160-174

Santosa S, et al. Nutr Rev. 2006;64:265-274.

Probiotic Supplements • Often not tested• Generally are considered safe• Look for USP, GMP certifications,• Take probiotic supplements with food• 2 hours before or after antibiotics• Changes may be transient

Probiotics – Typical StrainsGenus SpeciesLactobacillus > 50 species, found mostly in the small intestine

L. acidophillus 0 DDS-1L. caseiL. lactisL. rhamnosusL. salviarius

Bifidobacterium about 30 species, in the colon,

B. longumB. infantisB. bifidum

Sacharomyces (yeast) S. Boulardii (Brewer’s yeast)S. Cervisiae (Baker’s yeast)

Kumar A, Vandana. Int J Nutr Pharmacol Neurol Dis. 2013;3:219-228.

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Probiotics are known to work for:Clinical Condition Specific Strain of Organism/Effectiveness (A-C)

IBS B. infantis B5624, VSL#3 BIBD VSL#3 ADiarrhea Saccharomyces boulardii, L. reuteri SD2112 ANecrotizing enterocolitis

L. acidophilus NCDO1748, B. bifidumNCDO1453 A

Allergies LGG, B. lactis ALiver disease VSL#3 A

Floch, et al. Recommendations for probiotic use. J Clin Gastroenterol. 2015;49:S69-S73.

Probiotics for Diabetes• Samah, et al. systematic review of 6 RCT:Significant reductions in FBG (p<0.00001)A1C changes inconsistentAnti-inflammatory effects are inconsistent

• Future directions:Individualize therapiesSynbiotics – combination of prebiotics and

probiotics

Diabetes Res Clin Pract. 2016;118:172-182.

Plant-Polysaccharides• Indigestible oligosaccharides (soluble

dietary fiber) are fermented by bacteria in colon.

• End products are short chained fatty acids (SCFA):

– Butyrate– Propionate– Acetate Esteve E, et al. Curr Opin Clin Nutr Metab Care. 2011;14:483-490

Shen J, et al. Mol Aspects Med. 2013;34:39-58Tilg H, J Clin Invest. 2011;121(6):2126-2132Bibiloni R, et al. Ann Nestle Eng. 2009;67:39-47

SCFA – a Bidirectional Role• Enhances nutrient absorption.• Stimulates release of gut hormones.• Improve gut barrier integrity.

– Feeds and strengthens colonocytes.– Stimulates mucus production.

• Enhances mitochondrial activity.• Limits inflammation in gut and peripheral tissues.

Allin KH, et al. Eur J Endocrinol. 2015;172:R167-R177Tilg H, et al. Gut. 2014;63:1513-1521.Conlon et al. Nutrients. 2015;7:17-44.

Other Nutrient Induced Changes• Protein:BCFA, nitrosamines, phenols, and volatile sulfur

compounds Increases abundance of bile-tolerant species (Alistipes,

Bilophila and Bacteroides)

• Fat: Increases gut permeabilityDecreases SCFA production

Scott et al Pharmacol Res. 2013;69:52-60.David et al. Nature. 2014;23:559-563.

Intestinal Microbiota and CVD

Nat Med. 2013;19:576-585N Eng J Med. 2013;368:1575-1584

Trimethylamine →Trimethylamine-N-oxide (TMAO) TMAO

increases CVD risk

Carnitine and choline are metabolize to trimethylamine

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Impact of Diet on MicrobiotaDe Filippo et al.• Compared fecal microbiota of and rural 14

African children (BF) 15 European children (EU) (ages 1-6).

• BF diet: cereals (millet, sorghum), legumes (black-eyed peas) and vegetables.

• EU diet: animal protein, sugar, starch, fat, and low in fiber.

• Significant environmental differences.DeFilippo C, et al. PNAS 2010;107:14691-14696

Life in a rural village of Burkina Faso.

Carlotta De Filippo et al. PNAS 2010;107:14691-14696

©2010 by National Academy of Sciences

16S rRNA gene surveys reveal a clear separation of two children populations investigated.

Carlotta De Filippo et al. PNAS 2010;107:14691-14696©2010 by National Academy of Sciences

Burkina Faso Children European Children

↑Bacteroidetes ↑Firmicutes

↑ Prevotella ↑Bacteroides and Alistipes

↑ Gene c diversity ↓ Genetic diversity

↑fecal SCFA produc on ↓fecal SCFA

Summary of Findings

Dietary SwitchO’Keefe et al

• Colon Cancer Risk:Rural Africans: <5:100,000African Americans >65:100,000High animal protein and fatLow fiber (less SCFA production)Higher colonic secondary bile acids

• Rural African fiber intake >50 g/day

O’Keefe et al. Nat Commun. 2015;6:342

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↑ Bile acids

Deconjugation by bacteria

InflammatoryCarcinogenic

↑ Secondary bile acids

14 Day In-house Dietary Switch

• 40 healthy volunteers• African Americans consumed rural African

diet: 41 g fat/day and 55 g fiber/day• Rural Africans consumed the Western diet:

145 g fat/day and 7 g fiber/day

Rural Africans African Americans400% ↑in 2⁰ bile acids 70% decrease 2⁰ bile acids↑ Biophila wadsworthia ↓ B. wadsworthia↑ Biomarkers of colon CA risk ↓biomarkers of risk↓SCFA production ↑SCFA

Authors propose recommended fiber intake >55g/day

Results: Biomarkers of Colon CA risk changed in 2 weeks

Changing the diet can change the composition and metabolic activity of the microbiota.

Nutrition and Microbiota Health • Diet plays a significant role in the composition and

activity of the microbiota • Focus on high-fiber plant foods: Average American consumes 15 grams fiber/day Increase 14 grams fiber/day reduces energy intake by 10% Goal: 25-38 grams of fiber per day Greater than 50 grams of fiber may be therapeutic Ensure servings of prebiotics sources

Dietary Fiber Guide to Enhancing Gut HealthServings Size Total Fiber (grams)

2-3 whole grains 1 oz.1/3 c.

Brown rice, millet, barley, bulgur, buckwheatPrebiotic: whole wheat, oats

6 to 9

1 to 2 legumes ½ c.At least 3/week

Beans, peas, lentils, soy, tofuProbiotic: tempeh

7 to 14

3 to 5 vegetables 1 c. raw2 c. green leafy½ c. cooked½ c. starchy

Prebiotic: leeks, asparagus, Jerusalem artichoke, garlic, onions, dandelion greens Probiotic: sauerkraut, kimchi

12 to 20

2 to 4 fruit 1 medium½ c. chopped¾-1 c. berries2 T. dried

Prebiotic: apples, grapes, blueberries, bananas (green)

6 to 12

1 nuts/seeds 1 oz.At least 3/week

Walnuts, peanuts, cashews, flaxseeds, chia seedsPrebiotics: pistachios, almonds

2

Total: 33 to 57 gramsDietary Guidelines for Americans 2015

Microbes and Psychology• The microbiome communicates with the brain• Neurotransmitters produced in the gut:

– Serotonin (80% to 90%)– Dopamine and gamma-aminobutyric acid (GABA)

• Depression and anxiety often accompany intestinal disorders

• Stress alters the communities

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Known Benefits of Exercise• ↓ age-related cognitive impairment• Prevents colon cancer, CVD, PAD• Therapeutic for:

– Diabetes– IBS– Depression– Obesity

• Has anti-inflammatory effects

O’Sullivan, et al. Gut Microbes. 2015;6:131-136.

Exercise Bidirectional signaling between gut and brain via vagal nerve is improved with exercise

Improves mood and cognition and helps brain cope with stress.

Exercise enhances innate immunity which conditions the microbiota

Increases motility, reducing transient time

Improves gut peptide production which is modified by the microbiota

Prevents dysbiosisassociated with poor diet

Is associated with improved gut diversity

Reduces inflammationO’Sullivan, et al. Gut Microbes. 2015;6:131-136.https://www.hindawi.com/journals/omcl/2017/3831972/

Summary• Healthier microbiota produces healthy metabolites and

reduces inflammatory responses.• Diet shapes the composition and activity of the microbiota.• Focus on high-fiber plant foods.• Promote exercise and stress reduction.• Use of antibiotics only when necessary.• Moderate hygienic practices.• Be out in nature, don’t smoke, adopt an animal.• Stay living in the community as long as possible.

• Q & A• mjardine@pcrm.org