Understanding the Role of the Microbiome in PCOS
Felice L. Gersh, M.D.Medical Director
Integrative Medical Group of IrvineFaculty Reviewer
Fellowship in Integrative Medicine University of Arizona School of Medicine
Lecture Objectives
• Review what the gut microbiome is, how it develops, and its significance
• Discuss the “unhealthy gut microbiome” and its role in systemic inflammation, insulin resistance, weight gain, hyperandrogenemia, and ovulatory dysfunction (PCOS-like picture)
• Understand the dietary steps which can help to restore a healthy gut microbiome and establish metabolic homeostasis
New Concepts-What is a Human?
• DNA sequencing has redefined what it actually means to be human
• The gut microbiome impacts every aspect of our biological systems: digestion, metabolism, neurological, reproductive, cognitive, emotional, immune
• Our “modern” lifestyle has dramatically impacted our microbiome
• There are ways to modify the damage to our microbiomes … with diet!
Concept Of The Super-Organism
• Humans are home to vast numbers of microbial organisms-a complex ecosystem consisting of hundreds of bacterial species
• Microbes-greater than 100 trillion and outnumber our own cells 10:1
• Collective genomes of all gut microbiota-150X larger than the human gene complement: 3.3 million microbial genes
• The human gut microbiome is the most complex ecosystem ever discovered
Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 1977;; 31: 107-133 Science 2009: Vol. 326 no. 5960 pp. 1694-169Patterson E et al. Gut microbiota, obesity and diabetes. Postgrad Med J 2016;;0: 1-15
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Major Influences on the Microbiome
• Genotype of host• Type of birth-Vaginal vs. Cesarean Section, infant diet• Excessive hygiene• Physical activity, sleep• Diet: macronutrients, fiber, phytochemicals, alcohol• Probiotics and prebiotics• Medications: antibiotics, NASAIDs, OCPs, hormones, PPIs,H2 Blockers, laxatives, opioids
• Toxin content of ingested meal• Frequency of meals • Stress (emotional, social)
Foerster J et al. The influence of whole grain products and red meat on intestinal microbiota composition in normal weight adults. PLoS One. 2014;; 9(10):e109606
Metabolic Functions of the Microbiome
• Production of vitamins• Amino acid synthesis• Bile acid biotransformation• Performs essential structural, metabolic, and protective functions that benefit body homeostasis and health-builds mucus layer
• Production of Peptide YY: regulates gut motility and the hunger sensation
Mshvildadze M et al. The infant intestinal microbiome. Early Hum Dev 2010: 67-71Backhed F et al. Host-bacterial mutualism in the human intestine. Science 2005;; 307:1915-1920Wong JM et al. Colonic health. J Clin Gastroenterol 2006;; 40: 235-243
Beneficial Role of Gut Microbiome
• Microbiota produce bioactive metabolites-such as short-chain fatty acids from the fermentation of carbohydrates-involved in energy metabolism, appetite regulation, promoting healthy body weight and secondary bile acid, playing key role in glucose metabolism
• Abnormalities of gut microbiota linked to immune, metabolic, and neurological diseases
Round JL et al. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;; 9: 313-323
Role of Short-Chain Fatty Acids
• Can cause pathogen displacement- and secretes antimicrobials and competes for sites of nutrients (colonization resistance)
• Development of the immune system • Important for development of regulatory T-cells, T-helper 1 and 2 cells, and T-helper 17 cells
• Short-chain fatty acids (butyrate) may exert a strong immunomodulatory action–release of protective peptides, cytokines, chemokines, and phagocytes
Palmer C et al. Development of the human infant intestinal microbiota.PlosBiol 2007;; 5:e177
Western Diet and Endotoxemia
• Western diet increases endotoxemia-a disruption of the intestinal barrier, and an increase in the Gram negative bacterial content of the microbiota
• High fat, high simple carbohydrate meal induces comprehensive endotoxemia and inflammation, increases the expression of TLR-4 (specific receptor for endotoxin), and SOCS-3- a protein which interferes with insulin signal transduction
Guinane CM et al. Tole of the gut microbiota in health and chronic gastrointestinal disease. TherpAdvGastroenterol 2013;; 6: 295-308Turnbaugh PJ et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008;; 3: 213-223
Dysbiosis of Gut Microbiota Theory
Accounts for the 3 Defining Components of PCOS:
1. Anovulation/menstrual irregularity2. Hyperandrogenism: acne, hirsutism, alopecia3. Multiple small ovarian cysts
Tremellen K et al. Dysbiosis of Gut Microbiota (DOGMA)-a novel theory for the development of Polycystic Ovarian Syndrome. Med Hypothesis. Jul;;79(1):104-112
Serum LBP Associated with Insulin Resistance in Women with PCOS
• Compared with controls, PCOS subjects had significantly higher LBP concentration
• Applied to both lean and obese PCOS women compared with controls
• Serum LBP levels significantly elevated in PCOS and independently associated with IR in PCOS
Zhu, Qibo et al. Serum LBP is Associated with Insulin Resistance in Women with PCOS. PLOS One11(1) Jan 2016
Old/New Views on Obesity, Insulin Resistance, and Metabolic Syndrome • Formerly thought to be caused only by a positive caloric balance when caloric intake exceeds caloric expenditure and the excess of energy is stored in adipose tissue
• Studies show changes in the gut microbiota trigger the pathogenic mechanisms to promote obesity, T2DM, and metabolic syndrome
• Intestinal microbiota in T2DM patients exhibit dysbiosis
Qin J et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012;; 490:55-60
New Ways to View Food
FOOD AS INFORMATIONFOOD AS A HORMONEFOOD AS MEDICINE
Food as Information
• Think of food differently-identify food and food metabolite-receptor interaction to understand the relationship between the food we eat and diseases, including diabetes
• Food can be considered a blend of hormones-exert their effects on target tissues, activating cell-surface or nuclear receptors
• Food components interact with gut flora to induce indirect signals
Ryan K et al. Food as a Hormone. Science. 2013;;339(6122):918-919
Food as a Hormone
• Cannot just look at the macronutrient and micronutrient content of food to understand its actions
• Food can be considered a cocktail of “hormones”… food components travel through the blood and nutrient substrates can act as signaling molecules by activating cell-surface or nuclear receptors, to regulate metabolic health
Ryan K et al. Food as a Hormone. Science. 2013;;339(6122):918-919
Food as Medicine
• New fields of bio-therapeutics-focus on diet to include nutrients that positively affect the microbiota: key role of probiotics and prebiotics to modulate the human intestinal ecosystem
• Diet rich in fiber, prebiotics and probiotics is useful for improving the composition of the gut microbiota
Strowski MZ et al. Probiotic carbohydrates reduce intestinal permeabiltiy and inflammation in metabolic diseases. Gut 2009;; 58: 1044-1045
Importance of the gut microbiome
Chronic Disease• Obesity• Type II Diabetes• NAFLD• Dyslipidemia• Inflammatory Bowel Disease• Cardiovascular Disease• PCOS
Health & Wellness
Genetics
Diet/LifestyleEarly Colonization
Medicine
The composition of gut microbiome can shape a healthy immune response or predispose to disease.
Decreased gut diversity
Increased gut diversity
Cresci GA et al. Nutrition in Clinical Practice. 2015;; 1-13.
Gut dysfunction
TMAO is gut-derived metabolite formed from dietary nutrients
Wang Z et al. Nature. 2011;; 472: 57-63.
1Ingestion of dietary nutrients
2Gut bacteria metabolize
nutrients to TMA
3TMA converted to TMAO by the liver
Foods rich in dietary TMAO precursors
• TMAO precursors: Phosphatidylcholine, Choline, or L-Carnitine
Foods Rich in Dietary TMAO PrecursorsRed Meat Full-Fat Dairy Products Others
• Beef• Pork• Ham• Lamb• Veal• Processed meats
• Whole milk• Eggs• Yogurt• Cream cheese• Butter
• Energy drinks• Dietary supplements
Note: Certain types of fish are direct dietary contributors of TMAO.
Diet Modulates the Microbiome
• Low fat/High complex carbohydrate diet improved Metabolic Syndrome by altering the gut microbiome
• LFHCC diet-increase in F. prausnitzii• This bacterial strains increases the SCFA -butyrate
Haro, C. et al. Two healthy diets modulate gut microbial community improving insulin sensitvity in a human obese population;; J Clin Endocrinol Metab. 1-10;; Oct 2015
Probiotics and Prebiotics
• Probiotics: live microorganisms which when administered in adequate amounts confer a health benefit on the host
• Prebiotics: a non-digestible food ingredient that beneficially affect the host by selectively stimulating the growth and activity of one or a limited number of bacteria in the colon and improve host health
Gibson GR et al. Dietary modulation for the human colonic microbiota: introducing the concept of prebiotics. J Nutr1995;; 125: 1401-1412
Benefits of Prebiotics
• Not hydrolyzed by human intestinal enzymes• Selectively fermented by bacteria, benefiting the host, resist gastric acidity
• Directly simulate the selective growth of gut microbiota and increases diversity
• Benefits: reduced triglyceride levels, improved postprandial glucose levels, reduced intestinal permeability and inflammation
• Lowers LPS induced endotoxemia, systemic inflammation, and liver inflammation
Strowski MZ et al. Probiotic carbohydrates reduce intestinal permeability and inflammation in metabolic diseases. Gut 2009;; 58: 1044-1045
How to Build a Better Microbiome
• Dietary composition, modification, and interventions have a marked impact on gut microbiota diversity
• Plant based fiber is critical in influencing the composition and metabolic activity of the microbiome and determining levels of short chain fatty acids (SCFAs), improve colonic mucosal integrity, reduce gut apoptosis
• Agrarian diets high in fruit/legume fiber are associated with greater microbial diversity
Lattimer JM et al. Effects of dietary fiber and its components on metabolic health. Nutrients 2010;; 2: 1266-89
Macrobiotic Ma-Pi 2 Diet-Short to Medium Term Use
• Probable intestinal microbiota modulation• 21 day to 6 month study: improvements in fasting BS, HgbA1C, plasma lipid fractions, plasma insulin, BP, BMI, and homeostasis
• Rich in carbohydrates, whole grains, vegetables, no animal fat or protein, no added sugar
• An optimal short-medium term diet for PCOS women
Falluca F et at. Influence of diet on gut microbiota, inflammation and type 2 diabetes mellitus. First experience with macrobiotic Ma-Pi diet. Diabetes/Metab Res Rev 2014;;30(suppl 1):48-54Falluca et al. Gut microbiota and Ma-Pi 2 macrobiotic diet in the treatment of type 2 diabetes. World J Diabetes 2015;;6(3):403-411
Ma-Pi 2 Macronutrient Composition
• Protein 12%• Fats 18%• Carbohydrates 70%• Typical caloric intake is 1700-2200 kcal
Falluca F et at. Influence of diet on gut microbiota, inflammation and type 2 diabetes mellitus. First experience with macrobiotic Ma-Pi diet. Diabetes/Metab Res Rev 2014;;30(suppl 1):48-54Falluca et al. Gut microbiota and Ma-Pi 2 macrobiotic diet in the treatment of type 2 diabetes. World J Diabetes 2015;;6(3):403-411
Best PCOS Diet-Modified Ma-Pi 2 Diet
• Healthy fats-Omega 3 supplementation, Omega 6 and 9 from plants, Saturated fat from coconut oil
• Low protein (approximately 12%)• High Complex carbohydrates (70%)• Low fructose• No animal protein-including no dairy or eggs• No added sugars, No processed foods, Chemical free• Rich in complex carbohydrates: whole-grain cereals, vegetables, legumes
• Rich in natural fiber and prebiotic and probiotic products
A safe strategy to reduce markers of insulin resistance and inflammation!
Rapid improvements in all of the following:• Fasting blood glucose• Glycosylated hemoglobin• Serum lipid profile• Body mass index and percent fat• Body weight• Blood pressure • Reduction in IGF-1 Fallucca F et al. Ma-Pi macrobiotic diet intervention during 21 days in adult with type 2 diabetes mellitus. Minerva Endocrinol 2012;; 37(suppl. 4):116
Diet Composition
• Whole-grains-rice, buckwheat, millet, barley, corn, quinoa (50%-55%) No wheat
• Vegetables-carrots and other root vegetables, cabbage and other cruciferous, chicory, red radish, onions, parsley (35-40%)
• Legumes, beans, chickpeas, lentils, ground sesame seeds (8-10%)
• Fermented foods-miso, fermented soy sauce, sauerkraut, others
Probiotic Foods to Eat
Improve microbiota composition• Miso (fermented soy paste)• Tamari (fermented soy sauce)• Sauerkraut, Kimchi (fermented cabbage)• Kamboucha tea
Kootte RS et al. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab 2012;; 14(2): 112-120
Diet Fat Content
• 18% saturated• 46% monounsaturated• 36% polyunsaturated• No trans-fats• Omega 6: Omega 3 ratio of 5:1
Fat
• Types of fats consumed has a great impact on microbial diversity, composition, and state of overall inflammation
• Mice fed fish oil increased levels of Lactobacillus and Akkermansia
• Mice fed lard increased levels of Bilophila• Lard-induced White Adipose Tissue (WAT) inflammation is mediated through gut microbial activation of TLR4
Le Chatelier E et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;;500:541-6
Diet Specifics: Highly Beneficial!
• Nutrients and phyto-compounds with antioxidant, hypoglycemic, lipid lowering effects
• High amounts of vitamins, minerals, phytonutrients:Vitamin C, beta carotene and Vitamin A, magnesium, manganese, zinc, folates, chromium, phytosterols, dietary fiber (50-60 gms/day), inulin, polyphenols, tocotrienols, quercetin, prebiotic and probiotic products
Dr. Gersh Additions: Potato Starch
• Rats fed potato fiber had beneficial changes in SCFA concentrations
• Increase in Bifidobacterium and Lactobacillus • Goal: 2 tablespoons in 8 oz of water twice daily• Start slowly if gas and bloating occurs: ¼ tsp and work up
Paturi et al. Effects of potato fiber and potato resistant starch in rats fed diets containing red meat;; J Food Sci. 2012(10):H216-23
Benefits of Adding High Resistant Starch: High-Amylose Starch
Dr. Gersh Additions
• Green bananas• Plantains• Small quantity of macadamia nuts, walnuts, pecans, sunflower seeds
• Leafy greens, cruciferous vegetables, sea vegetables, and polyphenols such as green tea and 86% or higher organic chocolate
• Lots of spices: turmeric, curcumin, curry, oregano, basil, saffron, fennel, cayenne pepper, thyme, etc
• Avocados, coconut oil, olives• Omega 3 supplementation
Diversity of Microbiome Requires Dietary Diversity
• The importance of microbiota diversity cannot be overstated!
• Microbiota produce an abundance of important molecules for host
• Each particular macronutrient has the potential to be metabolized into unique metabolic signals
HeimanM et al. A healthy gastrointestinal microbiome is dependent on dietary diversity. Molecular Metab 2016;;1-4
Eat for Diversity-the Colors of the Rainbow for Microbiota Diversity
• With increased variation comes increased adaptability and increased range of physiological responses
• Elimination of one or more macronutrients results in selecting some microbiotic species over others
HeimanM et al. A healthy gastrointestinal microbiome is dependent on dietary diversity. Molecular Metab 2016;;1-4
Hormetic Effects of Phytochemicals
• Small amounts have profound effects• Hormone like action• Metabolic performance• Amplification of cell signaling pathways• Enhancing growth of beneficial bacteria • Competitively excluding specific pathogenic bacteria-some have bacterocidal/bacterostaticactions
Etxeberria U et al. Impact of Polyphenols and Polypenol-Rich Dietary Sources on Gut Microbiota Composition. J Agri and Food Chem 2013;; 61:9517-9533
Phytonutrients are Essential
Polyphenol-Rich Dietary Sources:Dr. Gersh Favorites
• Cocoa• Pomegranates• Apples• Grapes• Berries
Etxeberria U et al. Impact of Polyphenols and Polypenol-Rich Dietary Sources on Gut Microbiota Composition. J Agriand Food Chem2013;; 61:9517-9533
Consider Including Intermittent Fasting
• Various types proposed: 2/7, 8hr eating window, 5 Day Fasting Mimicking and Enhancing Diet developed at USC
• No data yet for PCOS but mice and human data published and looks highly encouraging!
• Human pilot study done at USC for 3 months: biomarkers for cardiovascular disease, aging, diabetes, and cancer all improved, without major adverse effects
Brandhorst S et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab 2015. (22) 1-14
Artificial Sweeteners-Avoid!
• Create compositional and functional alterations to the gut microbiota, promoting glucose intolerance
• They may have directly contributed to the very obesity epidemic they were intended to combat!
• Absolutely none permitted!!
Suez J et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;;514:181-186
Wheat Alternatives: Very Minimal Amounts of Flours
• Pea flour• Potato flour• Spelt• Kamut• Other Ancient varieties (Bob’s Red Mill)• Old wheat ancestors were not bred for milling qualities can often be enjoyed by gluten intolerant people
• Avoid all Glyphosate desiccated grains!!
How to Eat!
• 100% organic• Sugar free, artificial sweetener free• Gluten free• Dairy free• Non-‐GMO (data on Roundup and Glyphosate)• Real foods in natural state• Variety of colorful fruits and veggies• Limit processing
How to Eat!
• Local and home grown• Old/heritage seeds• Home cooked• Avoid refined oils/trans fats• Avoid alcohol• Avoid food allergens/consider elimination diet• Avoid toxic foods!
Negative Effects of Different Diets on the Microbiome
• Ketogenic Diets: diminish total bacterial levels of the gut microbiota
• Long term adherence to high protein, low fermentable carbohydrate/fiber “weight-loss” diets increase Bacteroides-likely increasing risk of colonic disease
De Filippo et al. Impact of diet in shaping gut microbiota. Proc Natl Acad Sci USA 2010;; 107:14691-6
Putting it all Together: What to EAT
• Prebiotic carbohydrates-food for the gut microbiota to ferment-creating a cascade of benefits to the host!
• Probiotic foods-increase in beneficial commensals and increased diversity
• Some healthy fats• Phytonutrients-recognize there are signaling properties of foods which create metabolic effects
• A great diversity of plants• Consider intermittent fasting of some form
