THE HUMAN GUT MICROBIOME—FACT AND FICTIONDr. Gabrielle Fundaro, CISSN, CHC

Renaissance Periodization Nutrition Coach

Overview

■ Introduction to the Gut Microbiome

■ Lifestyle and the Microbiome

■ Myth-Busting and Practical Application

INTRODUCTION TO THE MICROBIOME

■ All animals harbor microbiomes and microbiota– Genetic material and microorganisms– Oral, Skin, Vaginal, Intestinal (Gut), Fecal

■ The Gut Microbiome– Bacteria (~99%)■ ~100 trillion bacteria with 1000’s species

and millions of genes– Archaea■ Methanogens

– Fungi and Protists■ Saccharomyces, Candida

– Viruses■ Non-living human and bacterial pathogens

(bacteriophages)

Defining the Microbiome

50%

Supplements

Diet & Physical Activity

Species, Location, Ethnicity, Age, Gender

Forming the Gut Microbiome■ 1/3 human-species specific■ 2/3 individual

– Birth and Early Diet■ Vaginal/C-Section■ Breast/Bottle

– Location and Ethnicity■ African/African American

– Age■ 0-3, 3-12, 12-60, 60+

– Gender– Disease State

■ IBD, T2D– Diet– Physical Activity– Cohabitation?– Cleanliness?

Hierarchy of Influence on Diversity

Factors Influencing Microbial Profile

§ Acidity§ Oxygen availability§ Nutrient availability§ Structure

§ Numbers and diversity increase from stomach to large intestine

§ Luminal, mucosal, and fecal populations differ significantly

§ Bacteria may be luminal or loosely or tightly associated with the intestinal cells (mucosal)

(Jobin, 2015 & Neufeld, 2011)

Functions of the Gut Microbiome

(Andoh, 2018)

Functions of the Gut Microbiome

Escheria Genus Canis

Escheria coli Species Canis lupus

Nissle O104:H4 Shiga-toxin

Sub-Species (Strain)

Canis lupus familiaris

(dog)

Canis lupus dingo

(dingo)

§ Within a species, specific strains have variable functions§ E. coli Nissile is a

beneficial probiotic§ E. coli O104:H4 causes

food-borne illness§ Dogs love babies§ Dingoes eat babies

§ BUT, strains can be lost/gained without a change in gut function

§ AND low-abundance strains may have HUGE functional effects

Defining Diversity■ Taxonomic Diversity

– Richness: # of species– Evenness: representation– Phylogeny: relatedness

■ Functional Diversity– Metabolomics, proteomics,

transcriptonomics

(El-Ashram, 2017)

Defining Diversity■ Diversity

– Richness: # of species– Evenness: representation– Phylogeny: relatedness

■ Functionality– Metabolomics, proteomics,

transcriptonomics

(El-Ashram, 2017)

Consider the Entire System and Limitations■ Taxonomic diversity does not directly

indicate functional diversity– Important to consider

methanogens and under-represented taxa

– Genetic redundancy is beneficial and allows for taxonomic change without loss of function

■ View the microbiome as a complex ecosystem rather than a collection of discrete microbes

■ Consider limitations of sample site, methods of identification, and host species

Gut Health and Dysbiosis§ No definition or specific profile of

healthy or unhealthy microbial profile§ Healthy controls cluster by

geographic location

§ “Healthy”§ Stability due to diversity§ Resistant to perturbations

(Nam, 2011)

Gut Health and Dysbiosis§ No definition or specific profile of

healthy or unhealthy microbial profile

§ “Dysbiosis”§ Common characteristics of GI and

metabolic diseases§ Lack of diversity§ Intestinal permeability &

inflammation§ Metabolic endotoxemia

§ Elevated levels of plasma endotoxin (LPS) leading to chronic lo inflammation

Suzuki, 2012

Gut Health and Dysbiosis

OBESITY

COLORECTAL CANCER

INFLAMMATORY BOWEL DISEASES

Dysbiosis?Variability even occurs within a single disease

state!

Adapted from: Duvallet, 2017

Dysbiosis: Cause or Consequence?§ Rodent fecal microbiome

transplants (FMT) illustrate a microbiome-disease link

§ Method of replicating human disease states and responses to dietary interventions

§ Increased energy harvesting & appetite

§ Behavioral changes§ Inflammatory responses

§ Approaches ‘cause-effect’§ BUT, significant limitations

for applicability to humans

Aliosio, 2016

Adapted from: https://www.frontiersin.org/files/Articles/82367/fendo-05-00047-HTML-r1/image_m/fendo-05-00047-g001.jpg

Gut Health and Dysbiosis

Vertebrates cause pollution.

LIFESTYLE AND THE MICROBIOME

Key Note in Human

Intervention Studies

Individual differences have a much stronger effect than diet or physical activity.

Greater microbial diversity is negatively correlated with diet-induced or exercise-induced changes.

What does this mean?

A more diverse microbiome is a more resilientmicrobiome. Short-term interventions cannot mitigate the effects of long-term habits.

Core Microbiota Remain Stable Over Time and May Influence Response to Interventions§ Microbiomes ‘cluster’ based on

predominant taxa1) P: Japan, South Africa, Sweden2) B: Australia, Canada, Chile, Italy3) F: Poland

§ After 3 weeks on HCLF or LCHF, clusters remained stable § Specific changes to certain

taxa§ Differed significantly based on

cluster

(Morrison, 2019)

Carbohydrates and Fiber

§ Dietary plant diversity correlates with gut microbial diversity in humans

§ Digestible carbohydrates (simple sugars and starches) are primarily used by the host§ Further research needed for effects of

digestible carbohydrate

§ Indigestible carbohydrates (fiber and resistant starch) pass through to large intestine where they are fermented§ Soluble (readily fermentable) and insoluble

(bulk-forming)§ Production of gases and short-chain fatty acids§ pH regulation§ Bacterial & colonocyte fuel sources

https://selfhacked.com/blog/butyrate-health-benefits-butyrate-derivatives-sodium-butyrate-phenylbutyrate-trybutyrine-butyric-acid-butyrate-prodrugs-butyrate-producing-bacteria/

ProteinProtein intake correlates with diversity & improved body composition in physically-active humans

§ In the presence of sufficient fiber

§ Differing fatty acid, amino acid, and fiber content

§ Differing potential for lean/fat mass gain in mice

§ Low-fiber, high-protein diets may increase mucin-degraders and reduce diversity

§ Metabolites may influence health & disease§ Production of TMAO from carnitine is

microbiome-dependent§ Tryptophan -> indole. serotonin § BCAA’s -> barrier function

Singh, 2017 & Willing, 2019

Fats

Cell Metabolism 2015 22, 658-668DOI: (10.1016/j.cmet.2015.07.026)

HFD (>40% kcal) reduces diversity in rodents & humans§ Low in fiber and high in protein§ Bifidobacteria < Bacteroides§ Reduced butyrate

§ Usually high in sat fat§ Firmicutes : Bacteroidetes ratio shift § Intestinal permeability & increased circulating

endotoxin§ Metabolic endotoxemia

Fat source may affect microbiome (secondarily to total fat content)§ Saturated fat > protein in sedentary humans§ Omega-3 may reduce inflammation§ Rodent FMT reduced adiposity on lard-based diet

Caesar, 2015

Cardiovascular Fitness and Physical Activity Correlate with Diversity

Cardiovascular fitness may explain 15-20% of diversity in sedentary and recreationally active adults

Higher levels of fitness and physical activity associated with increased butyrate-producing bacteria and

fermentative efficiency(Estaki, 2018 & Bressa, 2017)

More fit, more diverse

Cardiovascular Fitness and Physical Activity Correlate with SCFA Production

Microbiota of elite athletes contains higher levels of specific genera & genes associated with lactate fermentation to

propionate

Higher levels of fitness and physical activity associated with increased butyrate production

(Estaki, 2018 & Scheiman, 2019)

Habitual Diet & Exercise Interactions■ Athletes’ diets are higher in protein, carbohydrates, and energy

– Diets may be lower in fiber and FODMAPs– May enrich bile-tolerant taxa and/or butyrate-producers

(Estaki, 2018)

Habitual Diet & Exercise Interactions

Protein intake is negatively correlated with diversity in distance-runners on a low-fiber diet.

Total fat intake is negatively correlated with Bifidoabundance in bodybuilders on a low-fiber diet.

(Park, 2019)

■ Sport-specific diets vary greatly in relative macronutrient contribution– Increased fat intake à reduced carbohydrate intake à loss of beneficial microbes

Improved Metabolic Health & Performance

Enhanced SCFA

Availability and Lactate Clearance

Enhanced Fermentative

Capacity

Diet & PAL

Clostridiales

Veillonella

Prevotella

Akkermansia

Roseburia

Faecalibacterium

m. Smithii

(archaea)

(Mailing, 2019)

Appetite regulationInsulin sensitivitypH modulationCell proliferationTight junction proteinsColonocyte energy source

“Gut health!”

Not fully realized during low-carb, high-fat diets or

low fiber intake!

MICROBIOME MYTHS AND PRACTICAL APPLICATIONS

Don’t fall for the fecal fallacies!

Diagnosing or curing dysbiosis

Diagnosing or curing leaky gut

Healing the gut Rebuilding or designing a healthy

biome

Dysbiosis as a cause for weight gain

What about the gut health ‘superfoods’?Fermented and Cultured Dairy

Fermented Vegetables, Grains, and Meats

Probiotics Digestive Enzymes

Glutamine Collagen and Bone

Broth

“Detoxes”

Dishonorable Mention: IgG Antibody food sensitivity

testing, MRT/LEAP testing, GI MAP testing, OAT, etc.

“Broad-spectrum” probiotics?Problem Probiotic

Diarrhea--prevention (antibiotic or traveler’s)

Diarrhea--treatment (pediatric)

S. boulardii, L. casei, L. acidophilus

L. rhamnosus GG, S. boulardiiIBS--treatment B. infantis, L. plantarum, L. rhamnosus, B. breve

IBD—treatment VSL-#3

Upper respiratory tract infection—prevention/treatment

L.casei Shirota, L. gasseri, B. longum, B. bifidum, B. animalis lactis

Diet-induced insulin resistance and dyslipidemia--prevention

Weak evidence—VSL-#3, L. casei, B. infantis, cultured dairy beverages

Probiotics for performance?Probiotics do not improve exercise performance or

recovery

• No effect in endurance athletes, team sports, or laboratory time trials

• Conflicting results in strength and markers of inflammation and soreness• Increased torque

production & reduced soreness unreplicated

Probiotics may improve GI distress in males

• Worsened effects in females

• Reduced duration but not severity

• Reduction in fecal zonulin unreplicated

Probiotics may reduce URTI incidence

• Reduced duration, severity, and frequency of upper respiratory tract infections some studies

• Reductions in some inflammatory markers (TNF-a, CRP, IL-6, Eppstein-Barr antibodies)

Gastric distress is common in athletes!■ Physical activity appears to promote ‘gut health,’ but…

■ 20-60% of athletes report exercise-related gastric distress– Cramping, nausea, diarrhea■ Impaired nutrient utilization■ Performance impediment

■ Most prevalent in endurance athletes and females– Heat and psychological stress– Intensities >80% VO2max– Hyperthermia, lack of blood flow, pH changes, free radicals, mechanical stress

■ Changes in intestinal permeability lead to increased circulating endotoxin– Commonly associated with GI distress

■ Athletes who ingest insufficient fiber with high protein intake may not fully realize beneficial effects of exercise on the microbiome

GI Distress Prevention

Carbohydrate-containing beverages may reduce markers of intestinal permeability

6-8% carbohydrate concentration•Glucose, glucose + fructose,

maltodextrin

Reducing FODMAP intake before/during exercise

Fructose, lactose, soluble fibers•Fruit, dairy, whole grains,

legumes, veggies

Limiting fat intake before/during exercise

Slows gastric emptyingMCT oil increases gastric distress

Avoiding intense exercise close to a meal GET usually 1-4 hours

Avoiding extreme endurance exercise in the heat

Consistent pattern of increased endotoxin levels in extreme endurance athletes

Practical Applications for Health

Emphasize

Plants and their fibers (especially soluble)

Omega-3 fats (fish, walnuts, flax, chia)

Plant-based & lean proteins

Regular physical activity and recovery

Limit

Dietary fats to <40% calories

Saturated fat to <10% calories

High-fat red meat and processed meat products

Only certain foods as needed (allergies &

intolerancesProbiotics:

Strain-specific effects

Bibbo, S., Ianiro, G., Giorgio, V., Scaldaferri, F., Masucci, L., Gasbarrini, A., & Cammarota, G. (2016). The role of diet on gut microbiota composition. European Review for Medical and Pharmacological Sciences, 20(22), 4742–4749.Bonder, M. J., Tigchelaar, E. F., Cai, X., Trynka, G., Cenit, M. C., Hrdlickova, B., … Zhernakova, A. (2016). The influence of a short-term gluten-free diet on the human gut microbiome. Genome Medicine, 8(1), 1–11. https://doi.org/10.1186/s13073-016-0295-yBrahe, L. K., Astrup, A., & Larsen, L. H. (2016). Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota? Advances in Nutrition (Bethesda, Md.), 7(1), 90–101. https://doi.org/10.3945/an.115.010587Byrne, C. S., Chambers, E. S., Morrison, D. J., & Frost, G. (2015). The role of short chain fatty acids in appetite regulation and energy homeostasis. International Journal of Obesity, 39(9), 1331–1338. https://doi.org/10.1038/ijo.2015.84Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., … Burcelin, R. (2007). Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes, 56(7). Retrieved from http://diabetes.diabetesjournals.org/content/56/7/1761Cani, P. D., Osto, M., Geurts, L., & Everard, A. (2012). Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes, 3(4), 279–88. https://doi.org/10.4161/gmic.19625Cerdá, B., Pérez, M., Pérez-Santiago, J. D., Tornero-Aguilera, J. F., González-Soltero, R., & Larrosa, M. (2016). Gut microbiota modification: Another piece in the puzzle of the benefits of physical exercise in health? Frontiers in Physiology, 7(FEB), 1–11. https://doi.org/10.3389/fphys.2016.00051Chambers, E. S., Viardot, A., Psichas, A., Morrison, D. J., Murphy, K. G., Zac-Varghese, S. E. K., … Frost, G. (2015). Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut, 64(11), 1744–1754. https://doi.org/10.1136/gutjnl-2014-307913Chung, W. S. F., Walker, A. W., Louis, P., Parkhill, J., Vermeiren, J., Bosscher, D., … Flint, H. J. (2016). Modulation of the human gut microbiota by dietary fibres occurs at the species level. BMC Biology, 14(1), 1–14. https://doi.org/10.1186/s12915-015-0224-3de Almada, C. N., Nunes de Almada, C., Martinez, R. C. R., & Sant’Ana, A. de S. (2015). Characterization of the intestinal microbiota and its interaction with probiotics and health impacts. Applied Microbiology and Biotechnology, 99(10), 4175–4199. https://doi.org/10.1007/s00253-015-6582-5Effects, M., & Sweeteners, O. F. N. (2016). HHS Public Access, 152(0 0), 450–455. https://doi.org/10.1016/j.physbeh.2015.06.024.METABOLICFrei, R., Akdis, M., & O’mahony, L. (2015). Prebiotics, probiotics, synbiotics, and the immune system: Experimental data and clinical evidence. Current Opinion in Gastroenterology, 31(2), 153–158. https://doi.org/10.1097/MOG.0000000000000151Harvie, R. M., Chisholm, A. W., Bisanz, J. E., Burton, J. P., Herbison, P., Schultz, K., & Schultz, M. (2017). Long-term irritable bowel syndrome symptom control with reintroduction of selected FODMAPs. World Journal of Gastroenterology, 23(25), 4632–4643. https://doi.org/10.3748/wjg.v23.i25.4632Hulston, C. J., Churnside, A. A., & Venables, M. C. (2015). Probiotic supplementation prevents high-fat, overfeeding-induced insulin resistance in human subjects. The British Journal of Nutrition, 113(4), 596–602. https://doi.org/10.1017/S0007114514004097loisio, I., Mazzola, G., Corvaglia, L. T., Tonti, G., Faldella, G., Biavati, B., … Mitchell, E. A. (2016). Building a Bene fi cial Microbiome from Birth 1 , 2. Applied Microbiology and Biotechnology, 7(1), 323–330. https://doi.org/10.3945/an.115.010694.FIGURELiu, H., Dicksved, J., Lundh, T., & Lindberg, J. (2014). Heat Shock Proteins: Intestinal Gatekeepers that Are Influenced by Dietary Components and the Gut Microbiota. Pathogens, 3(1), 187–210. https://doi.org/10.3390/pathogens3010187Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in Health and Disease, 15(1), 1–10. https://doi.org/10.1186/s12944-016-0357-6Managing irritable bowel syndrome: The low-FODMAP diet. (n.d.). https://doi.org/10.3949/ccjm.83a.14159Marone, P. A., Lau, F. C., Gupta, R. C., Bagchi, M., Bagchi, D., Shamie, A. N., & Udani, J. K. (2010). Safety and toxicological evaluation of undenatured type II collagen. Toxicology Mechanisms and Methods, 20(4), 175–189. https://doi.org/10.3109/15376511003646440Moshfegh, A. J., Friday, J. E., Goldman, J. P., & Ahuja, J. K. (1999). Presence of inulin and oligofructose in the diets of Americans. The Journal of Nutrition, 129(7 Suppl), 1407S–11S. Retrieved from http://jn.nutrition.org/content/129/7/1407S.abstractOsterberg, K. L., Boutagy, N. E., McMillan, R. P., Stevens, J. R., Frisard, M. I., Kavanaugh, J. W., … Hulver, M. W. (2015). Probiotic supplementation attenuates increases in body mass and fat mass during high-fat diet in healthy young adults. Obesity, 23(12), 2364–2370. https://doi.org/10.1002/oby.21230Pannaraj, P. S., Li, F., Cerini, C., Bender, J. M., Yang, S., Rollie, A., … Aldrovandi, G. M. (2017). Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatrics, 171(7), 647–654. https://doi.org/10.1001/jamapediatrics.2017.0378Pereira, M. A. (2014). Sugar-Sweetened and Arti fi cially-Sweetened Beverages in Relation to Obesity Risk. Advances in Nutrition, 5, 797–808. https://doi.org/10.3945/an.114.007062.evidence.Portune, K. J., Benítez-Páez, A., Del Pulgar, E. M. G., Cerrudo, V., & Sanz, Y. (2017). Gut microbiota, diet, and obesity-related disorders—The good, the bad, and the future challenges. Molecular Nutrition and Food Research, 61(1), 1–18. https://doi.org/10.1002/mnfr.201600252Sanz, Y. (2015). Microbiome and Gluten. Annals of Nutrition & Metabolism, 67(suppl 2), 28–41. https://doi.org/10.1159/000440991Schiffman, S. S., & Rother, K. I. (2013). Sucralose, a synthetic organochlorine sweetener: Overview of biological issues. Journal of Toxicology and Environmental Health - Part B: Critical Reviews, 16(7), 399–451. https://doi.org/10.1080/10937404.2013.842523Schirmer, M., Vatanen, T., Mujagic, Z., & Vila, A. V. (2017). HHS Public Access, 352(6285), 565–569. https://doi.org/10.1126/science.aad3369.Population-basedSanchez, B., Delgado, S., Blanco-Mïguez, A., Lourenzo, A., Gueimonde, M., & Margolles, A. (2017). Probiotics, gut microbiota, and their influence on host health and disease. Molecular Nutrition and Food Research, 61(1), 1–16. https://doi.org/10.1002/mnfr.201600240Simpson, H. L., & Campbell, B. J. (2015). Review article: Dietary fibre-microbiota interactions. Alimentary Pharmacology and Therapeutics, 42(2), 158–179. https://doi.org/10.1111/apt.13248Smith, T. N., Swanson, K. S., Padilla, J., & Vieira-potter, V. J. (2017). Function & Gut Microbiota in Obese Rats, 48(9), 1688–1698. https://doi.org/10.1249/MSS.0000000000000964.COMPARISONSuccessful Low-FODMAP Living — Experts Discuss Meal-Planning Strategies to Help IBS Clients Better Control GI Distress. (n.d.). Retrieved August 10, 2018, from http://www.todaysdietitian.com/newarchives/030612p36.shtmlSuez, J., Korem, T., Zilberman-Schapira, G., Segal, E., & Elinav, E. (2015). Non-caloric artificial sweeteners and the microbiome: Findings and challenges. Gut Microbes, 6(2), 149–155. https://doi.org/10.1080/19490976.2015.1017700The Low FODMAP Diet (FODMAP = Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols). (n.d.). Retrieved from www.uwhealth.org/nutrition.Thursby, E., & Juge, N. (2017). Introduction to the human gut microbiota, 0, 1823–1837. https://doi.org/10.1042/BCJ20160510Venkataraman, A., Sieber, J. R., Schmidt, A. W., Waldron, C., Theis, K. R., & Schmidt, T. M. (2016). Variable responses of human microbiomes to dietary supplementation with resistant starch. Microbiome, 4, 1–9. https://doi.org/10.1186/s40168-016-0178-xZhou, S., Xu, R., He, F., Zhou, J., Wang, Y., Zhou, J., … Zhou, W. (2016). Diversity of gut microbiota metabolic pathways in 10 pairs of Chinese infant twins. PLoS ONE, 11(9), 1–14. https://doi.org/10.1371/journal.pone.016162