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CORE COMPONENTS I: Gut Microbiome Essentials 2016 Tom Fabian, PhD

Module Outline 1. Microbiome overview: getting a sense of the microbiome, research, what we know 2. Bacteria: features, functions, communities & taxonomy 3. Other microbes: archaea, fungi, viruses, parasites (protozoa & helminths)

Microbiome Mucosa

1 2 3 4 5 6 CORE COMPONENTS I Gut Microbiome Essentials CORE COMPONENTS II Intestinal Barrier & Physiology Essentials KEY INTERACTIONS I Eubiosis & Dysbiosis in Health & Disease KEY INTERACTIONS II Factors That Influence Eubiosis & Dysbiosis PRACTICE ESSENTIALS I Assessment & Functional testing PRACTICE ESSENTALS II Therapeutic Strategies & Approaches

What Is the Microbiome? Definitions & Terminology

Microbiome Microbiota Microflora Microbes Metagenome

Metagenome Complete collection of genes within all microbes in the microbiome Determines the overall functional capacity of the microbiome i.e., what it can do for us (5 10 million genes)

By the Numbers: 40 trillion (bacteria) 5 to 10 million genes (250X) 2.5 lbs / 3 pints Rivals liver (size & functions)

Microbiota Types Bacteria Archea Viruses Fungi / yeasts Protozoa & Helminths

Source: WGO Handbook on Gut Microbes (World Gastroenterology Organisation)

Microbiome Science

Animal Studies Mice Germfree, gnotobiotic & normal (pathogen-free) Characterization & intervention studies Disease models Farm animals Characterization & intervention studies Animal health, gut health, addressing infectious disease

Immune system: underdeveloped, mice are highly susceptible to infection if exposed, prone to inflammation Digestive tract: underdeveloped, many reduced functions such as motility Behavioral differences Germfree Mice Body composition/metabolism: must consume substantially more food to sustain normal weight (due to reduced digestive function and/or lack of calories from bacterial fermentation)

Human Studies Characterization studies: comparative, epidemiological Interventional / experimental (controls + test subjects) Clinical trials (RCTs) vs. precision / individual outcomes

SOURCE:

Science Resources How We Study the Microbiome (from the Genetic Science Learning Center, University of Utah) - http://learn.genetics.utah.edu/content/microbiome/ study/ Gut Check: Exploring Your Microbiome (from the University of Colorado) - https://www.coursera.org/learn/microbiome

Basic Research: Progression Species composition Functions Complex interactions (microbes, our physiology, external factors)

Early stages of microbiome research Very complex interactions Range of study limitations Lack of intervention studies in humans Lack of studies addressing individual differences (emphasis is on clinical trials) Debates Research Limitations Too early to incorporate clinically? Mechanism-based vs. clinical trial-based approaches

Overview of Comparative Studies Variations within individuals Microbiome communities: Body regions and physiological microenvironments Lifespan Diet Many others: genetics, environment, lifestyle factors, etc. Variations between individuals & groups Geographic & cultural Healthy vs. disease

GI Communities AGE SOURCE:

SOURCE: Influencing AGEFactors

GI Physiology AGE SOURCE:

Early Microbiome Development Primary initial sources Prenatal (maternal) Birth (primarily maternal depending on delivery) Birth to ages 2 to 3 Diet (breast milk, formula, post-weaning diet) Microbe exposure (beneficial and pathogenic) Drugs (antibiotics) and other chemicals

Adult Lifespan Relatively stable / resilient throughout adulthood, until advanced ages Many factors can have a significant impact Largest impact: Major long-term diet changes, antibiotics (especially repeated), illness Elderly: depends on health status & living environment Long-term care facilities: lower diversity, more dysbiosis Healthy & not in long-term care: less dysbiosis, more like healthy younger adults

Geographic / Cultural Differences Westernized / Industrial Agrarian / Traditional Hunter-gatherer

Hygiene AGE Hypothesis Sufficient exposure to (mostly good ) microbes is essential for optimal health and immune balance Reduced exposures in westernized & industrialized societies has disrupted the balance and increased risk for immunerelated diseases

Summary: Characterization Studies Cultures & individuals differ significantly from one another in composition of microbiome Western, industrialized societies have lower diversity (associated with more chronic diseases) Key roles for diet, hygiene (microbial exposures, antibiotics), and environment in shaping the microbiome Microbes enable us to adapt to different diets (but with different health outcomes)

Module Overview 1. Microbiome overview: getting a sense of the microbiome, research, what we know 2. Bacteria: features, functions, communities & taxonomy 3. Other microbes: archaea, fungi, viruses, parasites (protozoa & helminths)

It is reasonable to propose that the composition of the microbiome and its activities are involved in most, if not all, of the biological processes that constitute human health and disease. Martin J. Blaser, PhD The Microbiome Revolution J. Clin. Invest. 124(10): 4162-4165

Digestive system Immune system Nervous system Endocrine system & metabolism Detoxification Biosynthesis Other aspects of physiology

Normal immune development Immune tolerance to harmless antigens (microbes, food, self) Restraining inflammation and autoimmunity Proper functioning of barriers and innate immunity Direct role in keeping pathogens at bay (colonization resistance) And much more! Immune Function

GI Function Normal gastrointestinal development Maintenance and function of the epithelial lining Regulating GI neurotransmitters and motility Influencing GI hormone production and nutrient signaling Digesting food components that we can t break down Producing metabolites (beneficial or harmful)

Influencing metabolism Other Functions Conversion of potential toxins to less harmful forms Activating/deactivating some drugs, supplements & food components (e.g., polyphenols) Produces some vitamins (B, K), amino acids, neurotransmitters Produce metabolites from food components that support interdependent microbes, and thus an overall healthy microbiome

Gastrointestinal & liver disorders Immune: allergies, asthma, autoimmunity Mood disorders & neurodegenerative diseases Obesity, diabetes, and metabolic syndrome Cardiovascular disease & cancer A growing list of others

Transplanted fecal samples from human twins (one obese, the other lean) Samples from obese twins caused normal mice to gain weight and exhibit altered metabolism Samples from lean twins prevented weight gain and metabolic changes in mice Co-housing lean and obese mouse recipients prevented the Ob mouse recipients from gaining weight Results were diet-dependent

First experiment: Mice treated with certain antibiotics became less timid (more exploratory behavior) Second experiment: Swapped fecal samples from a timid strain with a bold strain The samples from the bold strain made the timid strain more bold The samples from the timid strain made the bold strain more timid

Mice were sensitized to food allergy (peanut antigen) either by treatment with antibiotics or germfree status Introducing Clostridia bacteria into germfree mice (gnotobiotic mice) protected them against food allergen sensitization Showed that Clostridia promote immune tolerance to food antigen via specific immune mechanisms and tightening of the intestinal barrier

Comparison studies using DNA techniques in humans showed: Decreased diversity Increased Proteobacteria, including Enterobacteriaceae Decreased Clostridia, including Faecalibacterium Metabolite analysis showed several changes including decreased SCFAs Immune analyses indicate reduced regulatory T cells (which reduce inflammation)