core components i: gut microbiome essentials · advanced ages § many factors can have a...

© 2016 Tom Fabian, PhD

CORE COMPONENTS I:

Gut Microbiome Essentials

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)

Module Outline

Microbiome

Mucosa

CORE COMPONENTS I

Gut Microbiome Essentials1CORE COMPONENTS II

Intestinal Barrier & Physiology Essentials2KEY INTERACTIONS I

Eubiosis & Dysbiosis in Health & Disease3KEY INTERACTIONS II

Factors That Influence Eubiosis & Dysbiosis4PRACTICE ESSENTIALS I

Assessment & Functional testing5PRACTICE ESSENTALS II

Therapeutic Strategies & Approaches6

What Is the Microbiome?

Definitions & Terminology

Microbiome

Microbiota

Microflora

Microbes

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)

Metagenome

40 trillion (bacteria)

5 to 10 million genes (250X)

2.5 lbs / 3 pints

Rivals liver (size & functions)

By the Numbers:

Bacteria

Archea

Viruses

Fungi / yeasts

Protozoa & Helminths

Microbiota Types

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

Microbiome Science

§  Mice

•  Germfree, gnotobiotic & normal (pathogen-free)

•  Characterization & intervention studies

•  Disease models

§  Farm animals•  Characterization & intervention studies

•  Animal health, gut health, addressing infectious disease

Animal Studies

§  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

§  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)

Germfree Mice

§  Characterization studies: comparative, epidemiological

§  Interventional / experimental (controls + test subjects)

§  Clinical trials (RCTs) vs. precision / individual outcomes

Human Studies

SOURCE:

§  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

Science Resources

Species composition

Functions

Complex interactions (microbes, our physiology, external factors)

Basic Research: Progression

§  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•  Too early to incorporate clinically?

•  Mechanism-based vs. clinical trial-based approaches

Research Limitations

§  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

Overview of Comparative Studies

AGEGI Communities

SOURCE:

AGEInfluencing Factors

SOURCE:

AGEGI Physiology

SOURCE:

§  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

Early Microbiome Development

§  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

Adult Lifespan

§  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

Overview of Comparative Studies

Westernized / Industrial

Agrarian / Traditional

Hunter-gatherer

Geographic / Cultural Differences

AGEHygiene 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 immune-related 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)

§  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

Overview of Comparative Studies

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)

Module Overview

§  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

Overview of Comparative Studies

“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, PhDThe 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

§  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)

GI Function

•  Influencing metabolism

•  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

Other Functions

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)

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)

Module Outline