gut-brain-liver-immunome-environment axis · gut-brain-liver-immunome-environment axis ... ion 314...

The Selfish Microbiome Gut-Brain-Liver-Immunome-Environment Axis

Konkel, Environmental Health Perspectives 121 (9) 2013

METABIOME

• Concepts on Human Microbiome Project

• Analysis of Microbial Communities

• Molecular Systematics

• Systems Biology & Non-Linear Systems

• Obesity

• Non Alcoholic Liver Disease

• The Gut Brain Axis

• Selfish Microbiome

The Human Microbiome & Metabiomics:

Who we really are!

Ilya Ilyich Mechnikov

1845-1916 (died when he was 71 years old)

• Microbiology and Immunology

• Noble Prize in 1908 – Phagocytosis

• Gerontology – toxic putrefying bacteria in gut

• Lactic acid bacteria – Probiotics

• Ate Kefir all his life

Human Microbiome Project is 100 years old

Discovery of Gut Microbes

Theodor Escherich

1857 - 1911

Escherichia coli

1886

DNA Structure 1953

1962 Nobel Prize in Physiology or Medicine

DNA Sequencing 1977

1980 Nobel Prize in Chemistry

Wally Gilbert Fred Sanger

Carl Woese

Father of Molecular Systematics

1928-2012

• Universal Genetic Code - 1964

• RNA World - 1967

• Three Domains - 1977

• Accepted by mid 1980s

• First Microbial Genome - 1988

• Leeuwenhoek Medal - 1992

• Crafoord Prize – 2003

• Over 200 publications

• 33,000 citations in 22,000 articles

http://mbac.gmu.edu/mee/display_detail.php?tb=news&id=35

http://mbac.gmu.edu/mee/display_detail.php?tb=news&id=35

NIH Human Microbiome

Project (2005)

Human Microbiome

Mims et al. Medical Microbiology Textbook (2004)

• Gut 1014

• Skin 1012

• Vagina 1010

• Mouth 1010

• Nose 1010

• Throat 1010

10 x more prokaryote cells than eukatyotic cells in human body

White Plague on Coral (NURP-NOAA)

Shell Disease on Lobster (SeaGrant-NOAA)

Biofilms in the normal human large bowel:

fact rather than fiction

R. Bollinger, A Barbas, E. Bush, S. Lin,W. Parker

Gut 56 1481-1482 2007

Human Ecology = Environmental Ecology

Microbial Ecology

Mucosal Biofilm

Biofilms in the normal human large bowel: fact rather than fiction

R. Bollinger, A Barbas, E. Bush, S. Lin,W. Parker Gut 56 1481-1482 2007

http://www.bu.edu/histology/p/12001oba.htm

http://www.bu.edu/histology/p/12001oba.htm

Homeostasis

Immunome to Recognizes Biofilm as Self

B. Duerop, S. Vaishnava, and L. Hooper Immunity 31 368-376 2009

Disease State Exposure of Immunome to Foreign Antigen

B. Duerkop, S. Vaishnava, and L. Hooper Immunity 31 368-376 2009

METABIOME





• Obesity




The Challenge

How to monitor components of complex community?

Culturing bacteria

Less than 1 % of natural communities are culturable.

USE MOLECULAR APPROACHES

Cloning & Fluorescent Sequencing

NEXTGEN Sequencing Technology

Sequencing of amplicon library is costly & slow ($2000 / 200 clones)

• Faster

• Less labor

• Lower cost

Ion Torrent PGM

Semi-Conductor Sequencing

Jonathan Rothberg

454 Pyrosequencing (1999)

Ion Torrent (2007)

NEXTGEN Sequencing (Roche)

Emulsion PCR

Ion Torrent PGM

CMOS Chip

DNA Polymerization

H+

Sequencing by Synthesis

Incorporation of one base

No Incorporation

Ion S5 (Thermo-Fisher)

80 million wells

16 gigabase : Human Genome in 2 hour

Ion Torrent Output

400bp reads Reads GigaBases

Ion 314 Chip V2 3.7 hr 7 million 0.28



200bp reads

Ion S5 540 Chip 4 hr 80 million 16.00

Comparison of Output

96 Capillary Fluorescent Sequencer

10 million bases / year Ion S5

16 Giga bases/afternoon

Equal to 1000 years of cloning and sequencing

in an afternoon

tRNA (1977)

77 bases / 7 person years

Manual Dideoxy Sequencing (1990)

100,000 bases / person year

Human Genome Project (1990-2001)

Took 12 years / $2,700,000,000 / ~50,000 person years

Roche 454 NextGen Sequencer

A Genome in 3 months / $1,000,000

Ion Torent S5

A Genome in 1 days / $4,000

METABIOME





• Obesity




Diurnal Variation of Gut Microbes and High-Fat

Feeding on Host Circadian Clock Function

Leone et al (2015) Effects of diurnal variation of gut microbes and high-fat

feeding on host circadian clock function and metabolism. Cell Host Microbe

17(5):681-9.

Diurnal Variation of Gut Microbes and High-Fat

Feeding on Host Circadian Clock Function

METABIOME





• Obesity




Ossabaw Pigs

• Ossabaw Island, Georgia

• Original Pigs from Spain

• Hardy Phenotype: utilize food well

• Native Americans

Correlate Microbiome, Transcriptome

and Clinical data Sean Smith

• Probiotic : Bifodobacter

• Descriptive: gender, genetics, weight

• Clinical: cholesterol, glucose, triglyceride, liver function, kidney function

• Tissues: liver, blood, fat, proximal colon, jejunum

• Cytokines: toll receptors, IL6 etc

Study had to be shortened as the high fat cohort became too sick

Metabolic syndrome, Diabetes, Heart disease

High Fat = Western Diet

Low Fat Diet High Fat Diet High Fat +

Probiotic

PCO of Microbiome

• Lean Diet = Control

• High Fat Diet = Placebo

• High Fat Diet + Probiotic = Probiotic

PCO case scores (Bray Curtis)

Control

Placebo

Probiotic

Axis

2

Axis 1

-0.1

-0.2

-0.4

0.1

0.2

0.4

0.5

0.6

-0.1-0.2-0.4 0.1 0.2 0.4 0.5 0.6

USDA Porcine Probiotic Study

Edge = Correlation between nodes Nodes = Features

Pearson’s Correlation Analysis

Adipose

Blood

Liver

Brain Hypothalamus

Microbiome

Model Interactions between Components of

Metabiome

T. MacDonald and G. Monteleone Immunity, Inflammation, and Allergy in the Gut Science 307, 1920 2005

Homeostasis

METABIOME





• Obesity




Gut-Liver-Brain Axis

Normal

NAFL

Microbiome

Immunome

Cytokines

Endocrine

METABIOME





• Obesity




The Gut-Brain Axis

Smith Nature 526 312-314 2015

Hepatic Encephalopathy

Bajaj et al(2013) Modulation of the Metabiome by Rifaximin in Patients with

Cirrhosis and Minimal Hepatic Encephalopathy. Plos One 8(4).

Microbiome Before rifaximin therapy

Microbiome After rifaximin therapy

Correlation network before rifaximin therapy

Correlation network after rifaximin therapy

Correlation differences between before and

after rifaximin therapy networks

Intersection of the before and after rifaximin

networks

Model Interactions between Components of

Metabiome

T. MacDonald and G. Monteleone Immunity, Inflammation, and Allergy in the Gut Science 307, 1920 2005

Homeostasis

Correlation ≠ Causality

Knowledge Discovery Science

Hypothesis Driven Experimental Science

METABIOME





• Obesity




House Microbiome

Lax et al (2014) Longitudinal analysis of microbial interaction between humans and the indoor

environment. Science 345:1048-52

Microbiome Cloud

Meadow 2015) Humans differ in their personal microbial cloud. PeerJ 3:e1258;

DOI 10.7717/peerj.1258

Microbiome Cloud

Microbiome Cloud

What is “scent” to a Blood Hound?

Mycobiome and Alzheimers EFC: External Frontal Cortex

Pisa et al (2015) Nature Scientific Reports Different Brain Regions are Infected with

Fungi in Alzheimer’s Disease DOI: 10.1038/srep15015

Control

Diseased

DNA Fungi Neurons

The Selfish Microbiome Gut-Brain-Liver-Immunome-Environment Axis

Konkel, Environmental Health Perspectives 121 (9) 2013

The Selfish Microbiome

• Involved in what we eat and obesity

• Involved in Social Behavior-Autism

• Involved in Higher Thinking

• Involved in Health & Disease

We are only here to Propogate the Microbiome

gut-brain-liver-immunome-environment axis · gut-brain-liver-immunome-environment axis ... ion 314...

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