Microbiome: Why a few trillion germs can be a good thing

Paul KubesProfessor

Director Snyder Institute for Chronic Diseases

Dept of Physiology & Pharmacology,

Cumming School of Medicine

Kathy McCoyProfessor

Director - Western Canadian Microbiome Germ-Free Program

Dept of Physiology & Pharmacology,

Cumming School of Medicine

April 18, 2017

Paul KubesDepartment of Physiology & Pharmacology

Professor at the University of Calgary and Founding Director of the Snyder Institute for Chronic Diseases

Canada Research Chair in Leukocyte Recruitment in Inflammatory Disease

Research focus on understanding complex immune responses in the context of human clinical disease and imaging immune cells during Inflammation, Infection and tissue Injury

Canada’s Health Researcher of the year in 2011

Published >300 papers in top scientific journals

Kathy McCoyDepartment of Physiology & Pharmacology

Professor at the University of Calgary and Founding Director of the Western Canadian Microbiome Germ-free Program

PhD from Malaghan Institute for Medical Research and Otago University, New Zealand

Research focus on understanding the role of the microbiome in immunity, especially in early life

Published >80 papers in top scientific journals

Because we are still at WAR in 2014!

CHARLES REX ARBOGAST / THE ASSOCIATED PRESS

Antibiotic resistant microorganisms

Vancomycin-Resistant

Enterococcus

VRE

How close are we to a nightmarish

return to a pre-antibiotic era?

The Neutrophil – The Policeman

Bacteria

Most people think of bacteria as germs that make you sick, but in fact they are also critical to keeping you healthy

Microbiome

• Collection of bacteria living in and on your body or those living in a particular environment

The human microbiome

What are microbes?

• A “microscopic organism,” is a living thing too small to be seen with the naked eye

• Usually only one cell organism

Key definitions

Microbiota: a community of microbes

Microbiome: really refers to all the microbial genes

Microbe:• Bacteria: single cell organism usually what we look at in

microbiome• Stapholococcus• Streptococcus• E.coli

• Fungi• Virus• Amoeba

Bacteria

Fungi

Virus

Amoeba

Diversity increases with age

Microbiome and health

Even your two hands have different microbiomes!

Microbiome and health

You’re surrounded by a cloud of bacteria as unique as a fingerprint

Pigpen was not the only one!

You and your spouse share microbiome

Your microbiome starts at birth

• Vaginal birth begets different microbiome than Cesarean section (mostly skin) often of the doctor or nurse

• At home birth different than at hospital

• Breast milk versus formula

Influenced by diet

Genetics & disease

Our genes have not changed over last 30 years

Environment & disease

Environment & disease

Environment & disease

Environment & disease

Environment & disease

Environment & disease

What has changed?

Then

What has changed?

Now

Hygiene hypothesis

Antibiotics alter your microbiome

Antibiotics

It could take years to replenish a normal gut microbiome

Antibiotics no longer recommended

Antibiotics

Antibiotics can affect mom’s microbiome and its transfer to baby

Microbiome links to chronic diseases

◾Acne- teenage change in oils- P. acnes◾Eczema◾Asthma/allergies

◾Autism- often have GI disorders◾Depression and anxiety (metabolites)

◾Autoimmune diseases- RA, MS◾Inflammatory bowel diseases◾Gastric ulcers- H. pylori◾Cancer- H. pylori, viruses

◾Hardening of the arteries- gum disease, infected◾Malnutrition- bacteria help absorb nutrients ◾Obesity- microbiome transfers, change weight◾Diabetes- Type II- switch microbiome◾Dental cavities- Bacteria make acid

Antibiotics

Antibiotics save lives but need to be given appropriately

Takeaways

• Not all bacteria are bad

• There is a new organ: the microbiome

• Affecting the microbiome can affect our health

Man & microbe: A superorganism

All mucosal surfaces are home to microbiota

• All mucosal surfaces are colonized with bacteria

• Different mucosal surfaces are home to different diversities and composition

Cho & Blaser, Nature Reviews Immunology 2012

All mucosal surfaces are home to microbiota

• The intestine is a preferred site

• >70% of all bacteria are found in the large intestine (colon)

• >70% of all immune cells are found in the intestine

Sekirov et al, Physiol Reviews 2010

Colonization occurs in the first years of life

• Born germ-free

• Increasing numbers & increasing diversity within first year

• Heavily influenced by maternal colonization, environmental exposures, diet, antibiotics

McCoy & Köller Clinical Immunology 2015

Development of immune system

• Immune system of a newborn is not fully developed

• Requires signals from the microbiota for normal development

• ‘Missing’ microbiota at an important time during immune development could increase diseases susceptibility

Critical window

Early life colonization coincides with a time-limited period in which the immune system is permissive to education from the microbiota

Proper/improper immune education during critical window impacts on resistance/susceptibility to disease later in life

Birth

Prenatal Neonatal AdultYoung

Microbial diversity

Critical Window

Microbial colonization during critical window

• Gut

• Lung

• Skin

AllergyIBD

Asthma

Atopic dermatitisPsoriasis

Is the maternal microbiota important?

Exposure to antibiotics during pregnancy is associated with increased susceptibility of infant to immune-mediated diseases

Maternal microbiota effects

Birth

Prenatal Neonatal AdultYoung

Microbial diversity

Critical Window

Exposure to live intestinal microbes

Exposure to microbial products/metabolites

Gestational-ONLY colonization

Birth

Prenatal Neonatal AdultYoung

TransientMicrobial colonization

Baby

Microbial colonization

Gestational-ONLY colonization

Birth

Prenatal Neonatal AdultYoung

TransientMicrobial colonization

Baby

Microbial colonization

• Molecules (metabolites) originating from the maternal microbiota are transferred to the baby through the placenta and the milk

• These molecules stimulate development of innate immune cells in the offspring

• Maternal microbiota prepares the newborn to accept its own microbiota after birth without developing inflammation

Thanks Mom!

Strengthen your immune system & don’t destroy your microbiome

How to harness the power of the microbiome?

FMT:

Fecal microbial transplantation

Western Canadian Microbiome Centre (WCMC)

WCMC Platforms• Germ free• Genomics & Bioinformatics• Proteomics/Metabolomics• Cytometry• Imaging (in vitro & in vivo)• BioBanking

WCMC Priorities• Platforms• Collaborations• Partnerships• Communication• Education

WCMC One-stop shop for Microbiome Research

WCMC

Metabolomics

Platform

WCMC

BioBanking

Platform

WCMC

Cytometry

Platform

WCMC

Genomics

Platform

WCMC

Bioinformatics

Platform

WCMC

Imaging

Platform

WCMC Germ

Free Platform

F4/80 Ly6C CD11c

MHC-I MHC-II

CD206

CD11b Ly6G

Kupffer cells (F4/80+ CD11b+ Ly6Clo MHCII+ )

Dcs (CD11c+ F4/80-)

plasmacytoid Dcs (CD11c+ CD317+ F4/80-)

granulocytes (F4/80- Ly6G+ CD24-/low)

Dcs (CD11c+ F4/80-)

unidentified population

unidentified population

infiltrating monocytes (F4/80+ Ly6C+)

granulocytes (F4/80+ Ly6G+ CD24+) 1

2

3

4

5

6

7

8

9

11

12

basophils (FceR1+ CD11b+ CD44+) 10

infiltrating monocytes (F4/80- CD11clo Ly6C+)

Kupffer cells (F4/80+ CD11c+ CD11b+ Ly6Clo MHCII+ )

a

b

Sinusoidal zone

Pericentral zone F4

/80

C

X3

CR

1

CD

11

c

PE

CA

M-1

intravascular

extravascular

c d

e

f

g

LNPCs

h CD317

F4

/80

+

CD

11

c+

CX

3C

R1

+

0

100

200

300

400

Sinusoidal zone

Pericentral zone

*

Ce

lls/m

m2

Fig.1

F4/80 Ly6C CD11c

MHC-I MHC-II

CD206

CD11b Ly6G

Kupffer cells (F4/80+ CD11b+ Ly6Clo MHCII+ )

Dcs (CD11c+ F4/80-)

plasmacytoid Dcs (CD11c+ CD317+ F4/80-)

granulocytes (F4/80- Ly6G+ CD24-/low)

Dcs (CD11c+ F4/80-)

unidentified population

unidentified population

infiltrating monocytes (F4/80+ Ly6C+)

granulocytes (F4/80+ Ly6G+ CD24+) 1

2

3

4

5

6

7

8

9

11

12

basophils (FceR1+ CD11b+ CD44+) 10

infiltrating monocytes (F4/80- CD11clo Ly6C+)

Kupffer cells (F4/80+ CD11c+ CD11b+ Ly6Clo MHCII+ )

a

b

Sinusoidal zone

Pericentral zone F4

/80

C

X3

CR

1

CD

11

c

PE

CA

M-1

intravascular

extravascular

c d

e

f

g

LNPCs

h CD317

F4

/80

+

CD

11

c+

CX

3C

R1

+

0

100

200

300

400

Sinusoidal zone

Pericentral zone

*

Ce

lls/m

m2

Fig.1

Gomez de Agüero et al, Science 2016

Li & Limenitakis et al, Nature Communications 2015

Geuking et al, Immunity 2011

Key takeaways

We may set our microbiome early in life

Excessive antibiotic use will alter your microbiome and therefore impact your health

We need more evidence to support prebiotic and probiotic use

Microbiome transplantation does work in some situations, will be developed further!

www.lettemheatdirt.com

Thank you

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