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Allow Myself to Introduce … Myself. The Human Microbiome in Health and Disease CPT BC Kirkup, Ph.D. BLUF. Humans are partly bacterial There is a ‘normal flora’ Flora can ‘mis-provide’ functions dysbiosis* Flora have a role in trauma and healing. Dicksved 2008. Grice et al 2009 Science.

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Allow myself to introduce myself

Allow Myself to Introduce … Myself

The Human Microbiomein Health and Disease

CPT BC Kirkup, Ph.D.


Allow myself to introduce myself

BLUF

  • Humans are partly bacterial

  • There is a ‘normal flora’

  • Flora can ‘mis-provide’ functions

    • dysbiosis*

  • Flora have a role in trauma and healing

Dicksved 2008

Grice et al 2009 Science

* Sartor RB; and Sokol et al 2008 PNAS 105


Prokaryotic personality

Prokaryotic Personality

  • Humans are 90% bacterial

    • Cell counts

    • 99+% by gene diversity

  • Communication andcross-feeding

  • Integrates with systems

Davis CP 1976 AEM 31

Willing and Finlay 2009 Current Biology


Culture independence

Culture Independence

  • Culture independent methods

    • Detection

    • Quantification

    • Identification

  • Microscopy

  • Molecular methods (protein and nucleic acid)

  • Do not rely on ‘isolates,’ CFUs, Bergey’s

Rogers GB et al 2009, J. Med. Microbiol 58

Anderson et al 2004 J. Clin. Microbiol 42’

Klouche and Schroder 2008 Clin. Chem. And Lab. Med

Woo et al 2008. Clin. Microbiol. Inf. 14

Fenollar and Raoult D 2007. Int J. Antimicrob Agents 30

Frank and Pace 2008 Curr. Opin. Gastroenterol.


Current failures

Current Failures

  • Current Molecular Methods flawed

  • Detecting the known

  • Biases

  • Uninterpretable results

    • Higher taxonomic orders

    • Annotation problems

  • Lack of mechanism

Ashelford et al AEM 2005

Costello et al 2009 Science

Roratto et al 2008 Genet Mol Biol 31(1)


Diversity at one site

Diversity: At One Site

  • Stomach

    • Very different by culture

    • 100-250 OTUs or more

  • Palm

  • Forearm

Yang et al 2009

Fierer et al 2008 PNAS

Camp et al 2009

Costello et al 2009 Science


Diversity number of sites

Diversity: Number of Sites

  • What is a ‘site?’

  • Forearm vs. antecubital fossa

  • Left hand vs. Right hand

Fierer et al 2008 PNAS

Costello et al 2009 Science


The skin

The Skin

Costello et al 2009 Science


Spatial microdiversity

Spatial Microdiversity

  • Small Niches

  • Microcolonies

  • Biofilms

Poulsen et al 1994 Inf and Imm

Healy et al 2008 Otolaryngol Head Neck Surg

Grice 2008 Genome Res.


Genetic microdiversity

Genetic Microdiversity

  • Clonal expansions appear infrequent

    • Observations from marine bacteria

  • High diversity below the species level

    • Gene content, allelic, SNP variation all high

  • Selective sweeps

    • Small scale or rare?

    • Impact of phage?

  • Not well explored for human microbiome

    • Differs by genera, guild(?)

Tang et al. 2009 PLoS Comp. Bio.

Miragaia et al 2007 J. Bact.


Diversity similar hosts

Diversity: Similar Hosts

  • Individual Variation

  • Typically considered priority/founder or family effects

Dicksved 2008


Diversity local culture

Diversity: Local Culture

Nadsidze et al 2009 Genome Research

Salivary Flora

PCA


Diversity across species

Diversity: Across Species

Friswell et al PLOS One 2010

  • Different animals have different flora

  • Formerly study isolates

    • Studies of enterics

  • Allows for bigdiet differences

Ley RE et al. 2008 Nat. Rev. Micro.

Ley RE et al. 2008 Science


Diversity during the day

Diversity: During the Day

  • Diurnal cycles

  • Hand washing:

    • Down: Propionibacteria, Neisseriales, Burkholderiales, Pasteurallaceae

    • Up: Staphylococcus, Streptococcus, Lactobacillus

    • Reduces gender differences

    • Population reestablished quickly

Costello et al 2009 Science


Stability months years

Stability: Months & Years

  • Strain turn over

    • E. coli turns over 8 – 36 mo.

  • Changes in abundance

    • Occur during many life changes

  • New methods and long term effects…

Widely distributed image

Ley et al Nature 2006

Costello et al 2009 Science


Diversity over millennia

Diversity: Over Millennia

  • Evolution of symbionts and pathogens

Ley RE et al. 2008 Science


Local function

Local Function

  • Integrated Physiology

  • Mucosal Immunity: Subversion or cooperation?

  • Communication

  • Competitive exclusion

Hooper 2009

Medical Microbiology, UT 1996


Systemic function

Systemic Function

  • Systemic Immunity

  • Control inputs and process outputs

  • Function as a secretory organ

Martin et al 2008


Functional genomics

Functional Genomics

  • Another way to study bacterial function

  • Genes, not taxa

Jones et al 2009 PNAS

Bile Salt Hydrolases in different gut microbiomes

Adams et al 2008 Nature Education 1


Local disease

Local Disease

  • Heart Valve Infections

  • Cariogenesis

  • Acne

  • Asthma

  • Cystic Fibrosis

  • Chronic UTIs

BBC

Breitkopf et al 2005 Circulation 111

Voldstedlund M et al 2008 APMIS 116

Peterson et al 2008 Cell Host and Microbe 3(6)


Systemic disease

Systemic Disease

  • Obesity

  • Vascular disease

  • Autoimmune diseases

  • Fevers

Loscalzo et al 2006

The Scientist 1999


Systemic and local treatments

Systemic and Local Treatments

  • Local dysbiosis can yield systemic disease

  • Local treatment can yield systemic cure

  • Systemic treatment: collateral damage

    • Cure a local disease, cause other local dysbiosis

    • Expose more strains to adverse selection


Mistreatment

Mistreatment

  • Broad spectrum, systemic therapies

    • Changes the flora

    • Does the flora reappear?

  • Inappropriate nutritional inputs

Khafipour et al 2009

Dethlefsen et al 2008


Wounds

Wounds

Johnson & Johnson Wound Management

  • Initial contamination

  • Colonization and Critical Colonization

  • Spreading Infection, Sepsis

  • Non-healing wounds


Wounds1

Wounds

  • Chronic vs. Acute Wounds

    • False dichotomy

  • ‘Wounds with Co-morbidities’

    • Diabetes, vascular insufficiency

  • ‘Traumatic wounds’

    • Healthy tissue injured by physical forces

  • ‘Burns’

    • Heat and chemical degradation

DoD

Univ. of Glamorgen


Chronic wound ecology

‘Chronic Wound’ Ecology

  • Polymicrobial infections

Venous Leg

Wolcott et al 2009 BMC Microbiology

Diabetic

Dowd et al 2008 PLoS One

Dowd et al 2008 BMC Microbiology


Wound care

Wound Care

  • Full Spectrum Wound Care

    • Decontamination

    • Colonization management

    • Decolonization

    • Debridement of advanced infections

  • Logistics


Questions

Questions

  • About the microbiome?

  • About wound microbiology?

  • About innovative wound care concepts?

  • About Army microbiology?

The views expressed here are the author's alone and do not necessarily represent those of the Department of Army or the Department of Defense


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