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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
* Sartor RB; and Sokol et al 2008 PNAS 105 Grice et al 2009 Science
Dicksved 2008
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 independent methods– Detection– Quantification– Identification
• Microscopy• Molecular methods (protein and nucleic acid)• Do not rely on ‘isolates,’
CFUs, Bergey’sRogers GB et al 2009, J. Med. Microbiol 58 Anderson et al 2004 J. Clin. Microbiol 42’Klouche and Schroder 2008 Clin. Chem. And Lab. MedWoo et al 2008. Clin. Microbiol. Inf. 14Fenollar and Raoult D 2007. Int J. Antimicrob Agents 30Frank and Pace 2008 Curr. Opin. Gastroenterol.
Current Failures• Current Molecular Methods flawed• Detecting the known• Biases• Uninterpretable results– Higher taxonomic orders – Annotation problems
• Lack of mechanism
Roratto et al 2008 Genet Mol Biol 31(1)
Ashelford et al AEM 2005
Cost
ello
et a
l 200
9 Sc
ienc
e
Diversity: At One Site
• Stomach– Very different by culture– 100-250 OTUs or more
• Palm• Forearm
Fierer et al 2008 PNAS
Yang et al 2009
Camp et al 2009 Costello et al 2009 Science
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
Costello et al 2009 Science
Spatial Microdiversity
• Small Niches• Microcolonies• Biofilms
Grice 2008 Genome Res.
Poulsen et al 1994 Inf and Imm
Healy et al 2008 Otolaryngol Head Neck Surg
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(?)
Miragaia et al 2007 J. Bact.
Tang et al. 2009 PLoS Comp. Bio.
Diversity: Similar Hosts
• Individual Variation• Typically considered
priority/founder or family effects
Dicksved 2008
Diversity: Local Culture
Nadsidze et al 2009 Genome ResearchSalivary FloraPCA
Diversity: Across Species
• 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
Friswell et al PLOS One 2010
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
• Strain turn over– E. coli turns over 8 – 36 mo.
• Changes in abundance– Occur during many life changes
• New methods and long term effects…
Wid
ely
dist
ribut
ed im
age
Ley
et a
l Nat
ure
2006
Costello et al 2009 Science
Diversity: Over Millennia
• Evolution of symbionts and pathogens
Ley RE et al. 2008 Science
Local Function
• Integrated Physiology• Mucosal Immunity:
Subversion or cooperation?• Communication• Competitive
exclusion
Medical Microbiology, UT 1996
Hooper 2009
Systemic Function
• Systemic Immunity • Control inputs and process outputs• Function as a secretory organ
Martin et al 2008
Functional Genomics
• Another way to study bacterial function• Genes, not taxa
Jones et al 2009 PNASBile Salt Hydrolases in different gut microbiomes
Adams et al 2008 Nature Education 1
Local Disease
• Heart Valve Infections• Cariogenesis• Acne• Asthma• Cystic Fibrosis• Chronic UTIsBreitkopf et al 2005 Circulation 111Voldstedlund M et al 2008 APMIS 116
Peterson et al 2008 Cell Host and Microbe 3(6)
BBC
Systemic Disease
• Obesity• Vascular disease• Autoimmune diseases• Fevers
The Scientist 1999Loscalzo et al 2006
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
• Broad spectrum, systemic therapies– Changes the flora– Does the flora reappear?
• Inappropriate nutritional inputs
Dethlefsen et al 2008
Khafipour et al 2009
Wounds
• Initial contamination • Colonization and
Critical Colonization• Spreading Infection, Sepsis• Non-healing wounds
Johnson & Johnson Wound Management
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
Univ. of Glamorgen
DoD
‘Chronic Wound’ Ecology
• Polymicrobial infections
Dowd et al 2008 BMC MicrobiologyDowd et al 2008 PLoS One
Wolcott et al 2009 BMC Microbiology
Venous Leg
Diabetic
Wound Care
• Full Spectrum Wound Care– Decontamination– Colonization management– Decolonization– Debridement of advanced infections
• Logistics
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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