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Microbial determinants of chronic respiratory diseaseGeraint Rogers Slides may not be reproduced without the
express permission of Geraint Rogers
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World Health Organization, Fact sheet 310, 2014
Burden of lower respiratory infections
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• Protracted bacterial bronchitis• Cystic fibrosis• Non CF bronchiectasis• COPD• Primary ciliary dyskinesia• Idiopathic pulmonary fibrosis• Bronchopulmonary dysplasia
Roy et al., Nature 2014 505:412‐416Slides may not be reproduced without the express permission of Geraint Rogers
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Inflammation
Airway damage
Altered mucus secretion
Bacterial colonisation
Disease progression
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Development of culture-independent analysis
Rogers et al., Thorax doi: 10.1136/thoraxjnl‐2014‐205826
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Role of inter-species interactions
Faust et al., PLoS Comput Biol. 2012;8(7):e1002606.
Significant co‐occurrence and co‐exclusion relationships among the abundances of clades in the human microbiome
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Whiteson et al., ISME J. 2014 Jun;8(6):1247‐58.
Clinical importance of inter-species interaction
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The unexpected consequences of treatment
“oral flora”
P. aeruginosa
Ceftazidime E‐test strip
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Whiteson et al., ISME J. 2014 Jun;8(6):1247‐58.
IV antibiotics start IV antibiotics end
days
Relative abun
dance (%
)
‐1‐14 3 75 10 2114 28
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**Rogers et al., The Lancet Respiratory Medicine, 2014 doi:10.1016/S2213‐2600(14)70213‐9
H. influenzae P. aeruginosa
Change in relative abundance of P. aeruginosa and H. influenzae in bronchiectasis patients treated with erythromycin for 12 months
*Rogers et al., ISME J, 2014 2014 Jul 18. doi: 10.1038/ismej.2014.124Slides may not be reproduced without the
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Joana Ricou“Other Self. The human microbiome” “Tube within a tube”
Impact of non-respiratory human microbiota on lung disease
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Gut dysbiosis and respiratory disease progression in CF
Reduced bicarbonate levels
• Reduced pancreatic enzyme efficiency
• Precipitation of bile salts
• Malabsorption• Chronic inflammation• GIT dysbiosis
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*Bruzzese et al., PLoS One. 2014;9(2):e87796.
What is the impact of systemic antibiotic therapy in these vulnerable patients?
Lactobacillus GG resulted in a greater increase in FEV1**
**Bruzzese et al., Clinical Nutrition. 2007;26:322‐328.
Reduced SCFA production• Reduced anti‐inflammatory
effect• Reduced energy intake• Reduced hepatic function• Reduced gut motility• Disruption of blood glucose
levels
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Gut microbiota development
Birth Death
GIT m
icrobiota
complexity
Mode of delivery
Weaning
Unstable UnstableStable
Diet, genetics, illness, antibiotics, environment
Diet, illness, changing GIT physiology
• Metabolism/nutrition/obesity• Neurodevelopment• Immune development
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Ampicillin, gentamicin, metronidazole, vancomycin, neomycin
1 3 5 7 10 21
• Gut microbiota• Immune cell production• Immune modulatory gene expression
Deshmukh et al., Nat Med. 2014 May;20(5):524‐30.
Dysbiosis affects immune function
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Bacterial load Circulating neutrophils
Dysbiosis affects immune function
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Bone marrow neutrophils Hematopoietic stem cell and lineage progenitor cells
Dysbiosis affects immune function
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Abx exposure reduces survival following bacterial challenge
Dysbiosis affect immune function
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Dysbiosis affects immune function
*Namasivayam et al., Pediatrics. 2009;123:1132‐1141.
• Bronchopulmonary dysplasia is associated with preterm birth
• Preterm birth is associated with gut dysbiosis
• BPD is associated with reduced 1L‐17 expression*
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Dysbiosis and vaccine efficacy
Oh et al., Immunity. 2014 Sep 18;41(3):478‐92.
Does GIT dysbiosis influence response to infection later in life?
Tlr5‐/‐WT
Trivalent inactivated
influenza (TIV) vaccine
Assessment of TIV‐specific IgG and IgMantibody response
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Oh et al., Immunity. 2014 Sep 18;41(3):478‐92.
4 weeks abx
WT
Trivalent inactivated
influenza (TIV) vaccine
germ free
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Oh et al., Immunity. 2014 Sep 18;41(3):478‐92Slides may not be reproduced without the
express permission of Geraint Rogers
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Oh et al., Immunity. 2014 Sep 18;41(3):478‐92Slides may not be reproduced without the express permission of Geraint Rogers
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Does microbial exposure in early life influence our immune response to infective challenge in the long term?
Antibiotic ablation of gut microbiotaPCV13 or BCG
Assess antibody responses relative to
controls
David LynnEMBL Australia Group Leader
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Preterm neonatesEstimated that approx. 13 million preterm infants are born each year worldwide (9.6% of all births)*
*Lawn et al., Lancet 365:891‐900, 2005 **Clark et al., Pediatrics, 2006;117:1979
Drivers of dysbiosis in infants• Antibiotic exposure• Feeding/diet• Mode of delivery• Early infection• Non‐antibiotic therapy
How common is disruption of the microbiome in early life?
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Implications of early life dysbiosis for respiratory health in infancy
Pneumonia kills an estimated 1.1 million children under the age of five years every year – more than AIDS, malaria and tuberculosis combined (WHO, 2013).
What are the implications of early life dysbiosis for long term respiratory health?
Moore H et al., J Paediatr Child Health. 2007 Jun;43(6):451‐7.
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Microbial determinants of chronic respiratory disease – a summary
Adaptive immunity
Immune modulation
Host metabolismInfective respiratory
microbiota
GIT microbiota
Disease progression
• Time• Other microbes – fungi, viruses, archaea• Host genetics/lifestyle Slides may not be reproduced without the
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“Hey, we have the tools, we have the talent!”Ghostbusters, 1984
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A/Prof David Lynn
Lex Leong Jocelyn Choo Gianny Scoleri Brendan Kennedy
Dr Renee Smith A/Prof David Serisier Dr Kenneth Bruce
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