understanding the gut microbiome as an ecosystem...
TRANSCRIPT
Understanding the gut microbiome as an ecosystem in health and disease
Catherine Lozupone, Ph.D.Arab-American Frontiers Symposium,
2018Kuwait City, Kuwait
1
The Human Microbiome
Scientific American2
Culture-independent studies revolutionized our understanding of gut bacteria
• Culture-based studies over-emphasized the importance of easily culturableorganisms (e.g. E. coli).
Extract DNA/RNA from environmental samples.
Sequence!
Culture-independent surveys
3
Small Subunit of ribosomal RNA
• Everyone has it.
• Conserved enough to relate all organisms on earth.
4
Gut microbiota has simple composition at the phylum level
Lozupone et al. Nature. 2012
Different phyla: Animalsand plants
5
Fecal Samples from 4 different people
Microbiome is complex at species level
Lozupone et al. Nature. 2012 6
Microbiome is complex at the sub-species level
Strain Variation in Ruminococcus gnavusin individuals with IBDversus healthy controls
Hall et al. 2017 Genome Medicine7
Healthy gut microbiota composition differs with age
Lozupone et. al. 2013 Genome Research.8
Healthy gut microbiota differs with culture and with diet
Lozupone et. al. 2013 Genome Research.9
Bacterial families that differ with age and culture
10
Western population: all ages
Lozupone et. al. 2013 Genome Research.11
Individuals with Ileal Crohn’s disease look like infants
12
Can ecological theory about successioninform us about early development and
disease?
Primary succession
13
Recurrent C. difficile infection (CDI)
• Over 500,000 cases of C. difficile infection yearly
• Associated with antibiotic exposure– Clindamycin, betalactam, fluoroquinolone
• Recurrence rate after first case - 20-30%
• Recurrence rate after subsequent cases - 40-60%
• Individuals with cancer and IBD more likely to get CDI.
14
Fecal Transplants
15
Recurrent CDI resembles infant microbiome
Keith Hazeton
16
Gut Microbiome with Antibiotics
17
18
Alpha and beta diversity are affected more by antibiotics in the context of a Western diet
19
Mechanisms of recovery
20
Butyrate drives hypoxia
Kelly et al, Cell Host and Microbe 2018 21
“Germ-Free” Mice
22
Microbiota colonized mice but not germ free mice have “physiologic hypoxia”
Kelly et al, Cell Host and Microbe 2018 23
24Lozupone et al. Nature 2012
• More likely to be opportunistic pathogens.
• Important in early development and with disturbance.
Cosmopolitan Grow Fast
Compete forlabile substrates
Stress tolerant
25
Clostridium bolteae preferentially colonizes infants
Age (days)
Rel
ativ
e ab
un
dan
ce
• Colonizes an infant just after formula is introduced: low abundance in mother.
• Colonizes an infant late: high abundance in mother.
Rel
ativ
e ab
un
dan
ce
Age (days)
27
Log-rank test p=0.0026Log-rank for trend p=0.0127
28
Conclusions
• Next generation sequencing technologies have enabled deep characterization of gut microbiome composition and how it varies across human populations
• The same type of microbes tend to thrive in early life (infants) and with great disturbance of the gastrointestinal tract in adults.
• This may be relatable to the concept of primary/secondary succession.
• The degree to which an individual is susceptible to antibiotic disturbance conducive to Clostridium difficileinfection is increased by a Western diet in mice.
• Recovery to a complex state resistant to C. difficile infection may be augmented by substrates that encourage butyrate production by microbes that thrive in the disturbed gut.
29
The Lozupone Lab
30
Acknowledgements• Kristine Kuhn – germ free facility CU AMC.
• Rob Knight: – Gail Ackerman, Jesse Stombaugh, Antonio Gonzalez,
Matthew Gebert
• Jeffrey Gordon: Washington University, St. Louis– Janaki Lelwala-Guruge, J. Faith, Federico Rey
• Jeroen Raes (Karoline Faust): VIB, Flanders, Belgium
• Funding:– DOM Early Career scholar award.
31
32