Understanding the gut microbiome as an ecosystem in health and disease

Catherine Lozupone, Ph.D.Arab-American Frontiers Symposium,

2018Kuwait City, Kuwait

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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

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Small Subunit of ribosomal RNA

• Everyone has it.

• Conserved enough to relate all organisms on earth.

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Gut microbiota has simple composition at the phylum level

Lozupone et al. Nature. 2012

Different phyla: Animalsand plants

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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

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Western population: all ages

Lozupone et. al. 2013 Genome Research.11

Individuals with Ileal Crohn’s disease look like infants

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Can ecological theory about successioninform us about early development and

disease?

Primary succession

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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.

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Fecal Transplants

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Recurrent CDI resembles infant microbiome

Keith Hazeton

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Gut Microbiome with Antibiotics

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Alpha and beta diversity are affected more by antibiotics in the context of a Western diet

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Mechanisms of recovery

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Butyrate drives hypoxia

Kelly et al, Cell Host and Microbe 2018 21

“Germ-Free” Mice

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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

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Clostridium bolteae preferentially colonizes infants

Age (days)

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• Colonizes an infant just after formula is introduced: low abundance in mother.

• Colonizes an infant late: high abundance in mother.

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Age (days)

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Log-rank test p=0.0026Log-rank for trend p=0.0127

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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.

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The Lozupone Lab

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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.

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