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Species richness determines C. difficile invasion outcome in synthetic human gut communities

View ORCID ProfileSusan Hromada, Ryan L. Clark, Yili Qian, Lauren Watson, Nasia Safdar, View ORCID ProfileOphelia S. Venturelli
doi: https://doi.org/10.1101/2021.03.23.436677
Susan Hromada
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
2Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
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  • ORCID record for Susan Hromada
Ryan L. Clark
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
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Yili Qian
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
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Lauren Watson
3Division of Infectious Disease, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
4Department of Medicine, William S. Middleton Veterans Hospital Madison, Madison, WI, USA
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Nasia Safdar
3Division of Infectious Disease, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
4Department of Medicine, William S. Middleton Veterans Hospital Madison, Madison, WI, USA
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Ophelia S. Venturelli
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
2Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
5Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA
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  • For correspondence: venturelli@wisc.edu
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Abstract

Understanding the principles of colonization resistance of the gut microbiome to the pathogen Clostridioides difficile will enable the design of next generation defined bacterial therapeutics. We investigate the ecological principles of community resistance to C. difficile invasion using a diverse synthetic human gut microbiome. Our results show that species richness is a key determinant of C. difficile growth across a wide range of ecological contexts. Using a dynamic computational model, we demonstrate that C. difficile receives the largest number and magnitude of incoming negative interactions. We identify molecular mechanisms of inhibition including acidification of the environment and competition over glucose. We demonstrate that C. difficile’s close relative Clostridium hiranonis strongly inhibits C. difficile via a pH-independent mechanism. While increasing the initial density of C. difficile can increase its abundance in the assembled community, the community context determines the maximum achievable C. difficile abundance. Our work suggests that the C. difficile inhibitory potential of defined bacterial therapeutics can be optimized by designing communities that feature a combination of mechanisms including species richness, environment acidification, and resource competition.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 23, 2021.
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Species richness determines C. difficile invasion outcome in synthetic human gut communities
Susan Hromada, Ryan L. Clark, Yili Qian, Lauren Watson, Nasia Safdar, Ophelia S. Venturelli
bioRxiv 2021.03.23.436677; doi: https://doi.org/10.1101/2021.03.23.436677
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Species richness determines C. difficile invasion outcome in synthetic human gut communities
Susan Hromada, Ryan L. Clark, Yili Qian, Lauren Watson, Nasia Safdar, Ophelia S. Venturelli
bioRxiv 2021.03.23.436677; doi: https://doi.org/10.1101/2021.03.23.436677

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