Negative interactions determine Clostridioides difficile growth in synthetic human gut communities

• Published in: Molecular systems biology 2021-10, Vol.17 (10), p.e10355-n/a
• Main Authors: Hromada, Susan, Qian, Yili, Jacobson, Tyler B, Clark, Ryan L, Watson, Lauren, Safdar, Nasia, Amador‐Noguez, Daniel, Venturelli, Ophelia S
• Format: Article
• Language: English
• Subjects: Abundance; Acidification; Bacteria; Biodiversity; Clostridioides; Clostridioides difficile; Clostridium Infections - drug therapy; Colonization; Competition; computational modeling; Computer applications; ecological interactions; EMBO23; EMBO41; Gastrointestinal Microbiome; Humans; Intestinal microflora; Microbiomes; Microbiota; Molecular modelling; Ordinary differential equations; Organisms; pathogen invasion; Phylogenetics; Principles; Species richness; systems biology
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.202110355

Understanding the principles of colonization resistance of the gut microbiome to the pathogen Clostridioides difficile will enable the design of defined bacterial therapeutics. We investigate the ecological principles of community resistance to C. difficile using a synthetic human gut microbiome. Using a dynamic computational model, we demonstrate that C. difficile receives the largest number and magnitude of incoming negative interactions. Our results show that C. difficile is in a unique class of species that display a strong negative dependence between growth and species richness. We identify molecular mechanisms of inhibition including acidification of the environment and competition over resources. We demonstrate that Clostridium hiranonis strongly inhibits C. difficile partially via resource competition. Increasing the initial density of C. difficile can increase its abundance in the assembled community, but 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 featuring a combination of mechanisms including species richness, environment acidification, and resource competition. SYNOPSIS A combination of bottom‐up community assembly and computational modeling reveals determinants of Clostridioides difficile growth in synthetic human gut communities. The inferred interspecies interaction network reveals that C. difficile receives the largest number and magnitude of incoming negative interactions. The richness of a community, environmental acidification by a community, propagule pressure and resource competition are major determinants of C. difficile growth. Clostridium hiranonis consumes resources utilized by C. difficile and inhibits C. difficile growth. Graphical Abstract A combination of bottom‐up community assembly and computational modeling reveals determinants of Clostridioides difficile growth in synthetic human gut communities.