Biology subjects

Hromada, S.

Publications and source records attributed to Hromada, S..

2 recordsLinked to original sources

bioRxiv2022

Microbial interactions impact the growth response of Clostridioides difficile to antibiotics

In the human gut, the growth of Clostridioides difficile is impacted by a complex web of inter-species interactions with members of human gut microbiota. We investigate the contribution of inter-species interactions on the antibiotic response of C. difficile to clinically relevant antibiotics using bottom-up assembly of human gut communities. We discover two classes of microbial interactions that alter C. difficiles antibiotic susceptibility: infrequent increases in tolerance at high antibiotic concentrations and frequent growth enhancements at low antibiotic concentrations. Based on genome-wide transcriptional profiling data, we demonstrate that metal sequestration due to hydrogen sulfide production by the prevalent gut species Desulfovibrio piger increases metronidazole tolerance of C. difficile. Competition with species that display higher sensitivity to the antibiotic than C. difficile leads to enhanced growth of C. difficile at low antibiotic concentrations. A dynamic computational model identifies the ecological design principles driving this effect. Our results provide a deeper understanding of ecological and molecular principles shaping C. difficiles response to antibiotics, which could inform therapeutic interventions.

systems biology↗

bioRxiv2021

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

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. difficiles 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.

systems biology↗