Species richness determinesC. difficileinvasion outcome in synthetic human gut communities

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.

A spatially structured mathematical model of the gut microbiome reveals factors that increase community stability

“…In Data S2 , we show that species richness increases stability in the absence of spatial structure ( Figure S4 ; Table S1 ), which is consistent with previous work. 34 , 35 , 36 , 37 We also find that these designed communities are much less stable than the ones generated by the assembly scenario (median stability is 0.24 and 0.96, respectively, one-sided Wilcoxon rank-sum test: and ; Cliff’s delta is ), which is also consistent with recent findings. 23 , 26 Higher stability in the assembly scenario is due to higher species richness than in the design scenario ( Figures S5–S7 ).…”

“…Suppose we could increase the positive effects from the upstream to the downstream by increasing the upstream species richness. In that case, we can also expect that the upstream stability (i.e., the resistance to invasion upstream) increases as suggested by previous studies without spatial structure 35 , 36 , 37 (see also Data S2 ).…”

“…It is important to note that our measure of stability in a downstream community within two connected patches differs substantially from other measures of stability in the field: our stability is composed of resistance to invasion 32 , 33 , 34 , 35 , 36 , 37 and structural persistence (persistence despite environmental changes caused by upstream invasion events).…”

“…This criterion is important because invaders may decrease community function or drive one or more species in the community extinct. Previous studies suggest that species richness (i.e., the number of species in a community) increases the resistance to invasion both in theory 34 and experiments, 35 , 36 , 37 presumably because a species-rich community exploits available resources, making them inaccessible for invaders. 38 The second stability criterion we consider is resistance to environmental change caused by changes to the upstream community composition.…”

Two modes of evolution shape bacterial strain diversity in the gut for thousands of generations

“…Interestingly, we found that the resident E. coli persists independently of microbiota diversity. This highlights the need to understand diversity at the strain level to predict key functions of the microbiome, such as its capacity to provide colonization resistance to opportunists (Hromada et al, 2021).…”