We made significant progress in understanding Escherichia coli dynamics and pathogenicity. Our work focused on three key scientific objectives—unravelling colonisation dynamics, quantifying the selective forces acting on virulence genes, and modelling the evolution of antibiotic resistance—with the major transverse objective of generating new cohorts to study E. coli dynamics in healthy adults.
The pilot (50 healthy volunteers followed every two weeks for 4 months in Paris) was completed. For each sample, five randomly chosen E. coli colonies were typed and will be whole-genome-sequenced in early 2024. This dataset, including extensive host metadata, is already one of the most beautiful of its kind. The main cohort (200 volunteers planned, in Paris) is currently underway. An additional cohort (100 volunteers sampled every month in the North of Vietnam) with samples already collected by my collaborators in past work has been analyzed in a similar way, and will lead to similar insights in the very different context of Vietnam (middle income country, distinct diet, high prevalence of antibioresistances).
We quantified the dynamics of antibiotic resistance in healthy untreated individuals. We showed that contrary to assumptions, resistant strains coexisted with sensitive strains in untreated hosts for extended periods of time, before undergoing abrupt clearance. We currently explore the broader implications of these within-host dynamics on antibiotic resistance evolution at the between-host dynamics.
We investigated E. coli colonisation dynamics in healthy hosts using several datasets including our own pilot study. We reveal a remarkable and robust trade-off between colonisation and persistence. Major clones exhibiting a diversity of strategies organized along a trade-off from clones with long persistent times, to clones with large capacity to colonise new hosts. This trade-off together with niche differentiation explain the diversity of phylogroups circulating in the population, the more frequent occurrence of resistance in persister clones, and the coincidental evolution of virulence.
We also investigated similar trade-off at the level of individual virulence genes, confirming this trade-off and shedding light on how differentiation along the persistence-colonisation trade-off can emerge over evolutionary timescales.
Lastly, we conducted a systematic comparison of E. coli strains from infections and stool samples. We revealed significant genomic differences at all levels. A machine learning algorithm identified new genetic variants associated with pathogenicity, emphasizing the large heritability of this trait and predicting that pathogenicity has evolved upwards over 1980-2010 in France.
Together our results give a systematic picture of the determinants of E. coli pathogenicity, demonstrating that it is a highly heritable trait that may evolve (and has indeed evolved in the past) with important public health implications. Our examination of colonisation dynamics reveals intriguing patterns for antibiotic resistance, and general organizing principles at the level of major clones and virulence genes—such principles will be explored further in the coming years.
