Resource-access breadth marks protective strains against toxigenic Clostridioides difficile
- 1Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Abstract
Antibiotic disruption of gut microbiota creates opportunities for toxigenic Clostridioides difficile. One strategy is to occupy this niche with a non-toxigenic or weakly virulent strain, but even strains that cause little disease may fail to compete during pathogen challenge. We screened 21 sequence type 1 (ST1) isolates for their ability to protect mice co-colonized with toxigenic VPI10463, separating disease potential from protection. Some strains, such as ST1-75, caused little disease and protected, whereas others, such as ST1-68, caused little disease but failed to protect. Metabolomics showed that ST1-75 depleted more proline than ST1-68, whereas another protective strain, ST1-6, had a different metabolic profile; both protective strains nevertheless responded to many substrates. Substrate-utilization profiling revealed that protection across the 21 isolates correlated with amino-acid overlap with VPI10463, but not overall nutrient overlap or shared genome-encoded protein families. Relative amino-acid access explained variation beyond mono-colonization disease potential, and a consumer-resource model showed how nutrient overlap together with additional resource access can support persistence during competition. Additional experiments support that ST1-mediated protection occurs even in the absence of mature B and T cells. These findings distinguish low disease potential from protection, link protection to strain competition, and identify relative resource access as an informative phenotype for prioritizing strains for biotherapeutic testing.
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BibTeX
@misc{mishra2026resourceaccess,
title = {{Resource-access breadth marks protective strains against toxigenic Clostridioides difficile}},
author = {V. Mishra and K. Sia and C. Lindberg and S. Sharma and M. Wu and A. Djukovic and H. Jeong and M. Kamboj and Q. Dong and J. B. Xavier},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.756234},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756234v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Resource-access breadth marks protective strains against toxigenic Clostridioides difficile
AU - V. Mishra
AU - K. Sia
AU - C. Lindberg
AU - S. Sharma
AU - M. Wu
AU - A. Djukovic
AU - H. Jeong
AU - M. Kamboj
AU - Q. Dong
AU - J. B. Xavier
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.756234
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.756234v1
AB - Antibiotic disruption of gut microbiota creates opportunities for toxigenic Clostridioides difficile. One strategy is to occupy this niche with a non-toxigenic or weakly virulent strain, but even strains that cause little disease may fail to compete during pathogen challenge. We screened 21 sequence type 1 (ST1) isolates for their ability to protect mice co-colonized with toxigenic VPI10463, separating disease potential from protection. Some strains, such as ST1-75, caused little disease and protected, whereas others, such as ST1-68, caused little disease but failed to protect. Metabolomics showed that ST1-75 depleted more proline than ST1-68, whereas another protective strain, ST1-6, had a different metabolic profile; both protective strains nevertheless responded to many substrates. Substrate-utilization profiling revealed that protection across the 21 isolates correlated with amino-acid overlap with VPI10463, but not overall nutrient overlap or shared genome-encoded protein families. Relative amino-acid access explained variation beyond mono-colonization disease potential, and a consumer-resource model showed how nutrient overlap together with additional resource access can support persistence during competition. Additional experiments support that ST1-mediated protection occurs even in the absence of mature B and T cells. These findings distinguish low disease potential from protection, link protection to strain competition, and identify relative resource access as an informative phenotype for prioritizing strains for biotherapeutic testing.
ER -