Genetic bottlenecks limit the rise of pandemic cholera strains

A new study by the Genomics and Microbial Evolution Group at the Miguel Hernández University of Elche (UMH) together with the Department of Host-Microbe Interactions at St. Jude Children's Research Hospital in Memphis, USA, sheds light on one of the great enigmas of microbiology: why only certain strains of common bacteria become pandemic pathogens. The work, published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), focuses on Vibrio cholerae, the bacterium that causes cholera. It reveals that its most dangerous form arises from a specific combination of genes and allelic variants that give it an advantage in the human intestine. This research could pave the way for new strategies to predict and prevent future cholera outbreaks.

The study results from a collaboration between UMH researcher Mario López Pérez and Professor Salvador Almagro-Moreno of the St. Jude Children's Research Hospital. It also involved UMH Professor José M. Haro Moreno and predoctoral researcher Alicia Campos López, affiliated with the Department of Plant Production and Microbiology.

Through an extensive analysis of over 1,840 Vibrio cholerae genomes, the researchers identified eleven distinct phylogenetic clusters, with the pandemic group belonging to the largest and located within a lineage shared with environmental strains. Their findings suggest that the emergence of pandemic strains, responsible for global cholera outbreaks, is largely dependent on the acquisition of unique modular gene clusters and allelic variations that confer a competitive advantage during intestinal colonization.. These act as nonlinear filters that prevent most environmental strains from becoming human pathogens.

As a result, only a small group of Vibrio cholerae strains can cause cholera in humans, despite the species' vast natural diversity. We wondered why only this small subset has ever triggered pandemics."

Mario López, UMH researcher, lead author of the study

The study reveals that the emergence of pandemic V. cholerae clones is constrained by specific genetic bottlenecks. These require: a genetic background pre-adapted for virulence, the acquisition of key gene clusters such as CTXΦ and VPI-1, their organization into specific modular arrangements, and finally, the presence of unique allelic variants. "Only when all these elements come together can a strain evolve into a pandemic-capable pathogen," the researchers explain.

These features are absent in most environmental V. cholerae strains and appear to grant pandemic clones a key competitive advantage: enhanced ability to colonize the human gut.

"Interestingly, the genetic traits that enable V. cholerae to infect humans don't benefit the bacteria in their natural aquatic environment," López notes. In the wild, V. cholerae typically lives freely or in association with cyanobacteria colonies, mollusks, or crustaceans.

Cholera is endemic in parts of the world with poor water, sanitation, and hygiene infrastructure. Outbreaks can also occur after natural disasters that disrupt these systems. The disease is characterized by sudden, severe episodes of watery diarrhea, leading to rapid dehydration and, if untreated, potentially death.

"Our analytical model could be applied to other environmental bacteria to understand how pathogenic clones emerge from non-pathogenic populations," López emphasizes. The study also opens the door to more precise surveillance of strains with pandemic potential-an approach that could be highly useful for future public health preparedness.

The research was supported by the U.S. National Science Foundation (NSF) through the CAREER program (#2045671) and by the Burroughs Wellcome Fund's Investigator in the Pathogenesis of Infectious Disease program (#1021977). It also received funding from the Spanish "MICRO3GEN" project (PID2023-150293NB-I00), co-financed by the European Regional Development Fund (FEDER) and managed by the Spanish Ministry of Economy, Industry, and Competitiveness.