DOI: 10.1128/mbio.01127-26 ISSN: 2150-7511

Ecology of protection: probiotic biogeography and sepsis prevention in the neonatal intestine

Sierra C. Hansen, Christopher W. Hamm, Jeffrey R. Singer, Casey T. Weaver, Michael J. Gray
Show PDF Cite

ABSTRACT

Neonatal infection is a leading cause of morbidity and mortality worldwide, particularly among preterm and low birth weight infants. Probiotic bacteria are widely used in peri- and postnatal care and can reduce neonatal intestinal dysbiosis. However, formulations and efficacy remain highly variable, highlighting a critical gap in our understanding of the mechanisms that drive successful interventions in this population. Furthermore, current studies on probiotic efficacy rely on indirect or relative measures of intestinal bacterial burden. Here, we directly mapped the biogeography of intestinal colonization and quantified the probiotic effects of Escherichia coli Nissle 1917 (EcN) and Ligilactobacillus murinus strain V10 against Klebsiella pneumoniae dysbiosis across the neonatal murine intestine. Despite substantial differences in their spatial distribution along the intestine, both EcN and L. murinus V10 significantly reduced K. pneumoniae colonization and mortality from K. pneumoniae sepsis, with EcN providing greater protection. EcN’s probiotic activity was partially dependent on high-affinity oxygen respiration, implicating luminal oxygen availability as a key ecological determinant of probiotic efficacy. Contrary to the common assumption that multi-strain probiotics are inherently superior, simultaneous administration of EcN and L. murinus V10 was less effective than EcN treatment alone at preventing sepsis-related death. These findings identify intestinal niche occupancy, oxygen utilization, and strain-strain interactions as critical variables which should inform the rational design of future probiotic interventions for high-risk neonates.

IMPORTANCE

Late-onset sepsis (LOS) remains a devastating and difficult-to-treat complication of prematurity, and probiotics are increasingly used to reduce dysbiosis and infection risk in this vulnerable population. Probiotic regimens, however, are highly heterogeneous, and their mechanisms of action in the neonatal intestine are poorly defined, complicating efforts to design safe, effective, and regulatable interventions. In this work, we use a neonatal mouse model of LOS to rigorously test fundamental assumptions underlying the current paradigm for understanding the impact of probiotics on intestinal disease. We demonstrate that two distantly related probiotic bacteria, Escherichia coli Nissle 1917 and Ligilactobacillus murinus V10, each reduce intestinal colonization and mortality caused by the LOS pathobiont Klebsiella pneumoniae , but do so through distinct ecological and molecular mechanisms. These findings highlight ecological principles, including spatial niche occupancy, resource competition, and strain-strain interactions, as critical determinants of probiotic efficacy, and provide mechanistic insight that will be important for guiding rational probiotic strategies for high-risk neonates.

More from our Archive