Metabolic reprogramming of the infant gut by bifidobacteria-based probiotics drives exclusion of antibiotic-resistant pathobionts.

Abstract

Early-life probiotics that strengthen gut resilience in infants are a promising strategy to combat the global emergency of antibiotic resistance. Still, their effects on antibiotic-resistant opportunistic pathogens, i.e., pathobionts, remain unclear. We evaluate the effects of probiotic supplementation in 152 full-term Tanzanian infants enrolled in the ProRIDE trial. Oral probiotics during the first 4 weeks of life increase gut colonization by Bifidobacterium species, while suppressing pathobionts, including extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E). Integrated metagenomics and metabolomics show that probiotics reduce resistome load and mobilome richness at 6 weeks, accompanied by concurrent shifts in the fecal metabolome. Specifically, the intervention increases lactate and pyruvate and reduces cross-feeding pathways that lead to propionate and butyrate, which partly explains the reduction in ESBL-E carriage. Our study documents putative pathways by which probiotic-driven Bifidobacterium colonization modulates the infant gut toward a lower level of antibiotic resistance.