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

Early-life probiotics have emerged as a promising strategy to combat the global emergency of antimicrobial resistance by enhancing gut resilience in infants. However, how exactly probiotic bacteria affect resistant opportunistic pathogens, i.e ., pathobionts, remains nascent. We investigated effects of probiotic supplementation in 152 full-term, healthy Tanzanian infants, a sub-cohort of the ProRIDE trial ( NCT04172012 ). Administration of oral probiotics during the first 4 weeks of life led to enhanced gut colonization by the probiotic Bifidobacterium species while suppressing pathobionts such as extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E). Integration of metagenomics with metabolomics revealed that probiotics decreased resistome load and mobilome richness at 6 weeks, with concurrent shifts in metabolome. Specifically, the intervention increased fecal lactate and pyruvate and reduced cross-feeding pathways leading to propionate and butyrate, which partly explained the reduced ESBL-E carriage. Our findings provide mechanistic insights into how probiotic-driven Bifidobacterium colonization modulates infant gut ecosystem to attenuate antimicrobial resistance in infancy.