Host genetics shapes the recovery of the gut microbiome after antibiotic treatment: the role of the blood group related <i>B4galnt2</i> gene

The intestinal microbiota is integral to host health, metabolism, and colonization resistance. Antibiotics can disrupt microbial homeostasis, leading to dysbiosis and altered colonization resistance. While antibiotic-induced microbiota disruption is well-documented, less is known about how host genetics shapes post-antibiotic recovery. Here, we investigate the impact of <i>B4galnt2</i>, a blood-group-related glycosyltransferase gene, on microbiota recovery following antibiotic treatment. Using a longitudinal, multi-omic approach-including 16S rRNA gene sequencing, metagenomics, and metatranscriptomics-we compare the microbiota dynamics of <i>B4galnt2^+/-</i> and <i>B4galnt2^-/-</i> mice after treatment with streptomycin, kanamycin, and vancomycin. Our findings reveal that <i>B4galnt2^-/-</i> mice exhibit faster recovery of microbial diversity and composition following streptomycin treatment compared to their <i>B4galnt2^+/-</i> counterparts. This accelerated recovery is associated with higher relative abundance of taxa such as <i>Blautia</i>, <i>Dorea,</i> and other Lachnospiraceae, and increased expression of motility-related genes, and differential regulation of antibiotic resistance genes (ARGs), including the aminoglycoside nucleotidyltransferase genes <i>aadA</i> and <i>aadE</i>. Genotype-dependent differences in recovery were most pronounced following streptomycin and were not consistently observed with kanamycin or vancomycin, indicating an antibiotic-by-genotype interaction shaped by the <i>B4galnt2</i>-associated microbiota. These results underscore the role of host genetics in shaping microbiota response and recovery following antibiotic exposure. By demonstrating the interplay between glycosylation-mediated microbiota composition, antibiotic response, and microbial recovery, our study may provide insights into the potential for personalized approaches to mitigate dysbiosis-related health outcomes.<h4>Importance</h4>Antibiotic treatments disrupt the gut microbiome, often leading to long-term alterations that potentially affect host health. While much is known about how antibiotics cause microbial dysbiosis, little is understood about the factors that could influence the speed of microbial community recovery, such as host genetic differences. Using a mouse model, this study reveals that genetic variation at the blood group-related <i>B4galnt2</i> gene significantly alters recovery after streptomycin treatment. Mice lacking intestinal <i>B4galnt2</i> expression recover faster, with distinct changes in microbial composition, activity, and antibiotic resistance gene expression. These findings highlight how a single host gene can shape microbiota dynamics following antibiotic-induced disruption. The work emphasizes the importance of considering host genetic factors when predicting microbiome responses to antibiotics and suggests potential for genotype-guided strategies to reduce the adverse effects of microbiome-targeted therapies.