Replication of Host St6galnac1-Microbiome Association Across Distinct Experimental Conditions in Heterogeneous Stock Rats

The gut microbiome is influenced by both environmental and hereditary factors. To comprehend the heritability of traits linked to the microbiome, it is crucial to pinpoint particular host genes. The St6galnac1 gene encodes a sialyltransferase critical for mucin O-glycosylation. A study by Tonnele et al. (2025) revealed a significant correlation between a gene locus containing the St6galnac1 gene and an increased presence of the Paraprevotella genus in cecal samples obtained from fasting animals.

This connection was subsequently confirmed in multiple cohorts and aligned with a previously observed association between a gene with similar function, ST6GAL1, and Paraprevotella in humans.

Considering the microbiome's sensitivity to factors like sampling location, feeding status, and analytical framework, it is vital to replicate these findings independently. Moreover, it is essential to determine if the association remains consistent across various conditions or is strictly confined to specific environments. To address these concerns, researchers conducted a replication study using stool samples from 174 heterogeneous stock rats.

These rats had not been fasted before sample collection. The microbial community structure of the stool samples was examined using 16S rRNA gene sequencing and compositionally aware methods. Genetic analysis of the rats focused on the top SNP associated with Paraprevotella in the Tonnele et al. (2025) study. To test the association between genotype and Paraprevotella abundance, researchers employed a linear mixed model that considered sex, cohort, and genetic relatedness.

The replication of the St6galnac1 - Paraprevotella association (p=0.015) confirms the robustness of this connection across diverse sampling strategies and experimental conditions, suggesting that the relationship is not limited to specific environments.