Baseline co-occurrence of Faecalibacterium prausnitzii and Ruminococcus bromii is associated with greater increases in selected short-chain fatty acid-related pathways following resistant starch type 2 intervention across diverse populations.

Type 2 resistant starch (RS2) can be fermented by the gut microbiota and contribute to short-chain fatty acid (SCFA) production; however, microbial responses to resistant starch vary substantially across individuals and populations, and the role of baseline microbiota in this variability remains incompletely understood. In this study, we integrated four publicly available paired metagenomic datasets representing diverse experimental and host contexts and performed cross-dataset analyses of taxonomic and functional responses. Faecalibacterium prausnitzii was among the taxa consistently enriched after resistant starch-related intervention or exposure across multiple datasets. Exploratory baseline stratification further suggested that the presence of F. prausnitzii was associated with changes in selected SCFA- and carbohydrate metabolism-related pathways. We subsequently examined its relationships with the representative resistant starch degraders Ruminococcus bromii and Bifidobacterium adolescentis. Baseline association analyses identified a reproducible positive association between R. bromii and F. prausnitzii. In cohort-adjusted analyses of mutually exclusive microbial configurations, the Fp + Rb configuration was associated with greater increases in the acetate/lactate-related pathways P41-PWY and PWY-5100 than the Fp + Rb + Ba configuration, whereas no significant differences were observed for the other selected SCFA-related pathways. Continuous abundance analyses provided no significant evidence for abundance-dependent effects of Rb or Fp or for an Rb × Fp interaction. These findings identify baseline Fp + Rb co-occurrence as a hypothesis-generating microbial configuration associated with responses in selected SCFA-related pathways and provide a basis for independent experimental validation.