Abstract Fermentation products released by bacteria in the large intestine, such as butyrate and propionate, play central roles in host physiology and health. While the metabolic pathways producing these short-chain fatty acids (SCFAs) are well-characterized, less is known about their relative prevalence across hosts and gut conditions. Here, we introduce a genome-resolved, abundance-weighted bioinformatics framework that integrates pathway-based gene identification with extensive literature validation to systematically quantify the potential for butyrate and propionate production across bacterial species and human gut microbiomes. By comparing pathway predictions against over 700 experimentally characterized strains, we demonstrate high concordance with reported metabolic phenotypes, validating our approach beyond prior purely computational studies. Weighted by species abundance across ~18,000 metagenomic samples, we find that dominant gut taxa disproportionately drive SCFA production, with butyrate pathways enriched in Bacillota and propionate pathways in Bacteroidota. This abundance-weighted analysis reveals that pathway presence is well conserved at the family level, highlighting the ecological relevance of dominant taxa for community-level fermentation potential. Our results further show pronounced inter-individual variation and associations with age, birthing method, and inflammatory bowel disease, emphasizing how shifts in microbiota composition influence SCFA availability. By combining pathway-level resolution, abundance-weighted inference, and literature-based validation, our framework provides a robust, scalable approach to link microbial functional potential with host-relevant outcomes.
Christensen et al. (2026) studied this question.