The role of lactate metabolism in shaping intestinal microbiota and health.

Lactate, particularly the D-isomer, which is produced exclusively by microbial fermentation, is usually low or undetectable in the healthy colon but can accumulate when there is a microbial imbalance, contributing to low pH and inflammation. Intestinal lactate-utilizing bacteria, such as Anaerobutyricum soehngenii, Anaerostipes species, and Coprococcus catus, convert lactate to short-chain fatty acids, including butyrate, potentially important for health. Here, we mined genomes of lactate utilizers for genes involved in propionate formation and conducted metabolic network modeling to investigate the cross-feeding mechanism. Genomes were also mined for antibiotic resistance genes, important when considering strains for biotherapeutics. Metabolic models were computed to elucidate the potential cross-feeding mechanisms between lactate utilizers in the human gut. Bioinformatics analysis revealed that the butyryl CoA:acetate CoA-transferase route was the dominant pathway for butyrate formation. The propanediol utilization compartment was annotated in A. halli, A. soehngenii, Eubacterium limosum, and C. catus. Of the genomes of key lactate utilizers assessed for antibiotic resistance genes, several possessed genes for multidrug resistance; however, other strains of Anaerostipes, C. catus, and Megasphaera elsdenii exhibited no antibiotic resistance genes. Metabolic modeling revealed that lactate-utilizing strains, including Anaerotignum, Eubacterium, and Anaerostipes, are key symbionts in maximizing the metabolic capabilities of the gut microbial community. Clinical interest in lactate-utilizers as next-generation probiotics is developing, and these data underscore the exciting therapeutic potential of targeting lactate metabolism to restore microbial and metabolic balance, in addition to potentially mitigating inflammatory diseases.