Association of lactose intake and lactase persistence genotype with microbial taxa and function in healthy multi-ethnic U.S. adults

Lactase persistence is a genetically inherited trait that enables continued lactose digestion into adulthood. Lactase non-persistence (LNP) individuals often experience incomplete lactose digestion, allowing undigested lactose to reach the colon, where it may shape microbial composition and function. We investigated the relationship between the lactase persistence (LP) genotype, lactose consumption, and the taxonomic and functional profiles of the fecal microbiome. Participants from the USDA Nutritional Phenotyping Study, a cross-sectional observational study designed to assess how dietary factors impact human health, whose fecal microbiome profile was measured using shotgun metagenomic sequencing (n = 330) were included in this analysis. Fecal SCFA levels were measured using GC-MS. Fecal microbiome taxonomy and gene abundance were quantified using shotgun metagenomic sequencing. Lactose consumption and yogurt intake were estimated based on Automated Self-Administered 24h Dietary Assessment Tool (ASA24®) dietary recalls or Food Frequency Questionnaire. The LP/LNP genotype was determined by a single nucleotide polymorphism (SNP ID: rs4988235). Several genera of lactic acid bacteria (Veillonella, Lactobacillus, Lacticaseibacillus, and Lactococcus) were differentially abundant between recent high-lactose consuming (>10.0 g lactose per day) and low-lactose consuming (<3.3 g lactose per day) individuals. Among the LNP participants who self-identified as Caucasian or Hispanic, high-lactose consumers (>10.0 g per day via 24-h recall) had significantly higher relative abundances of lactic acid bacteria and lactate-utilizing bacteria (Lacticaseibacillus, Lactobacillus, Megamonas, and Veillonella) than low-lactose consumers (<3.3 g per day). Independent of lactose intake, LNP participants had a higher abundance of fecal microbial β-galactosidase genes than LP participants. Among the LNP participants, those with high recent lactose consumption also showed a significant shift towards more fecal propionate. The abundance of the yogurt-associated microbe, Streptococcus thermophilus, was positively associated with yogurt intake independent of the genotype. Alternative milk consumption was significantly negatively associated with fecal SCFAs both in the full cohort and the Caucasian/Hispanic subset, regardless of the genotype. Our results suggest that functional and persistent host lactase enzymes may work to competitively exclude lactic acid bacteria, contributing to a smaller realized niche for lactic acid bacteria in LP individuals compared to LNP individuals. However, regardless of the host genotype, consumption of alternative milk may be associated with reduced production of health-promoting intestinal metabolites, such as SCFAs.