Distinct Clinical Phenotypes in Lactase Nonpersistence: Symptomatic, Asymptomatic, and Gassy-Asymptomatic.

Abstract

Introduction: Lactase deficiency allows undigested lactose to reach the colon, where fermentation triggers gastrointestinal symptoms. Although lactase persistence (LP) vs non-persistence (LNP) is genetically defined, many LNP individuals are symptoms-free, suggesting additional determinants of the phenotype. We aimed to define clinically relevant LNP subgroups and examine microbiome features that differ among them.

Methods: In 146 healthy adults, LP-associated single nucleotide polymorphisms were genotyped and a standardized 25 g lactose load was administered. Breath hydrogen, methane, blood glucose, and symptom scores were collected over 3 hours. Microbiome composition (n = 60) was profiled by 16S-rRNA sequencing of stool samples.

Results: Among LNP individuals (116/146, 79%), 3 distinct phenotypes emerged: Symptomatic (35/116, 30%), who produced hydrogen and reported symptoms; Gassy Asymptomatic (67/116, 58%), who produced hydrogen without symptoms; and Asymptomatic (14/116, 12%), who neither produced hydrogen nor had symptoms. All LNP subgroups showed similarly low blood glucose elevations after lactose load compared with LP. A novel metric, peak hydrogen production rate (ppm/hour), improved correlation with symptom severity (R = 0.49) vs the conventional hydrogen peak (R = 0.34). Microbiome analyses revealed higher abundances of certain genera such as Lactobacillus and Megasphaera in asymptomatic LNP subgroups, suggesting possible microbial contributions to the absence of symptoms.

Discussion: Seventy percent of genetically LNP adults tolerate lactose without symptoms. Classifying LNP individuals into distinct subgroups and incorporating hydrogen production rate into breath-test interpretation may enhance diagnostic precision, prevent unnecessary dietary restrictions, and generate new hypotheses linking fermentation kinetics and symptoms. Microbiome associations remain correlative and warrant functional validation in larger, controlled studies.