Dietary intake of live microbes is inversely associated with fatigue and modified by serum folate among adults aged 40 years or more

OBJECTIVES: To investigate the independent associations between dietary live-microbe intake, as well as circulating levels of folate metabolites, and fatigue, and to examine their interaction as a potential biological pathway underlying fatigue in aging adults. STUDY DESIGN: Cross-sectional analysis of adults aged ≥40 years participating in the National Health and Nutrition Examination Survey 2011-2023. MAIN OUTCOME MEASURES: Fatigue was assessed using the Patient Health Questionnaire fatigue item and categorized as none/low versus moderate/severe. Dietary intake of live-microbe foods was derived from two 24-h recalls and classified as low, medium, or high. Total serum concentrations folate and its metabolites, including 5-methyltetrahydrofolate, were quantified. Survey-weighted logistic regression, adjusted for sociodemographic, dietary, and clinical covariates, estimated main effects and interactions between the effects of 5-methyltetrahydrofolate and of live-microbe intake; sensitivity analyses additionally adjusted for depressive symptoms and sleep disturbance. RESULTS: Moderate/severe fatigue was reported by 16.3% of 14,376 participants and 15.0% reported no intake of live-microbe foods. High versus low live-microbe intake was associated with lower odds of moderate/severe fatigue (odds ratio [OR] 0.60; 95% confidence interval [CI] 0.46-0.79). Higher serum 5-methyltetrahydrofolate levels were also associated with lower odds of moderate/severe fatigue (OR 0.85; 95% CI 0.73-0.98). In stratified analyses, high live-microbe intake corresponded to 38-65% lower odds of moderate/severe fatigue only among adults with higher levels of 5-methyltetrahydrofolate, with no significant associations among those with lower levels. CONCLUSIONS: Intake of microbe-rich foods and higher levels of circulating 5-methyltetrahydrofolate are both associated with lower levels of fatigue in midlife and older adults, and folate sufficiency appears to potentiate the fatigue-reducing benefits of live-microbe foods, supporting a nutrient-microbe pathway relevant to healthy aging.