Associations between gut microbiota and menopause symptoms: novel insights from the ZOE PREDICT 3 cohort

Microbiome composition may differ according to menopause status, which may be partially mediated by diet (1) . Peri- and post-menopausal symptom burden is associated with diet quality (2) , however, knowledge on the association between menopause symptoms and gut microbiome composition is limited (3) . This study investigates the associations between gut microbiome composition and menopause symptoms. Data was analysed from 70,399 peri- (N = 27,926) and post-menopausal women (N = 42,473) from the PREDICT 3 cohort (NCT04735835), examining the gut microbiome composition (using metagenomic sequencing) and diet quality using Healthy Eating Index (HEI) scores derived from the PREDICT Food Frequency Questionnaire. Data was also collected on menopause symptoms, grouped into vasomotor, sexual, psychological and somatic domains. A Menopause Symptom Tracker Score (MSTS) (0-100) was used to capture symptom prevalence (out of 20 symptoms) and impact on quality of life (0-not at all, 1-a little, 3-quite a bit and 5-extremely), with higher score values reflecting greater symptom burden (4) . Using random forest machine learning (ML) models, we found that microbiome composition was predictive of the MSTS (AUCall = 0.70; AUCperi = 0.66; AUCpost = 0.65), as well as physical (e.g., fatigue, weight gain and slowed metabolism, thinning hair) and psychological (e.g., low mood or depression, anxiety and mood changes) domain scores (AUCall = 0.70; AUCperi = 0.66; AUCpost = 0.68 and AUCall = 0.70; AUCperi = 0.65; AUCpost = 0.66 respectively). Microbiome was also predictive of diet quality (HEI; AUCall = 0.77; AUCperi = 0.77; AUCpost = 0.75). Subsequently, we compared the top 50 species predictive for the HEI and MSTS respectively, and identified 32 common predictive species. Notably, the top predictive species for both HEI and MSTS was the not-yet-characterised Lachnospiraceae species-level genome bin SGB4964. To the best of our knowledge, this is the first time associations between menopause symptoms and the gut microbiome have been identified. Further work is needed to unravel diet-microbiome-symptom interrelationships and investigate a potential causal role of microbiome in menopause symptom burden. This knowledge could ultimately lead to novel, microbiome-based strategies for improving the quality of life for women during and after the menopausal transition.