Do health effects of milk involve gut microbiome or branched-chain amino acids?

Abstract

 Milk provides protein and micronutrients, and is recommended by some dietary guidelines, particularly for bone health. In western populations, milk is also a major dietary source of branched-chain amino acids (BCAAs) that may be involved in the aetiology of adiposity. The human gut microbiome, partly shaped by diet, has also been implicated in cardio-metabolic disorders. However, observational studies may be biased by many factors, such as socio-economic position, lifestyle or health status, while the available randomized-controlled trials are too small to have sufficient power, do not test effects on disease outcomes, and/or do not target specific gut microbiota taxa. No Mendelian randomization studies on these topics have been conducted. This thesis took advantage of publicly available genotyped studies to assess the causal effects of these inter-related exposures, i.e., milk, circulating BCAAs and gut microbiota, on osteoporosis, ischemic heart disease (IHD), type 2 diabetes mellitus (T2DM), adiposity, lipids and glycemic traits in adults. Milk consumption was predicted by a genetic variant functionally relevant to lactase persistence (rs4988235 (MCM6)). Genetically predicted circulating BCAAs and 27 gut microbiota genera were based on genome-wide association studies among people of Mendelian randomization, was used to obtain unconfounded estimates. Inverse variance weighting with fixed effects was used to combine uncorrelated genetic predictors and weighted generalized linear regression to combine correlated ones. MR-Egger and weighted median methods were used for sensitivity analyses. Multiple comparisons were adjusted for using a Bonferroni correction. Eye colour was used as a negative control for IHD, as it mirrors the distribution of lactase persistence and IHD in Western Europe. Higher milk intake was not clearly associated with osteoporosis, IHD or T2DM, but was associated with higher body mass index (BMI), lower high-density lipoprotein cholesterol (HDL-C), lower low-density lipoprotein cholesterol (LDL-C) and higher fasting insulin after Bonferroni correction. Eye colour was not associated with IHD. Higher circulating BCAAs were not robustly associated with higher BMI in either men or women and were not associated with waist-hip ratio or body fat percentage. Genera Acidaminococcus, Aggregatibacter, Anaerostipes, Bifidobacterium, Blautia, Desulfovibrio, Dorea and Faecalibacterium were nominally associated with IHD, T2DM, BMI, waist-hip ratio, HDL-C, LDL-C or insulin resistance. Higher Bifidobacterium abundance was associated with lower BMI and higher LDL-C after Bonferroni correction, but these associations could be due to pleiotropic effects. The lack of association of milk consumption with bone health, IHD or T2DM suggests few beneficial effects of milk although milk may promote adiposity. BCAAs do not appear to play a causal role in the pathogenesis of adiposity. The eight gut microbiota genera identified as related to cardiometabolic factors should be given priority in the search for new means to prevent and treat leading causes of global morbidity and mortality.