Exploring the causal role of the human gut microbiome in endometrial cancer: a Mendelian randomization approach

Endometrial cancer presents a major public health issue, particularly in post-menopausal women. Whilst there are known risk factors for the disease, including oestrogen and obesity, these factors do not fully explain risk variability in cancer outcomes. The identification of novel risk factors may aid in better understanding of endometrial cancer development and, given the link with oestrogen metabolism, obesity and the risk of various cancers, the gut microbiome could be one such risk factor. Mendelian randomization (MR), a method that reduces biases of conventional epidemiological studies (namely, confounding and reverse causation) by using genetic variants to proxy exposures, was used to investigate the effect of gut microbial traits on endometrial cancer risk. Whilst our initial analyses showed that the presence of an unclassified group of bacteria in the Erysipelotrichaceae family increased the risk of oestrogen-dependent endometrial cancer (odds ratio (OR) per approximate doubling of the genetic liability to presence vs. absence: 1.13; 95% CI 1.01, 1.26; P = 0.03), subsequent sensitivity analyses, including colocalisation, provided insufficient evidence to support causality. This work highlights the importance of using a robust MR analysis pipeline, including sensitivity analyses to assess the validity of causal effect estimates obtained using MR.