Introduction
Intestinal diseases are complex and common digestive system diseases, leading to a heavy burden on the healthcare system globally.1 Investigating potential environmental risk factors would provide valuable insights into the prevention of intestinal diseases while identifying the causal potential therapeutic targets represents an important first step toward the treatment of diseases. Epidemiological studies have investigated these potential associations. An umbrella review incorporating 71 environmental factors revealed the detrimental impact of smoking, soft drink consumption and vitamin D deficiency on inflammatory bowel disease.2 The association of obesity, alcohol consumption and hyperlipidaemia with elevated colorectal cancer risk has been summarised in a meta-analysis.3 However, the unavoidable confounding bias and reverse causation constrained the ability to establish a definitive causal link between risk factors and diseases in observational studies. Therefore, the causal association between the factors identified in previous observational studies and the risk of intestinal diseases remains unverified. There are many clinical trials investigating intestinal diseases, primarily focused on evaluating the safety and effectiveness of various medications and supplements.4 5 Despite the high-quality evidence provided by randomised controlled trials (RCTs), certain inquiries are ill-suited for RCT methodology, particularly those concerning modifiable lifestyles. For instance, ethical considerations preclude the random assignment of participants to sustained smoking or excessive alcohol consumption. Moreover, the execution of large-scale, multidecade RCTs is frequently hindered by prohibitive costs and time constraints, thus constraining their feasibility.
Analogous to an RCT, Mendelian randomisation (MR) is an epidemiological method that uses genetic variants as instrumental variables to explore the potential causal association between exposure and outcome.6 As genetic variants are randomly allocated at conception, MR is less prone to confounding and reverse association in contrast to observational design. To obtain valid and reliable results from MR analysis, instrument variables should meet the following three assumptions (figure 1): (1) instrument variables are strongly associated with the exposure; (2) genetic instruments should not be associated with any confounders; (3) genetic instruments should impact the outcome through exposure, not alternative pathways or direct influence. The current review aims to provide a comprehensive summary of the available evidence regarding potential causal risk factors for intestinal disease. Moreover, this review will also offer valuable insights into the potential future advancements of MR studies in the field of intestinal disease.