Associations of genetically predicted iron status with 24 gastrointestinal diseases and gut microbiota: a Mendelian randomization study

Background: Iron status has been implicated in gastrointestinal diseases and gut microbiota, however, confounding factors may influence these associations.

Objective: We performed Mendelian randomization (MR) to investigate the associations of iron status, including blood iron content, visceral iron content, and iron deficiency anemia with the incidence of 24 gastrointestinal diseases and alterations in gut microbiota.

Methods: Independent genetic instruments linked with iron status were selected using a genome-wide threshold of p = 5 × 10-6 from corresponding genome-wide association studies. Genetic associations related to gastrointestinal diseases and gut microbiota were derived from the UK Biobank, the FinnGen study, and other consortia.

Results: Genetically predicted higher levels of iron and ferritin were associated with a higher risk of liver cancer. Higher levels of transferrin saturation were linked to a decreased risk of celiac disease, but a higher risk of non-alcoholic fatty liver disease (NAFLD) and liver cancer. Higher spleen iron content was linked to a lower risk of pancreatic cancer. Additionally, higher levels of liver iron content were linked to a higher risk of NAFLD and liver cancer. However, certain associations lost their statistical significance upon accounting for the genetically predicted usage of cigarettes and alcohol. Then, higher levels of iron and ferritin were associated with 11 gut microbiota abundance, respectively. In a secondary analysis, higher iron levels were associated with lower diverticular disease risk and higher ferritin levels with increased liver cancer risk. Higher levels of transferrin saturation were proven to increase the risk of NAFLD, alcoholic liver disease, and liver cancer, but decrease the risk of esophageal cancer. MR analysis showed no mediating relationship among iron status, gut microbiota, and gastrointestinal diseases.

Conclusion: This study provides evidence suggesting potential causal associations of iron status with gastrointestinal diseases and gut microbiota, especially liver disease.