Abstract
BACKGROUND: A chronic illness with increasing global frequency, inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), profoundly affects patients' quality of life and healthcare systems. IBD pathogenesis consists of changes in gut microbiota, immune system dysregulation, and genetic predisposition. Although emerging data suggests that gut microbiota and circulating inflammatory proteins play critical roles in IBD, their utility as biomarkers for predictive, preventive, and personalized medicine (PPPM) remains incompletely understood. WORKING HYPOTHESIS AND METHODS: We hypothesized that specific gut microbiota and inflammatory proteins causally influence IBD risk and mediate pathways between gut microbiota and IBD development. We employed Mendelian randomization (MR) using genome-wide association studies (GWAS) to explore these causal relationships, including further analyses on UC and CD subtypes. RESULTS: We identified eight gut microbiota species linked to IBD, with four protective and four increasing risk. Nine inflammatory proteins were also associated, six increasing risk and three protective. MMP-10 and IL-10Rα mediated the effects of Clostridiaceae1 on IBD risk. For UC, five microbiota species were protective, five were risk factors, and two proteins increased risk while three were protective. IL-10Rα mediated the effects of Clostridiaceae1 on UC risk. For CD, eight microbiota species were protective, four increased risk, and nine proteins were implicated. However, no mediation pathways were supported by multivariable MR. CONCLUSIONS: This study highlights specific gut microbiota and inflammatory proteins that may serve as therapeutic targets for PPPM in IBD, UC, and CD. These findings offer new insights into IBD pathogenesis and suggest potential avenues for improved prevention, early detection, and personalized treatment strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00384-2.