Editorial: Advanced glycation end products - a dietary culprit for IBD in the genetically susceptible?

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), affects several million people worldwide, mainly in the Western world. However, the incidence is sharply rising in newly industrialized countries.^{1, 2} The adoption of a Western lifestyle, particularly a diet high in sugar, fat and ultra-processed foods, may contribute to this trend.²

As a result, dietary compounds have been investigated for their role in the pathogenesis of IBD.^{3, 4} Among these, advanced glycation end products (AGEs), which are formed during thermal processing of foods, have come to the fore as they increase oxidative stress and inflammation.⁵ Studies have linked AGEs to alterations in the gut microbiome and to pro-inflammatory immune responses.⁶ However, evidence on their role in the risk of developing IBD remains sparse and inconclusive.^{7, 8}

Jiang et al. have reported novel findings from a cohort based on the UK Biobank, including 121,978 individuals without IBD.⁹ Of these, 671 (0.55%) developed IBD during a median follow-up of almost 14 years. Their intake of three AGEs was estimated by dietary questionnaires. Interestingly, the authors found that one of the AGEs was associated with an increased risk of developing IBD, but only CD (adjusted hazard ratio: 1.09; 95% CI: 1.01–1.18). In stratified analyses, the association was strongest in the overweight, the physically inactive and non-smokers. The authors used polygenic risk scores to explore the interaction of diet with the background genetic risk. They found that all three AGEs were associated with a higher risk of CD in individuals at high genetic risk but, again, saw no association for UC.

Strengths of their study are its large population and the comprehensive genetic profiling. Major limitations include the lack of information on dietary changes over time and measurement bias due to the use of dietary questionnaires to estimate AGEs. Because exact concentrations of AGEs are unknown, these data do not provide sufficient evidence to link these associations to a specific AGE or signalling pathway.

Nevertheless, this study has elegantly demonstrated the importance of diet in the development of IBD, especially in those with a high background genetic risk. However, several questions remain unanswered. Are AGEs the primary culprit or other compounds present in ultra-processed food and if yes, which specific AGE molecules or pathways are involved? Is there a dose–response relationship between AGEs and the risk of IBD? Can individuals with a high genetic risk of IBD prevent or delay disease onset by maintaining a healthy lifestyle and avoiding high intake of AGEs? In addition, the finding of a stronger association in overweight and physically inactive individuals raises the question of whether the metabolic syndrome with chronic low-grade inflammation might be the actual spark to chronic gut inflammation.

Moving from correlation to causation is necessary to design preventive dietary strategies for individuals with a high genetic risk of developing IBD. To achieve this, further population-based studies with longitudinal measurements of dietary intake, and studies with granular data on dietary molecules are needed. We are convinced that such efforts will be worthwhile. After all, diet is modifiable, whereas genetics—at least for now—are static.

Fahim Ebrahimi: Conceptualization; writing – original draft; writing – review and editing; methodology. Anders Forss: Project administration; supervision; methodology; writing – original draft; writing – review and editing; conceptualization.

Declaration of funding interests: This study was funded in part by the Swiss National Science Foundation (grant number P500PM_210866). Research grants from the Bengt Ihre Foundation (grant number SLS-974469), Bengt Ihre Fellowship (2023-1), and the Swedish Society of Medicine also supported this study (grant number SLS-973638).

This article is linked to Jiang et al paper. To view this article, visit https://doi.org/10.1111/apt.18218