Metabolic Gut Inflammation in Crohn's disease

Introduction

The rising incidence of inflammatory bowel diseases such as Crohn's disease (CD) has become a global health care issue in the 21st century. The complex genetic underpinning is increasingly appreciated, while environmental cues and specifically a Western diet are suspected to impact the development and course of the disease. Mechanistic insights that would support this assumption remain scarce, and specific nutrients that trigger a flare are unknown.

Dietary Influences

Westernisation of dietary habits is partly characterised by the enrichment of long-chain fatty acids, which fuel metabolic inflammation of tissues beyond the gut. Here, we propose to establish the concept of metabolic gut inflammation as a fuel for CD.

Research Approach

By analysing transgenic mice, human CD organoids, and two independent CD patient cohorts, we seek to establish how dietary polyunsaturated fatty acids (PUFAs) affect gut inflammation and disease course. The proposed work is based on our previous observations that dietary PUFAs trigger a chemokine response and Crohn's-like enteritis in mice, which is restricted by intestinal epithelial Glutathione peroxidase 4 (GPX4).

Role of GPX4

GPX4 is an evolutionarily conserved anti-oxidative enzyme that shows impaired activity in CD epithelium. The proposed work will identify how dietary PUFAs elicit gut inflammation in mice and which epithelial lineage executes the inflammatory response.

Crosstalk and Mechanisms

In a next step, I propose to establish a critical crosstalk between GPX4 and metabolic hubs in gut epithelium to provide a basis for the concept of metabolic gut inflammation.

Translation of Findings

Finally, we seek to translate findings by establishing that PUFAs evoke an inflammatory response from CD epithelium, and that PUFA intake impacts disease course.

Conclusion

MEGI CD comprehends basic and translational science to set the basis for novel therapeutic strategies in a complex illness that requires better treatment modalities. The study will prove the concept of metabolic gut inflammation as a major driver of human CD, providing a basis for nutritional therapy.