Determining the mechanisms behind goblet cell dysfunction

Introduction

Goblet cells are specialized epithelial cells that secrete mucus and antimicrobial proteins which together form the gut mucus barrier. The mucus barrier protects the host from bacterial invasion and subsequent activation of an inflammatory response, while also providing food for the microbiome.

Goblet Cell Dysfunction

Dysfunction of goblet cells and high penetrability of the mucus barrier are hallmarks of inflammatory bowel diseases (IBD). While the reasons for goblet cell dysfunction are unclear, it is thought that:

• Inflammation
• Host genetics (specifically mutations in autophagy genes)
• Environmental factors

These factors can affect their function. Yet despite their importance, the basic biology of goblet cells is not understood as they are part of a heterogeneous tissue.

Research Development

I developed a new mouse model that allows isolation of ribosomes specifically from goblet cells in vivo, thus revealing the translational response of goblet cells to various conditions. In preliminary studies, we found that:

• Altering the autophagy process in vivo led to modification of the colonic mucus barrier
• Alteration of the microbiome
• Resistance to colitis

We also found that antibiotic treatment, an environmental factor which increases the risk for IBD, altered the mucus barrier and instigated gut inflammation in mice.

Research Goals

Our goal is to mechanistically determine how inflammation, autophagy, and antibiotics affect goblet cell function during health and IBD. We will:

1. Define goblet cell function during IBD development in vivo and test if goblet cells fail to regain proper function during remission, leading to relapse.
2. Use a novel mouse model of augmented autophagy to determine the role of autophagy in preserving goblet cell function during IBD.
3. Use germ-free mice to reveal the microbiome-dependent and -independent effects of antibiotics on goblet cell function and IBD.

Conclusion

Our study will provide new understanding of goblet cell biology and may lead to new therapeutics which target goblet cells.