FABP4 in Paneth cells regulates antimicrobial protein expression to reprogram gut microbiota

Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4(fl/fl) pvillin(CreT) mice were highly resistance to Salmonella Typhimurium (S.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPAR gamma after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. Firmicutes/Bacteroidetes (F/B) ratio in FABP4(fl/fl) pvillin(C)(reT) mice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases.

Automated summary

This study reveals that FABP4 in the Paneth cells can downregulate the expression of defensins by degrading PPAR-gamma. This downregulation not only occurs in mice, but also in humans. Additionally, a high-fat diet induces an increase in FABP4 in Paneth cells, leading to a decrease in defensin expression. These findings are important for understanding the underlying factors of modern diseases.