An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer

Abstract

Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses to the intestinal microbiota, and by chronic intestinal inflammation. Several recent studies demonstrate the importance of innate microbial recognition by immune and nonimmune cells in the gut. Paradoxically, either diminished or exacerbated innate immune signaling may trigger the breakdown of intestinal homeostasis, leading to IBD and colitis-associated cancer (CAC). This dichotomy may reflect divergent functional roles for immune sensing in intestinal epithelial cells and leukocytes, which may vary with distinct disease mechanisms.

Figure 1.

Diminished or enhanced intestinal PRR signals may promote intestinal inflammation and tumorigenesis. PRR signals are maintained at a critical threshold to maintain intestinal homeostasis. PRR signals may be required to restore barrier function after epithelial insult and for protective immunity against pathogens; impairment of these processes caused by insufficient PRR signaling may result in pathogen outgrowth and, indirectly, excessive subsequent inflammation (left). Excessive PRR-driven repair or inflammatory responses (right) may also threaten homeostasis, e.g., through dysregulated epithelial proliferation leading to tumorigenesis and overexuberant pathogenic inflammatory responses to the intestinal microbiota.