In this article, we discuss the current understanding of how the intestinal mucosa may exert control over luminal bacteria, and how intestinal inflammation could ensue when this control is lost. We shall review research showing how Paneth cells, and evolutionarily conserved innate immune mechanisms, are emerging as key mediators of intestinal mucosal defence.

THE SMALL BOWEL CHALLENGE

Maintenance of a sterile environment in the small intestinal lumen represents a formidable challenge for the host. The multitude of villi and crypts create an expansive epithelial surface of approximately 400 m², allowing efficient nutrient absorption but a wealth of potential entry sites for invading microbes. To heighten the challenge, the intestinal mucosa comprises a single layer of epithelial cells, unlike the multiple layers found at other mucosal surfaces. This aids nutrient absorption and water and electrolyte transport, yet spreads defensive strategies thinly. The nutrient rich luminal content would appear to provide an ideal culture medium, and there is constant exposure to a large population of micro-organisms, both ingested along with food and from the adjacent colon with its heavy bacterial load. In addition, epithelial cells are replaced every 2–5 days from pluripotential stem cells in the base of the crypts¹ and so continuous antimicrobial protection for these stem cells is of paramount importance as damage to or parasitisation of stem cells would have severe consequences for the maintenance of the normal digestive epithelium. Against all the odds, microbial density in the healthy proximal small intestine (duodenum, jejunum, proximal ileum) is low.² In contrast, in the distal ileum and colon, there is extensive resident bacterial flora (total ∼10¹⁴) consisting of ∼400 different species of anaerobic and aerobic bacteria.³ Mucosal defence mechanisms in the proximal small bowel are able to maintain a crucial barrier to microbial invasion yet allow efficient nutrient absorption. …