PerspectiveMicrobiology

Keeping Bacteria at a Distance

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Science  14 Oct 2011:
Vol. 334, Issue 6053, pp. 182-183
DOI: 10.1126/science.1213909

The human intestine harbors enormous amounts of bacteria that have an essential role in host metabolism, but how this mutualistic balance is maintained is unclear. The current understanding has focused on the concept that bacteria continuously interact with the intestinal immune system in a balanced proinflammatory and tolerogenic way. The discovery of a protective inner mucus layer in the colon that separates bacteria from the epithelium has broadened this view (1). On page 255 of this issue, Vaishnava et al. (2) show that the antibacterial protein RegIIIγ secreted by specialized epithelial cells is involved in limiting the epithelial contact with bacteria in the small intestine. This observation further substantiates the role of intestinal epithelial cells and the mucus that covers them as important parts of the innate immune defense.

The small intestine and colon are quite different organs, especially when it comes to the relation between bacteria and host. The colon is protected by an inner mucus layer that is firmly attached to the epithelium and protects it from bacteria and from mechanical stress. This layer is continuously converted to an outer, less dense mucus layer, which is the habitat for the commensal bacteria (see the figure) (1, 3). By contrast, such a compact inner mucus layer in the small intestine would be detrimental as the small intestine must absorb nutrients. Fast peristaltic propulsion in the distal direction, fluid and mucus secretion, and antibacterial proteins instead maintain homeostasis in this intestinal region. The type of mucus that covers the small intestine, unlike that of the colon, is not attached to the epithelium and is permeable to bacteria (4). Yet, Vaishnava et al. show that bacteria are kept at a distance from the epithelium by the antibacterial protein RegIIIγ, which is secreted into the small intestinal mucus by the enterocytes (2).

The mucus of both the small intestine and colon is organized around the net-like polymer formed by the MUC2 mucin (3). It is unclear why the same protein gives rise to mucus with different properties in these organs. In the small intestine, the mucus gel acts as a mesh that retains the antibacterial proteins capable of killing the trapped bacteria. The mucus gel is also continuously replenished by secretion from the mucus-secreting goblet cells, providing a rapidly renewable system protecting the small intestine. Vaishnava et al. show that in RegIIIγ-deficient mice, more bacteria reach the small intestinal epithelium and trigger the adaptive immune response with increased immunoglobulin A (produced by B cells located beneath the epithelial cells, throughout the intestine) and T helper 1 cells. RegIIIγ is not produced in the colon, where instead the inner mucus layer provides protection. In the absence of the MUC2 mucin in the colon, bacteria reach the epithelium and trigger an overt immune reaction and colitis (1, 5).

Intestinal protection.

The intestinal epithelium is covered by mucus. In the colon, the inner stratified mucus layer acts as a physical barrier separating bacteria from the epithelium. The commensal bacteria are kept at a distance in the penetrable outer mucus layer. The small intestine is only covered with penetrable mucus, where antibacterial molecules such as RegIIIγ generate a bacteria-depleted region close to the epithelium.

CREDIT: B. STRAUCH/SCIENCE

In the small intestine, invaginations of the epithelium called crypts contain Paneth cells and the epithelial stem cells (6). The Paneth cells constitutively produce high amounts of antibacterial peptides, lysozyme (hydrolyzes bacterial cell wall peptidoglycans), and MUC2 mucin (7, 8). These antibacterial peptides (such as defensins) become trapped in the intestinal mucus. Vaishnava et al. show that the more common cells in the intestinal epithelium, the enterocytes, have a regulated feedback system through which bacteria are sensed, probably by Toll-like receptors (TLRs). These receptors signal through the adaptor protein MyD88 and induce RegIIIγ secretion. The enterocytes thereby control and limit the bacterial load at the epithelial surface. RegIIIγ specifically affects Gram-positive bacteria, and only the mucus-associated bacteria showed reduced numbers as compared to RegIIIγ-deficient mice. How the number of commensal Gram-negative bacteria in the small intestine is controlled is not understood. No RegIIIγ-dependent alterations in the luminal flora were evident in RegIIIγ-deficient mice suggesting that the antibacterial protein was inactivated, degraded, or sufficiently diluted when it reached the intestinal lumen.

The findings of Vaishnava et al. emphasize the role of intestinal epithelium and its enterocytes in orchestrating the intestinal defense system (9). The epithelium not only senses the intestinal bacterial milieu and responds by secreting RegIIIγ, but also relays information to the host's adaptive immune system about microbial penetration of the mucus (10). Reciprocally, the intestinal epithelium also responds to signals from the immune system to alter the mucus properties and turnover as suggested from studies of parasite infections (8).

The separation of bacteria and epithelium has emerged as a new concept underlying host-microbiota homeostasis in the small intestine and colon, although by different mechanisms. The different ways these organs solve the challenge of bacterial colonization must have evolved to meet the different physiological needs. However, there is still much to learn about how mucus properties are controlled and how enterocytes sense and coordinate the host response to intestinal bacteria.

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