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Intestinal epithelial cells (green) are transiently activated and produce MIP-2 (red) during vaginal birth.

A trip down the vaginal tract teaches the intestinal cells of newborn mice to ignore their germy cohabitants, according to Lotz and colleagues on page 973.

Gut cells calmly cohabitate with millions of intestinal bacteria. To avoid constant inflammation, these cells must learn to ignore or tolerate the immune-activating structures (such as lipopolysaccharide, or LPS) that protrude from the surface of the bugs. Gut cells are not simply blind to their microbial neighbors—as was once thought—as they express the LPS receptor Toll like receptor (TLR) 4.

This education in tolerance, according to Lotz and colleagues, begins during birth. Intestinal epithelial cells isolated from fetal mice produced inflammatory cytokines in response to LPS stimulation. Cells from newborn mice, by contrast, produced low levels of cytokines without stimulation, but did not respond to LPS.

Exposure to microbial ligands in the vaginal tract during birth appears to trigger this tolerance. Immediately after birth, gut epithelial cells were transiently activated, as measured by the production of the chemokine MIP-2 and the activation of the transcription factor NF-κB. This brief activation was triggered by oral exposure to LPS in the birth canal, as it did not occur in mice lacking TLR4 or in mice delivered by Cesarean section. Activation was restored in Cesarean-born mice by feeding them small amounts of LPS.

The TLR4-induced signals that establish tolerance are not completely defined, but a decrease in the TLR signaling molecule IRAK-1, seen in newborn gut cells, appears to be involved. The authors suspect that this tolerance induction might facilitate colonization of the newborn gut with microflora—a process that begins shortly after birth—without inciting an inflammatory response.

This study might help explain why premature babies sometimes develop uncontrolled gut inflammation—a disease known as necrotizing enterocolitis. It is possible that underdeveloped gut cells have not yet acquired the machinery needed to curtail the activation triggered by maternal LPS and thus fail to establish tolerance, but this idea remains to be tested.