Select: Gut Microbes

Our intestines host trillions of bacteria, most of which are beneficial to our health most of the time. Occasionally, however, a change in conditions, or the entry of a pathogenic strain, leads to disease. Recent papers shed new light onto the complex interactions that determine intestinal health and disease. Intestinal cells first come into contact with bacteria after birth, as they transition from the sterile uterine environment to the outside microbe-filled world. Given that encounters with bacteria normally trigger immune activation and inflammation, which may cause tissue damage, neonatal intestinal epithelial cells are programmed to undergo a period of tolerance, in which bacteria do not elicit an immune response. Chassin et al. (2010) now show in mouse that during tolerance the microRNA miR-146a suppresses the inflammatory pathway mediated by Toll-like receptors by repressing the translation of the interleukin 1 receptor associated kinase 1 (IRAK1). Things, however , are not as simple as they seem. In a surprising twist, the authors find that Toll-like receptor 4 (TLR4) signaling in the neonate epithelium is required for the downregulation of IRAK1. Furthermore, both TLR4 and IRAK1 are required for maintaining elevated miR-146a levels, and both are also required for expression of genes that regulate cell survival, differentiation, and metabolism and hence promote cellular homeostasis. In other words, the immune pathway is not simply turned off at birth but is rather actively modulated to accomplish tolerance and to allow intestinal cells to express the set of genes necessary for their maturation. Interestingly, the authors find that IRAK1 expression reappears at weaning (21 days after birth in mice), when mice begin eating solid food—the point at which mice may encounter pathogenic bacteria and need to mount an immune response. At this time epithelial proliferation increases, ending the continuous TLR4/IRAK1 signaling that maintains tolerance and lowering miR-146a expression. The ultimate triggers that initiate and end tolerance remain unknown, however, and it would be particularly interesting to study the regulation of the corresponding pathway in humans. Despite significant differences in the maturity of the neonate gut between mice and men, both have to cope with the sudden exposure to microbial stimuli after birth and to establish a lifelong , stable host-microbe homeostasis. Rapid turnover of epithelial cells is a hallmark of healthy intestines. The rate of proliferation is regulated by both Wnt signaling and microbes, at least in adult tissue. A study from the Guillemin lab (Cheesman …