Helpful bacteria in the gut protect themselves by inducing the gut epithelia and local immune cells to secrete tissue repair factors and low, protective levels of cytokines and heat-shock proteins. This noninflammatory response is triggered by the binding of bacterial components to Toll-like receptors (TLRs). It has been assumed that these bacteria are helpful rather than harmful because the resulting TLR signals are less potent than those triggered by foreign pathogens.
Turer et al. now show, however, that TLR signals triggered by symbiotic microbes are potentially lethal unless they are held in check. The team had previously found that mice lacking an antiinflammatory protein called A20 died from inflammation-related complications even in the absence of infection. They now find that this deadly inflammation is triggered by ligands from the host's own symbiotic bacteria.
Depleting the resident gut bacteria using antibiotics rescued the mice, as did knocking out the TLR adaptor protein MyD88. Protection was less effective, however, if MyD88 was lost only from immune cells, suggesting that A20's inhibitory effect primarily acts in nonimmune cells—possibly in gut epithelial cells. The team is now investigating whether A20 is required for cells to differentiate between pathogenic and protective TLR signals.