The microbiota regulates susceptibility to Fas-mediated acute hepatic injury.

ABSTRACT

Whereas a significant role for intestinal microbiota in affecting the pathogenesis and progression of chronic hepatic diseases is well documented, the contribution of the intestinal flora to acute liver injury has not been extensively addressed. Elucidating the influence of the intestinal microbiota on acute liver inflammation would be important for better understanding the transition from acute injury to chronic liver disease. Using the Concanavalin A (ConA)-induced liver injury model in laboratory mice, we show that the severity of acute hepatic damage varies greatly among genetically identical mice raised in different environments and harboring distinct microbiota. Through reconstitution of germ-free (GF) mice, and the co-housing of conventional mice, we provide direct evidence that manipulation of the intestinal flora alters susceptibility to ConA-induced liver injury. Through deep sequencing of the fecal microbiome, we observe that the relative abundance of Ruminococcaceae, a Gram(+) family within the class Clostridia, but distinct from segmented filamentous bacteria, is positively associated with the degree of liver damage. Searching for the underlying mechanism(s) that regulate susceptibility to ConA, we provide evidence that the extent of liver injury following triggering of the death receptor Fas varies greatly as a function of the microbiota. We demonstrate that the extent of Fas-induced liver injury increases in GF mice after microbiota reconstitution, and decreases in conventionally raised mice following reduction in intestinal bacterial load, by antibiotic treatment. We also show that the regulation of sensitivity to Fas-induced liver injury is dependent upon the toll-like receptor signaling molecule MyD88. In conclusion, the status and composition of the intestinal microbiota determine the susceptibility to ConA-induced acute liver injury. The microbiota acts as a rheostat, actively modulating the extent of liver damage in response to Fas triggering.