The role of gut commensals in regulating susceptibility to acute liver damage / by Stela Celaj.
Author Celaj, Stela.
Title The role of gut commensals in regulating susceptibility to acute liver damage / by Stela Celaj.
Abstract Liver disease of different etiologies confers significant morbidity and mortality and hence it constitutes a major health concern worldwide. Stemming from a range of causes, such as viral, drug-induced, alcoholic, or autoimmune, the rate of progression is highly variable, and the environmental factors dictating the outcome remain poorly identified. A growing body of evidence from both the research and clinical world has established that gut microbiota sculpts basic metabolic and homeostatic processes, and regulates the development of proper immune responses. Therefore, a strong interest lies in characterizing the link between an imbalanced state of the commensal bacteria (dysbiosis) and disease progression in the host. Research reveals that microbiota not only modulates the course of disease in the gut but also in extra-intestinal disorders among which include obesity, rheumatoid arthritis, type I diabetes, etc. Whereas a significant role for the effects of intestinal microbiota on 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 a better understanding of the transition from acute injury to chronic liver disease. In this thesis, Concanavalin A (ConA)- and Fas-induced liver damage were utilized as models of acute liver injury in mice. Here, we demonstrate 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. Furthermore, the extent of liver injury following triggering of the death receptor Fas varies greatly as a function of the microbiota. Liver damage was increased in GF mice after microbiota reconstitution, and decreased in conventionally raised mice following reduction of intestinal bacterial load, by antibiotic treatment. Moreover, it is shown that the regulation of sensitivity to FAS induced liver injury is dependent upon the Toll-like Receptor signaling molecule MyD88. Overall, these studies demonstrate that the status and composition of the intestinal microbiota determine the susceptibility to Con A-induced acute liver injury. The microbiota acts as a rheostat, actively modulating the extent of liver damage in response to Fas triggering.
Description xiv, 163 leaves : ill. (some col.)
College Dartmouth Medical School. Department of Microbiology and Immunology.
DOI http://dx.doi.org/10.1349/ddlp.1232
The role of gut commensals in regulating susceptibility to...