NKT cell- NASH murine model - Microbiome: study 1

Causal and modulatory mechanisms underlying Non-alcoholic steatohepatitis (NASH) are not yet understood and an effective therapeutic approach to halt this disease is still lacking. Using a murine model of NASH, we have identified distinct roles of type I and type II natural killer T (NKT) cells: in Ja 18-/- mice, which lacks type I NKT cells specifically, steatohepatitis / fibrosis which determines the terminal stages of NASH, is significantly compromised elucidating a pathological role of these cells. We also have found that a RAR-? inhibitor (Tazarotene) and a type II NKT activator (Miltefosine), intervene in the NKT cells in vivo and prevent NASH progression in mice. Our preliminary data also show involvement of specific subsets of dendritic cell, that migrate from gut and stimulate type I NKT cells at different stages of disease. We wish to investigate whether gut microbiota and other gut factors are involved in NKT cell-mediated regulation of NASH and compare with other liver diseases. NASH is a major type of Non-alcohol-induced fatty liver disease (NAFLD), which is the most frequent chronic liver disease and affects 10–20% of the population in developed countries and is increasing in prevalence with the rise of diabetes and obesity. NAFLD is characterized by abnormal accumulation of fat within the liver, or steatosis, that can progress to severe inflammatory cell infiltration or NASH accompanied by fibrosis, necrosis or in some cases leads to liver cirrhosis and hepatocellular carcinoma (HCC). Unravelling the NKT cell-mediated regulation in NASH would allow development of novel therapeutic and diagnostic opportunities along with improving the knowledge in basic biology of liver diseases.