Abstract: An isogenic murine animal model for liver disease resulting from a Western (high fat, high sugar) diet is provided. This phenotypically and genotypically stable model sequentially develops steatosis (4-8 weeks), steatohepatitis (12-16 weeks), progressive fibrosis (16 week onwards) and spontaneous HCC (32-52 weeks), but only when fed a diet high in fat and sugar. The mice also develop obesity, insulin resistance and dyslipidemia, and the mouse hepatic transcriptome is concordant with the human NASH transcriptome at early and late time points, including activation of lipogenic, inflammatory and apoptotic signaling. The mouse HCC gene signature resembles S1 and S2 human HCC subclasses. This simple model of NASH and HCC that mirrors the development of human disease in terms of its triggers, serology, phenotype, histology, transcriptome and outcomes has utility in new target discovery, biomarker discovery, diagnostic test development, and screening and development of drugs for the corresponding liver conditions.

Abstract: A systems biology approach is used to characterize and relate the intestinal (gut) microbiome of a host organism (e.g. a human) to physiological processes within the host. Information regarding the types and relative amounts of gut microflora is correlated with physiological processes indicative of e.g., a patient's risk of developing a disease or condition, likelihood of responding to a particular treatment, for adjusting treatment protocols, etc. The information is also used to identify novel suitable therapeutic targets and/or to develop and monitor the outcome of therapeutic treatments. An exemplary disease/condition is the development of hepatic encephalopathy (HE), particularly in patients with liver cirrhosis.