This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. NAFLD includes a spectrum of hepatic pathology that ranges from fatty liver (steatosis) at the most clinically indolent extreme, to cirrhosis at the opposite extreme where most liver specific morbidity and mortality occurs. Indeed, NAFLD is now thought to be responsible for most of what was once classified as 'cryptogenic cirrhosis.' Cryptogenic cirrhosis accounts for half of the annual liver-related deaths in the United States. The study of NAFLD has been hindered by the lack of an easily measurable, clinically relevant outcome measure. Safe, inexpensive, well-tolerated treatments for NAFLD are greatly needed. While the basic mechanisms that initiate hepatic steatosis and subsequent progression to cirrhosis remain unknown, recent breakthroughs using animal models have advanced understanding and provide hope for the development of effective treatments. Based on extensive work in our own laboratory, our OVERALL HYPOTHESIS is that alcohol and lipopolysacchride (LPS) production by intestinal bacterial overgrowth (IBO) cause inflammatory signaling in the liver that leads to hepatic insulin resistance and NAFLD. To evaluate this possibility, we treated a murine model of NAFLD with probiotics or anti-tumor necrosis factor a (TNFa) antibodies. We hypothesized that either probiotics or anti-TNFa would decrease inflammation and improve insulin resistance and hepatic steatosis. Indeed, both treatments decreased activation of well-defined molecular inflammatory pathways and improved steatosis by biopsy. This exciting preliminary data provides rationale for studying probiotics in humans. Therefore, this project has a single SPECIFIC AIM: to determine if probiotic therapy can decrease hepatic steatosis in humans with NAFLD.
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