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. 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. Recent breakthroughs using animal models have advanced understanding of the pathogenesis of NAFLD 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 (TNF) antibodies. 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. We propose a double-blinded, randomized, placebo-controlled four month pilot study of 30 patients with NAFLD. The main outcome measure will be grade of hepatic steatosis evaluated by biopsy. We will also measure steatosis by magnetic resonance spectroscopy (MRS). The possibility that probiotics, which are safe, well-tolerated and natural therapies, might improve NAFLD is exciting because liver-related morbidity and mortality are late complications of most chronic liver diseases, including NAFLD. Thus, the safety profile of probiotics makes them an attractive treatment option for a disease that will likely require chronic therapy. If the efficacy of probiotics is established one type of chronic liver disease, the possibility that similar biological therapies might benefit other chronic inflammatory states would merit further evaluation.
| Spacek, Lisa A; Mudalel, Matthew; Tittel, Frank et al. (2015) Clinical utility of breath ammonia for evaluation of ammonia physiology in healthy and cirrhotic adults. J Breath Res 9:047109 |
