Hepatic fibrogenesis and activation of hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, almost exclusively occur in an inflammatory environment. Proinflammatory signaling pathways contribute to fibrogenesis by activating survival pathways in HSCs and by promoting the recruitment of leukocytes. We have recently shown that lipolysaccharide (LPS) and its receptor toll-like receptor 4 (TLR4) are required for hepatic fibrogenesis and that HSCs are highly responsive to LPS. LPS is one on the strongest known inducers of inflammation and an important contributor to hepatic injury and inflammation. Hepatic fibrosis is associated with elevated portal and systemic levels of LPS in patients as well as in mouse models. Elevations of LPS are caused by abnormalities in the intestinal mucosal structure, intestinal motility as well as changes in the bacterial flora and subsequent increases in bacterial translocation. We hypothesize that commensal intestinal bacteria contribute to hepatic fibrogenesis, and that their modulation by probiotics in early stages of hepatic fibrogenesis will reduce HSC activation and extracellular matrix deposition. To test this hypothesis, we will investigate whether probiotics alone or sequential treatment with antibiotics and probiotics (i) alter the intestinal flora in different models of experimental murine fibrogenesis, and (ii) whether these regimens reduce bacterial translocation and hepatic LPS exposure during early stages of experimental fibrogenesis (Aim 1). We will test the effects of single strain and multi-strain probiotic regimens on the development of hepatic fibrosis in two different mouse models using extracellular matrix production and markers of HSC activation as readouts (Aim 2). The pursuit of these aims will not only allow to characterize changes in the commensal enteric microbiota during hepatic fibrogenesis but also evaluate whether probiotics alone or the combination of antibiotics and probiotics are useful for the prevention hepatic fibrosis. While long-term antibiotic treatment has severe side effects in patients with hepatic fibrosis, probiotics have a high safety profile and can be easily combined with other treatment modalities. Thus, data from our study will reveal whether probiotics represent a novel and safe preventative treatment option for early stages of hepatic fibrosis.
This application investigates probiotics as a potential treatment option for liver fibrosis. Probiotics have been shown to be a feasible and safe treatment option in patients. Thus, results from experimental murine fibrosis in this study may have clinical implications and lead to future studies that investigate the efficacy of probiotics in patients with chronic liver disease and liver fibrosis.
| Luedde, Tom; Schwabe, Robert F (2011) NF-?B in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 8:108-18 |
