The human gut microbiome as a source of drugs for chronic inflammatory diseases

Title : The human gut microbiome as a source of drugs for chronic inflammatory diseases

Abstract:

Chronic infection with the hepatitis B virus (HBV) is a primary risk factor for the development of hepatocellular carcinoma (HCC). HCC is the sixth most common cancer type worldwide with few treatment options. The HBx oncoprotein encoded by HBV plays a crucial role in the pathogenesis of HCC.  HBx alters signaling pathways important to cell proliferation, survival, and the immune response, as well as promotes epigenetic changes that silence tumor suppressor genes and activate host oncogenes.  Short chain fatty acids (SCFA) have anti-inflammatory properties, induce apoptosis in cancer cells, and act as histone deacetylase inhibitors (HDACi) to alter gene expression. Feeding HBx transgenic mice (HBxTg) a diet of SCFA for three months resulted in a decrease in tumor frequency and sizes compared to control mice.  Results demonstrated that SCFA prevented the progression of HCC pathogenesis. Proteomic analysis using perfused liver tissues from treated and control HBxTg was performed to investigate the differential expression of proteins possibly involved in the delay of tumor progression. An enrichment of proteins involved in chromatin remodeling (e.g. SWI/SNF complex subunits, methyltransferase CARM1), the proteasome/ubiquitin system (e.g. ubiquitin protein ligases, proteasome inhibitor subunits), and the NF-κB pathway (e.g. ELKS, APPL1) was detected among treated mice. Furthermore, expression of the tumor suppressor gene disabled homolog 2 (DAB2), known to be epigenetically silenced in HCC, increased after treatment. Dab2 influences many pathways active in HCC pathogenesis and was found to interact with many proteins detected by the proteomic analysis. Western blot was performed to confirm the alteration of Dab2 in all samples. Lastly, immunocompromised nude mice subcutaneously injected with Huh7-x cells treated with SCFA had slower tumor growth compared to controls at both high and low doses. Thus, SCFAs delay the development of HCC in a preclinical model where chronic inflammation contributes to tumor development.  Further work proved clinical utility among patients with psoriasis without adverse effects, suggesting that this approach is a viable option for further clinical development against a variety of chronic inflammatory diseases.

Biography:

Mark Feitelson received his Ph.D. in Microbiology and Immunology in 1979 from the UCLA School of Medicine. He was an American Cancer Society postdoctoral fellow at Stanford University from 1980-82 and was then recruited to the Fox Chase Cancer Center by Dr. Baruch Blumberg (Nobel laureate). In 1991, Dr. Feitelson became Associate Professor of Pathology and Cell Biology and head of the Molecular Diagnostics Lab in Microbiology at Thomas Jefferson University. In 2007, Dr. Feitelson moved to Temple University, where he is now Professor of Biology.  His research has been supported by NIH, industry, and foundations for more than 35 years, has more than 150 publications and is presently head of the Professional Science Master’s program in Biotechnology at Temple University. Since 1980, his research interests have encompassed the pathogenesis of chronic hepatitis B infection and development of hepatocellular carcinoma on the cell and molecular levels.  More recently, he co-founded the biotechnology start-up, SFA Therapeutics, which is developing anti-inflammatory and anti-tumor drugs from the gut microbiome.