ABSTRACT Primary sclerosing cholangitis (PSC), a progressive cholestatic hepatobiliary disease characterized by inflammation and fibrosis of the bile ducts, has a pathophysiology that is not understood. No effective therapies exist. The only treatment option for PSC is liver transplant. We undertook a pilot randomized trial of diet to investigate the pathophysiology of the disease, the role of diet and to advance potential therapy. We enrolled 20 patients with PSC and randomly assigned them to a Low Protein/low sulfur Diet (LPD, n=10) or the Specific Carbohydrate Diet (SCD, n=10) for 8 weeks. Results showed that low protein intake benefits PSC patients, whereas higher protein levels exacerbate the condition. We further identified gut bacterial markers useful for distinguishing LPD responders (mostly PSC with concomitant ulcerative colitis) from non-responders. Additionally, by integrating multi-omics data, we propose that this diet modifies the intestinal sulfur cycle reducing hydrogen sulfide (H 2 S) production. Our findings provide an understanding of the beneficial effect of LPD as well as insights into a possible key driver of inflammation in PSC.
AbstractExpression of anti-apoptotic genes is frequently elevated in tumors, where they increase resistance to chemotherapeutic agents and predict poor patient outcomes. However, key cellular factors regulating anti-apoptotic genes in tumors remain unknown. Increased expression of the regenerating (Reg) genes is commonly observed in gastrointestinal (GI) malignancies including colorectal cancer (CRC). We therefore examined Reg gene expression and associated changes in anti-apoptotic genes in an animal model of GI tumorigenesis. Using real time RT-PCR, we measured expression of Reg genes in human colorectal adenocarcinoma specimens, colon adenocarcinoma cell lines and adenomas from multiple intestinal neoplasia (min) mice heterozygous for a germ-line mutation of the adenomatous polyposis coli (APC) gene. Expression of Reg genes is increased in human colorectal adenocarcinomas and in the intestine of APCmin/+ mice at 4 weeks of age, a time preceding the spontaneous second mutation in the APC gene. Individual Reg genes exhibited regional expression profiles across the GI tract in mice. Adenomas from 14-week old mice had significant increases in at least one member of the Reg gene family, most commonly Reg IV and an associated increase in expression of the anti-apoptotic gene, Bcl-2. Addition of exogenous recombinant human Reg IV to human colon adenocarcinoma cells significantly increased Bcl-2 and Bcl-xL expression and induced resistance to ionizing radiation. These results show that dysregulation of Reg genes occur early in tumorigenesis. Furthermore, increased expression of Reg genes, specifically Reg IV contribute to adenoma formation and lead to increased resistance to apoptotic cell death in CRC.
