Inflammation is a major mediator of CKD progression and is partly driven by altered gut microbiome and intestinal barrier disruption, events which are caused by: urea influx in the intestine resulting in dominance of urease-possessing bacteria; disruption of epithelial barrier by urea-derived ammonia leading to endotoxemia and bacterial translocation; and restriction of potassium-rich fruits and vegetables which are common sources of fermentable fiber. Restriction of these foods leads to depletion of bacteria that convert indigestible carbohydrates to short chain fatty acids which are important nutrients for colonocytes and regulatory T lymphocytes. We hypothesized that a high resistant starch diet attenuates CKD progression. Male Sprague Dawley rats were fed a chow containing 0.7% adenine for 2 weeks to induce CKD. Rats were then fed diets supplemented with amylopectin (low-fiber control) or high fermentable fiber (amylose maize resistant starch, HAM-RS2) for 3 weeks. CKD rats consuming low fiber diet exhibited reduced creatinine clearance, interstitial fibrosis, inflammation, tubular damage, activation of NFkB, upregulation of pro-inflammatory, pro-oxidant, and pro-fibrotic molecules; impaired Nrf2 activity, down-regulation of antioxidant enzymes, and disruption of colonic epithelial tight junction. The high resistant starch diet significantly attenuated these abnormalities. Thus high resistant starch diet retards CKD progression and attenuates oxidative stress and inflammation in rats. Future studies are needed to explore the impact of HAM-RS2 in CKD patients.

Patients and animals with chronic kidney disease (CKD) exhibit profound alterations in the gut environment including shifts in microbial composition, increased fecal pH, and increased blood levels of gut microbe-derived metabolites (xenometabolites). The fermentable dietary fiber high amylose maize-resistant starch type 2 (HAMRS2) has been shown to alter the gut milieu and in CKD rat models leads to markedly improved kidney function. The aim of the present study was to identify specific cecal bacteria and cecal, blood, and urinary metabolites that associate with changes in kidney function to identify potential mechanisms involved with CKD amelioration in response to dietary resistant starch. Male Sprague-Dawley rats with adenine-induced CKD were fed a semipurified low-fiber diet or a high-fiber diet [59% (wt/wt) HAMRS2] for 3 wk (n = 9 rats/group). The cecal microbiome was characterized, and cecal contents, serum, and urine metabolites were analyzed. HAMRS2-fed rats displayed decreased cecal pH, decreased microbial diversity, and an increased Bacteroidetes-to-Firmicutes ratio. Several uremic retention solutes were altered in the cecal contents, serum, and urine, many of which had strong correlations with specific gut bacteria abundances, i.e., serum and urine indoxyl sulfate were reduced by 36% and 66%, respectively, in HAMRS2-fed rats and urine p-cresol was reduced by 47% in HAMRS2-fed rats. Outcomes from this study were coincident with improvements in kidney function indexes and amelioration of CKD outcomes previously reported for these rats, suggesting an important role for microbial-derived factors and gut microbe metabolism in regulating host kidney function.

Background: Chronic kidney disease (CKD) impairs intestinal barrier function which by allowing influx of noxious products causes systemic inflammation. We have recently shown that intestinal barrier dysfunction in CKD is due to degradation of epithelial tight junction (TJ) which is, in part, mediated by influx of urea and its conversion to ammonia by microbial urease. We hypothesized that by adsorbing urea and urea-derived ammonia, oral activated charcoal (AST-120) may ameliorate CKD-induced intestinal epithelial barrier disruption and systemic inflammation. Methods: Rats were randomized to the CKD or control groups. The CKD group was fed a chow containing 0.7% adenine for 2 weeks. They were then randomized to receive a chow with or without AST-120 (4 g/kg/day) for 2 weeks. Rats consuming regular diet served as controls. Animals were then euthanized, colons were removed and processed for Western blot and immunohistology, and plasma was used to measure endotoxin and oxidative and inflammatory markers. Results: Compared with the controls, the untreated CKD rats showed elevated plasma endotoxin, IL-6, TNF-α, MCP-1, CINC-3, L-selectin, ICAM-1, and malondialdehyde, and depletions of colonic epithelial TJ proteins, claudin-1, occludin, and ZO1.Administrationof AST-120 resulted in partial restoration of the epithelial TJ proteins and reduction in plasma endotoxin and markers of oxidative stress and inflammation. Conclusions: CKD animals exhibited depletion of the key protein constituents of the colonic epithelial TJ which was associated with systemic inflammation, oxidative stress and endotoxemia. Administration of AST-120 attenuated uremia-induced disruption of colonic epithelial TJ and the associated endotoxemia, oxidative stress and inflammation.

Background Gut inflammation is prevalent in chronic kidney disease (CKD) and likely contributes to systemic inflammation via disruption of the epithelial tight junction with subsequent endotoxin and bacterial translocation. Aims To study the expression profile of inflammatory and tight junction proteins in the colon from CKD rats compared to healthy controls, and demonstrate the role of Nrf2 (transcription factor nuclear factor erythroid 2-related factor 2) using a potent Nrf2 activator. Methods CKD was induced via 5/6 nephrectomy in Sprague-Dawley rats, and dh404 (2 mg/kg/day) was used to study the effects of systemic Nrf2 activation. The experimental groups included sham, CKD and CKD? dh404 rats. Blood and colon tissues were analyzed after a 10-week study period. Results Colon from CKD rats showed histological evidence of colitis, depletion of epithelial tight junction proteins, significant reduction of Nrf2 and its measured target gene products (NQO1, catalase, and CuZn SOD), activation of NFkB, and upregulation of pro-inflammatory molecules (COX-2, MCP-1, iNOS, and gp91 phox ). Treatment with dh404 attenuated colonic inflammation, restored Nrf2 activity and levels of NQO1, catalase and CuZn SOD, decreased NFkB and lowered expression of COX-2, MCP-1, iNOS, and gp91 phox . This was associated with restoration of colonic epithelial tight junction proteins (occludin and claudin-1). Conclusions CKD rats exhibited colitis, disruption of colonic epithelial tight junction, activation of inflammatory mediators, and impairment of Nrf2 pathway. Treatment with an Nrf2 activator restored Nrf2 activity, attenuated colonic inflammation, and restored epithelial tight junction proteins.

Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Poria cocos (PC) is a medicinal product widely used in Asia. This study was undertaken to define the alterations of lipid metabolites in rats fed a high-fat diet to induce hyperlipidemia and to explore efficacy and mechanism of action of PC in the treatment of diet-induced hyperlipidemia. Plasma samples were then analyzed using UPLC-HDMS. The untreated rats fed a high-fat diet exhibited significant elevation of plasma triglyceride and total and low-density lipoprotein (LDL) cholesterol concentrations. This was associated with marked changes in plasma concentrations of seven fatty acids (palmitic acid, hexadecenoic acid, hexanoylcarnitine, tetracosahexaenoic acid, cervonoyl ethanolamide, 3-hydroxytetradecanoic acid, and 5,6-DHET) and five sterols [cholesterol ester (18:2), cholesterol, hydroxytestosterone, 19-hydroxydeoxycorticosterone, and cholic acid]. These changes represented disorders of biosynthesis and metabolism of the primary bile acids, steroids, and fatty acids and mitochondrial fatty acid elongation pathways in diet-induced hyperlipidemia. Treatment with PC resulted in significant improvements of hyperlipidemia and the associated abnormalities of the lipid metabolites.