raffinose and Chronic-Disease

Topics: Acute Disease; Adenosine; Allopurinol; Animals; Chronic Disease; Glutathione; Graft Rejection; Humans; Insulin; Intestine, Small; Organ Preservation; Organ Preservation Solutions; Raffinose; Reperfusion Injury; Transplantation, Homologous

Dietary patterns and psychosocial factors, ubiquitous part of modern lifestyle, critically shape the gut microbiota and human health. However, it remains obscure how dietary and psychosocial inputs coordinately modulate the gut microbiota and host impact. Here, we show that dietary raffinose metabolism to fructose couples stress-induced gut microbial remodeling to intestinal stem cells (ISC) renewal and epithelial homeostasis. Chow diet (CD) and purified diet (PD) confer distinct vulnerability to gut epithelial injury, microbial alternation and ISC dysfunction in chronically restrained mice. CD preferably enriches Lactobacillus reuteri, and its colonization is sufficient to rescue stress-triggered epithelial injury. Mechanistically, dietary raffinose sustains Lactobacillus reuteri growth, which in turn metabolizes raffinose to fructose and thereby constituting a feedforward metabolic loop favoring ISC maintenance during stress. Fructose augments and engages glycolysis to fuel ISC proliferation. Our data reveal a diet-stress interplay that dictates microbial metabolism-shaped ISC turnover and is exploitable for alleviating gut disorders.

Topics: Animals; Bacteria; Carbohydrate Metabolism; Cell Proliferation; Cell Self Renewal; Chronic Disease; Diet; Epithelial Cells; Female; Fructose; Gastrointestinal Microbiome; Glycolysis; Intestines; Lactobacillus; Mice, Inbred BALB C; Polyphenols; Raffinose; Stem Cells; Stress, Physiological

Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-beta (TGF-beta) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.

Topics: Adenosine; Allopurinol; Animals; Anticoagulants; Azetidines; Base Sequence; Benzylamines; Chronic Disease; DNA Primers; Fibrosis; Glutathione; Humans; Insulin; Kidney; Kidney Transplantation; Male; Models, Animal; Organ Preservation; Organ Preservation Solutions; Oxidative Stress; Plasminogen Activator Inhibitor 1; Raffinose; RNA, Messenger; Signal Transduction; Swine; Temperature; Tissue Donors; Tissue Plasminogen Activator; Transforming Growth Factor beta; Transplantation, Autologous

Topics: Animals; Chronic Disease; Colitis; Disaccharidases; Dogs; Enteritis; Glucosidases; Glycoside Hydrolases; Humans; Intestinal Mucosa; Intestine, Small; Jejunum; Raffinose; Rats; Trehalase