Background: Increased intestinal permeability due to barrier dysfunction is supposed to cause microbial translocation which may induce low-grade inflammation in various diseases. However, this series of events has not been comprehensively evaluated yet. Summary: Intestinal epithelial barrier dysfunction and increased permeability have been described in patients with inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), alcoholic liver disease, nonalcoholic steatohepatitis (NASH), liver cirrhosis, acute pancreatitis, primary biliary cholangitis (PBC), type 1 and type 2 diabetes, chronic kidney disease, chronic heart failure (CHF), depression, and other diseases. Most clinical reports used either permeability assays of challenge tests or measurement of circulating bacterial markers like endotoxin for assessment of ‘the leaky gut'. The intestinal permeability assessed by the challenge tests has often been related to the changes of tight junction proteins in the epithelium or circulating endotoxin levels. In patients with IBD, alcoholic liver disease, NASH, liver cirrhosis, PBC, obstructive jaundice, severe acute pancreatitis, and CHF, endotoxemia and proinflammatory cytokinemia have been found in addition to increased permeability. In the serum of patients with IBS and depression, antiflagellin antibodies and antilipid A antibodies were detected, respectively, together with increased permeability and proinflammatory cytokinemia. The site of infection, which is localized to the intestine in IBD and IBS, includes various extraintestinal organs in other diseases. The relation of gut dysbiosis to intestinal barrier dysfunction has gradually been clarified. Key Messages: Although no direct cause-and-effect relationship has been confirmed, all clinical and experimental data suggest the importance of intestinal hyperpermeability in the inflammatory changes of various diseases. Increased intestinal permeability is a new target for disease prevention and therapy. Considering the close relationship of ‘the leaky gut' and gut dysbiosis to the major diseases, we can conclude that meticulous dietetic and probiotic approaches to recover healthy microbiota have the potential to make a breakthrough in the management of these diseases tomorrow.

Although the chromosomal localization (9q34) of the gene encoding the human form of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) and its exclusive expression in the liver have been established, the cells that produce this enzyme are yet to be determined. We investigated the expression of ADAMTS13 mRNA and protein in fresh frozen specimens obtained during liver biopsies of 8 patients with liver diseases. In situ hybridizations to localize ADAMTS13 mRNA showed positive signals exclusively in perisinusoidal cells with irregularly elongated dendritic processes extending between hepatocytes. Furthermore, ADAMTS13 was detected immunohistochemically in perisinusoidal cells, whereas no staining was observed in hepatocytes. The positive cells varied in shape from unipolar to dendritic with irregularly elongated cytoplasmic processes, features common to hepatic stellate cells (HSCs). Double-labeling experiments revealed that the ADAMTS13-positive cells also expressed α-smooth muscle actin, confirming that these cells were activated HSCs. These results suggest that HSCs may be major cells producing ADAMTS13 in human liver.

A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin, activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.

STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. STEM CELLS is read and written by clinical and basic scientists whose expertise encompasses the rapidly expanding fields of stem and progenitor cell biology. STEM CELLS welcomes original articles and concise reviews describing basic laboratory investigations of stem cells and the translation of their clinical aspects of characterization and manipulation from the bench to patient care. The journal covers all aspects of stem cells embryonic stem cells/induced pluripotent stem cells; tissue-specific stem cells; stem cell technology: epigenetics, genomics, proteomics, and metabonomics; cancer stem cells; translational and clinical research; and regenerative medicine.