Oral food intake influences the morphology and function of intestinal epithelial cells and maintains gastrointestinal cell turnover. However, how exactly these processes are regulated, particularly in the large intestine, remains unclear. Here we identify microbiota-derived lactate as a major factor inducing enterocyte hyperproliferation in starvation-refed mice. Using bromodeoxyuridine staining, we show that colonic epithelial cell turnover arrests during a 12-to 36-h period of starvation and increases 12-24 h after refeeding. Enhanced epithelial cell proliferation depends on the increase in live Lactobacillus murinus, lactate production and dietary fibre content. In the model of colon tumorigenesis, mice exposed to a carcinogen during refeeding develop more aberrant crypt foci than mice fed ad libitum. Furthermore, starvation after carcinogen exposure greatly reduced the incidence of aberrant crypt foci. Our results indicate that the content of food used for refeeding as well as the timing of carcinogen exposure influence the incidence of colon tumorigenesis in mice.

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The Sd a blood group carbohydrate structure is expressed in the normal gastrointestinal mucosa. We reported previously that the expression of Sd a carbohydrate structures and B1,4-N-acetylgalactosaminyltransferase (B1,4GalNAcT) activity responsible for Sd a synthesis were remarkably decreased in cancer lesions of the gastrointestinal tract. In this study, we found that Sd a antigen was expressed mainly in chief cells of normal stomach but not in cancer tissue by immunohistologic staining. In separated gastric mucosal cells, the Sd a glycolipids and B1,4GalNAcT activity were concentrated in a fraction that contained chief cells as a major population. We cloned the cDNA encoding the glycosyltransferase that catalyzes the synthesis of Sd a (Sd a -B1,4GalNAcT). Introduction of this cloned cDNA into KATO III gastric or HT29 colonic cancer cell lines, which originally expressed the E-selectin ligands, sialyl Lewis x and sialyl Lewis a , resulted in a marked increase in cell-surface expression of Sd a along with the concomitant total loss of both sialyl Lewis x and sialyl Lewis a . Both KATO III and HT29 cells transfected with the Sd a -b1,4GalNAcT gene showed significantly decreased adhesion to activated human umbilical vein endothelial cells when compared with mock-transfected cells. Sd a determinants showed no direct binding to . These Sd a -B1,4GalNAcT-transfected cells showed strikingly reduced metastatic potential in vivo when compared with mock-transfected cells. In summary, forced expression of Sd a carbohydrate determinant caused remarkable elimination of carbohydrate ligands for selectin and reduced metastasis of human gastrointestinal tract cancer cells. (Cancer Res 2005; 65(14): 6220-27)

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Cholera toxin (CT) is a potent adjuvant; however, the mechanism for its ability to enhance mucosal immunity has not been fully elucidated. We report here that CT exerts its adjuvant properties by signaling through the GM1 ganglioside receptor. When ganglioside-defective mice were given the antigen (Ag) ovalbumin (OVA) with CT by the oral route, CT failed to support either OVA-specific antibody or CD4 + T cell responses. In vitro treatment of murine bone marrow-derived dendritic cells (DC) with CT induced full maturation as evidenced by upregulation of the costimulatory molecules, as well as by an enhanced ability to effectively present OVA for Ag-specific T cell responses. On the other hand, ganglioside-defective DC failed to differentiate to full function as Ag-presenting cells in response to CT. Since ganglioside-defective DC showed a mature phenotype after stimulation with lipopolysaccharide (LPS), the effects of CT on DC was independent of signal transduction through adjuvant receptor for LPS, the Toll-like receptor 4. Furthermore, CT also induced nuclear translocation of nuclear factor (NF)-‹ B in DC in a GM1-dependent fashion. These results highlight gangliosides expressed by DC for recognition of the non-self protein bacterial enterotoxin, which employ a unique signaling pathway to induce both innate and adaptive immunity.

Leucine-rich repeat kinase 2 (LRRK2) has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). Experimental evidence indicates that LRRK2 may play an important role in the pathology induced by abnormal phosphorylation of tau. In the present study, we demonstrated that LRRK2 directly associates with GSK-3b, and that this interaction enhances the kinase activity of GSK-3b. Furthermore, we found that LRRK2-mediated activation of GSK-3b induces high phosphorylation of tau at Ser396 in SH-SY5Y cells. From our present findings, we conclude that LRRK2 may function as a novel enhancer for GSK-3b and as a physiological regulator of neurite outgrowth and axonal transport through regulation of the GSK-3b-mediated phosphorylation of tau at the cellular level. Since LRRK2 is detected in tau-positive inclusions in brain tissue affected by various neurodegenerative disorders, including PD, LRRK2-stimulated phosphorylation of tau by GSK-3b may be involved in development of pathological features in the initial stage of PD. Structured digital abstract• LRKK2 physically interacts with GSK-3B by anti bait coimmunoprecipitation (View interaction)• LRRK2 physically interacts with GSK-3B by anti tag coimmunoprecipitation (View interaction)• LRRK2 binds to GSK-3B by pull down (View interaction)• GSK-3B physically interacts with LRRK2 and TAU by pull down (View interaction)