Increased Abundance of M cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases

Systemic inflammation with enhanced brain activation contributes to more severe delay in postoperative ileus

BACKGROUND: The severity of postoperative ileus (POI) has been reported to result from decreased contractility of the muscularis inversely related to the number of infiltrating leukocytes. However, we previously observed that the severity of POI is independent of the number of infiltrating leukocytes, indicating that different mechanisms must be involved. Here, we hypothesize that the degree of tissue damage in response to intestinal handling determines the upregulation of local cytokine production and correlates with the severity of POI. METHODS: Intestinal transit, the inflammatory response, I-FABP (marker for tissue damage) levels and brain activation were determined after different intensities of intestinal handling. KEY RESULTS: Intense handling induced a more pronounced ileus compared with gentle intestinal manipulation (IM). No difference in leukocytic infiltrates in the handled and non-handled parts of the gut was observed between the two intensities of intestinal handling. However, intense handling resulted in significantly more tissue damage and was accompanied by a systemic inflammation with increased plasma levels of pro-inflammatory cytokines. In addition, intense but not gentle handling triggered enhanced c-Fos expression in the nucleus of the solitary tract (NTS) and area postrema (AP). In patients, plasma levels of I-FABP and inflammatory cytokines were significantly higher after open compared with laparoscopic surgery, and were associated with more severe POI. CONCLUSIONS & INFERENCES: Not the influx of leukocytes, rather the manipulation-induced damage and subsequent inflammatory response determine the severity of POI. The release of tissue damage mediators and pro-inflammatory cytokines into the systemic circulation most likely contribute to the impaired motility of non-manipulated intestine.status: publishe