The role of intestinal flora on the interactions between nonparenchymal cells and hepatocytes in coculture

Kupffer cells are exposed directly to a number of factors in the portal circulation that can modify or regulate their responses to septic stimuli. The gut represents a potential source of a number of these factors including endotoxin, lymphokines, and prostaglandins. We examined Kupffer cells from germfree rats and germfree rats exposed to endotoxin or bacteria via their GI tracts to determine the importance of the intestinal flora in maintaining or modulating Kupffer cell responses. Kupffer cells from germfree animals were reduced in numbers and failed to respond to LPS in Kupffer cell:hepatocyte coculture. When germfree rats were exposed to bacterial endotoxin or bacteria via the gastrointestinal tract their Kupffer cells increased in numbers to normal and the cells responded to LPS in culture. Intestinal overgrowth with Escherichia coli for 2 days activated the Kupffer cells and significantly increased Kupffer cell sensitivity to LPS. These data suggest that the environment of the gastrointestinal tract is important for normal Kupffer cell responses and that intestinal bacterial overgrowth can modify Kupffer cell responses to septic stimuli.