J. Christian Bode

It is generally accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators plays an important role in the development of alcoholic liver disease (ALD). The mechanisms involved in the ethanol-induced activation of monocytes/macrophages (including Kupffer cells) are however, still a matter of debate. The brief review will summarize the published data from the literature on the two main pathomechanisms discussed until now: I) Gut-derived bacterial toxins, specially endotoxin; and II) metabolic changes induced by alcohol oxidation (independent of mechanism I). For pathomechanism I, clear evidence has been published from numerous groups: Alcohol induces mucosal injury in the upper gastrointestinal tract and leads to marked increase in the permeability of the gut mucosa to macromolecules such as endotoxin. The resulting endotoxemia then leads to activation of Kupffer cells and other macrophages. The increased release of pro-inflammatory mediators (e.g., TNF-alpha, Il-1, reacting oxygen species) and infiltration of other inflammatory cells (e.g., neutrophils) finally causes liver damage. Regarding the second pathomechanism it has repeatedly been argued that the metabolic alterations which are induced by chronic administration of ethanol to rats or mice might increase the sensitivity of monocytes/macrophages to secrete TNF-alpha and other pro-inflammatory mediators thereby increasing the susceptibility to ethanol-induced liver injury. However, in all feeding experiments the effect of ethanol on intestinal permeability and enhanced translocation of bacterial toxins (endotoxin) is likely to occur (or at least cannot be excluded). The latter holds true also for experiments using isolated macrophages/Kupffer cells from ethanol fed animals. Therefore, to clarify whether or not alterations related to ethanol metabolism ("direct" effects of ethanol) contribute to the activation of the innate immune system studies using germ-free animals are needed to exclude the "indirect" effect of ethanol via gut-derived bacterial toxins.

When alcohol is consumed, the alcoholic beverages first pass through the various segments of the gastrointestinal (GI) tract. Accordingly, alcohol may interfere with the structure as well as the function of GI-tract segments. For example, alcohol can impair the function of the muscles separating the esophagus from the stomach, thereby favoring the occurrence of heartburn. Alcohol-induced damage to the mucosal lining of the esophagus also increases the risk of esophageal cancer. In the stomach, alcohol interferes with gastric acid secretion and with the activity of the muscles surrounding the stomach. Similarly, alcohol may impair the muscle movement in the small and large intestines, contributing to the diarrhea frequently observed in alcoholics. Moreover, alcohol inhibits the absorption of nutrients in the small intestine and increases the transport of toxins across the intestinal walls, effects that may contribute to the development of alcohol-related damage to the liver and other organs.