Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: Summary of a symposium

This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram negative bacteria in the intestine which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, L-glutamine, oats supplementation, or zinc thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram negative bacteria and preserving intestinal permeability to endotoxin may attenuate alcoholic liver and other organ injuries

Alcohol, burn injury, and the intestine

A significant number of burn and other traumatic injuries are reported to occur under the influence of alcohol (EtOH) intoxication. Despite this overwhelming association between EtOH intoxication and injury, relatively little attention has been paid to determining the role of EtOH in post-injury pathogenesis. This article reviews studies which have evaluated the impact of EtOH on post-burn intestinal immunity and barrier functions. The findings from these studies suggest that while a smaller burn injury by itself may not have an adverse effect on host defense, when combined with prior EtOH intoxication it may become detrimental. Experimental data from our laboratory further supports the notion that EtOH intoxication before burn injury suppresses intestinal immune defense, impairs gut barrier functions, and increases bacterial growth. This results in increased bacterial translocation which may contribute to post injury pathogenesis. Altogether, the studies reviewed in this article suggest that EtOH intoxication at the time of injury is a risk factor, and therefore blood EtOH should be checked in burn/trauma patients at the time of hospital admission

Alcohol and inflammatory responses: Highlights of the 2015 Alcohol and Immunology Research Interest Group (AIRIG) meeting

On September 27, 2015 the 20th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite symposium at the annual meeting of the Society for Leukocyte Biology in Raleigh, NC. The 2015 meeting focused broadly on adverse effects of alcohol and alcohol-use disorders in multiple organ systems. Divided into two plenary sessions, AIRIG opened with the topic of pulmonary inflammation as a result of alcohol consumption, which was followed by alcohol\u27s effect on multiple organs, including the brain and liver. With presentations showing the diverse range of underlying pathology and mechanisms associated with multiple organs as a result of alcohol consumption, AIRIG emphasized the importance of continued alcohol research, as its detrimental consequences are not limited to one or even two organs, but rather extend to the entire host as a whole

T cell IFN-γ suppression following alcohol and burn injury is independent of miRNA155.

miRNA155 has been implicated in normal T cell function and their differentiations into the Th1 subtype. We have shown that acute alcohol (ethanol) intoxication combined with burn injury suppresses T cell IFN-γ release. Herein, we examined whether the decrease in IFN-γ is resulted from altered expression of miRNA155 and transcription factors--NFAT, Tbx21, Jun and Fos--in T cells following ethanol and burn injury. Mice received ethanol (∼3 g/Kg) 4 hours prior to ∼12.5% total body surface area sham or burn injury and were sacrificed one day after injury. Splenic T cells were harvested and cultured with anti-CD3 (2 µg/ml) in the presence or absence of rIL-12 (10 ng/ml) or PMA (10 ng/ml) plus ionomycin (50 ng/ml) for 48 hours. We observed a significant decrease in miRNA155, NFAT, Tbx21, Jun and Fos expression as well as IFN-γ release in T cells cultured with anti-CD3 following ethanol and burn injury compared with shams. The co-treatment of T cells with rIL-12 prevented the decrease in IFN-γ and NFAT, Tbx21, Jun and Fos, but not miRNA155. In contrast, the co-treatment with PMA plus ionomycin normalized the expression of NFAT. It did not prevent the decrease in IFN-γ, Tbx21, Jun, Fos and miRNA155. Finally, results obtained in miRNA155-/- mice did not show any change in T cell release of IFN-γ or expression of nuclear factors compared to wildtype mice. Together, these findings suggest that while ethanol and burn injury decreases the expression of miRNA155, it may not be involved in decreased IFN-γ under those conditions

Transforming growth factor-β negatively modulates T-cell responses in sepsis

AbstractSepsis is associated with depressed T-cell functions and increased circulating levels of immunosuppressive agents. TGF-β is a potential anti-inflammatory cytokine that can modify T-cell growth and differentiation. The up-regulation of TGF-β and the mechanism of its action on the T-cells during septic injury have not been resolved. We hypothesized that in sepsis TGF-β produced by macrophages acts on T-cells in a paracrine manner to suppress interleukin (IL)-2 production and proliferation. In this study, we examined the circulating TGF-β levels in a rat model of Gram-negative bacterial sepsis, and compared the abilities of adherent and non-adherent splenocytes to produce TGF-β. Additionally, we investigated the causal relationships of hrTGF-β to concanavalin A (ConA)-induced T-cell responses and the intracellular mechanism of the generation of these responses in normal splenic rat T-cells. Sepsis was induced in rats by intra-abdominally implanting fecal pellets containing Escherichia coli (150 CFU) and Bacteroides fragilis (10 000 CFU). Adherent and non-adherent splenocytes were isolated by differential adherence using Ficoll gradient centrifugation. T-cells were purified by use of Nylon wool columns. We observed a 3–6-fold increase in the circulating levels of TGF-β in sepsis. Western blots and ELISA determinations revealed a 2.5–3-fold increase in cell-associated TGF-β protein levels in adherent splenic cells. Northern analyses also showed a marked increase in TGF-β mRNA expression in adherent cells during sepsis. On the other hand, a significant change was not observed in the TGF-β protein and mRNA expression in non-adherent splenocytes. Pretreatment of control rat T-cells with hrTGF-β decreased both ConA-induced proliferation (by 35–40%) and IL-2 mRNA expression (by >50%). Further, whereas incubation of control rat T-cells with either ConA or TGF-β for 24 h resulted in a 10–15-fold increase in cAMP generation, the addition of hrTGF-β along with ConA resulted in a 50–60-fold increase in cAMP. These results suggest that in sepsis, TGF-β produced by splenic macrophages can act in a paracrine manner on T-cells to depress their IL-2 mRNA expression, IL-2 production and proliferation after up-regulation of cAMP which can interfere with T-cell signaling for proliferation