Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment

Osna, Natalia A.; Kharbanda, Kusum K.

doi:10.3390/biom6020020

Cited by 28 publications

(15 citation statements)

References 26 publications

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“…High-dose chronic ethanol consumption is now known to disrupt gut microbial concentration and diversity, otherwise known as gut dysbiosis. This resulting microbial disturbance allows for the overgrowth of opportunistic pathogens, which promotes gut barrier disruption and release of endotoxins into circulation [3]. Endotoxins including lipopolysaccharides (LPSs) can enter the liver through portal circulation and activate pattern recognition receptors including toll-like receptors [4].…”

Section: Introductionmentioning

confidence: 99%

A Designer Synbiotic Attenuates Chronic-Binge Ethanol-Induced Gut-Liver Injury in Mice

et al. 2019

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Gut dysbiosis and altered short-chain fatty acids are associated with ethanol-induced liver injury. SCFA are fermentation byproducts of the gut microbiota known to have many beneficial biological effects. We tested if a designer synbiotic could protect against ethanol-induced gut-liver injury. C57BL/6 female mice were exposed to chronic-binge ethanol feeding consisting of ethanol (5% vol/vol) for 10 days, followed by a single gavage (5 g/kg body weight) 6 h before euthanasia. A group of mice also received oral supplementation daily with a designer synbiotic, and another group received fecal slurry (FS); control animals received saline. Control mice were isocalorically substituted maltose dextran for ethanol over the entire exposure period. Ethanol exposure reduced expression of tight junction proteins in the proximal colon and induced hepatocyte injury and steatosis. Synbiotic supplementation not only mitigated losses in tight junction protein expression, but also prevented ethanol-induced steatosis and hepatocyte injury. Ethanol exposure also increased hepatic inflammation and oxidative stress, which was also attenuated by synbiotic supplementation. Mice receiving FS were not protected from ethanol-induced liver injury or steatosis. Results were associated with luminal SCFA levels and SCFA transporter expression in the proximal colon and liver. These results indicate supplementation with a designer synbiotic is effective in attenuating chronic-binge ethanol-induced gut-liver injury and steatosis in mice, and highlight the beneficial effects of the gut microbial fermentation byproducts.

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Section: Introductionmentioning

confidence: 99%

A Designer Synbiotic Attenuates Chronic-Binge Ethanol-Induced Gut-Liver Injury in Mice

et al. 2019

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“…Our three novel mouse models support similar findings that binge alcohol creates tissue specific effects in a multi-hit process that requires system level and organ-organ interaction analysis in order to more fully understand the role of comorbidities such as binge alcohol intoxication co-occurring with B . pseudomallei or near-neighbor infections in humans [55]. The data from these studies support the public health responses being developed in melioidosis-endemic regions that emphasize the nature of alcohol consumption as a prime concern [3, 6].…”

Section: Discussionmentioning

confidence: 52%

Persistence of Burkholderia thailandensis E264 in lung tissue after a single binge alcohol episode

et al. 2019

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BackgroundBinge drinking, an increasingly common form of alcohol use disorder, is associated with substantial morbidity and mortality; yet, its effects on the immune system’s ability to defend against infectious agents are poorly understood. Burkholderia pseudomallei, the causative agent of melioidosis can occur in healthy humans, yet binge alcohol intoxication is increasingly being recognized as a major risk factor. Although our previous studies demonstrated that binge alcohol exposure increased B. pseudomallei near-neighbor virulence in vivo and increased paracellular diffusion and intracellular invasion, no experimental studies have examined the extent to which bacterial and alcohol dosage play a role in disease progression. In addition, the temporal effects of a single binge alcohol dose prior to infection has not been examined in vivo.Principal findingsIn this study, we used B. thailandensis E264 a close genetic relative of B. pseudomallei, as useful BSL-2 model system. Eight-week-old female C57BL/6 mice were utilized in three distinct animal models to address the effects of 1) bacterial dosage, 2) alcohol dosage, and 3) the temporal effects, of a single binge alcohol episode. Alcohol was administered comparable to human binge drinking (≤ 4.4 g/kg) or PBS intraperitoneally before a non-lethal intranasal infection. Bacterial colonization of lung and spleen was increased in mice administered alcohol even after bacterial dose was decreased 10-fold. Lung and not spleen tissue were colonized even after alcohol dosage was decreased 20 times below the U.S legal limit. Temporally, a single binge alcohol episode affected lung bacterial colonization for more than 24 h after alcohol was no longer detected in the blood. Pulmonary and splenic cytokine expression (TNF-α, GM-CSF) remained suppressed, while IL-12/p40 increased in mice administered alcohol 6 or 24 h prior to infection. Increased lung and not intestinal bacterial invasion was observed in human and murine non-phagocytic epithelial cells exposed to 0.2% v/v alcohol in vitro.ConclusionsOur results indicate that the effects of a single binge alcohol episode are tissue specific. A single binge alcohol intoxication event increases bacterial colonization in mouse lung tissue even after very low BACs and decreases the dose required to colonize the lungs with less virulent B. thailandensis. Additionally, the temporal effects of binge alcohol alters lung and spleen cytokine expression for at least 24 h after alcohol is detected in the blood. Delayed recovery in lung and not spleen tissue may provide a means for B. pseudomallei and near-neighbors to successfully colonize lung tissue through increased intracellular invasion of non-phagocytic cells in patients with hazardous alcohol intake.

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“…(AOR meta = 0.4) showed greater associations in terms of both significance and effect size. AUD has been implicated in multiple organ damage [9] and is well positioned to contribute to multiorgan failure which is a common cause of COVID-19-related mortality [10]. Based on an approximate estimation, this network has >85% of P meta values as <0.05, which is a 17-fold enrichment comparing to the whole GWAS data (~5.2%).…”

Section: For Genetic Databases Used)mentioning

confidence: 99%