Endotoxemia and gut barrier dysfunction in alcoholic liver disease

Rao, Radhakrishna

doi:10.1002/hep.23009

Cited by 388 publications

(366 citation statements)

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“…Previous studies have reported acute EtOH binge exposure (Rivera et al., 1998) and acute restraint stress (Ait‐Belgnaoui et al., 2012) increase plasma endotoxin. Elevated plasma endotoxin occurs through enhanced gut leakiness, leading to bacterial translocation into the peripheral circulation (Rao, 2009). Interestingly, treatment with antibiotics to reduce gut bacteria reduces stress‐induced blood endotoxin and CORT as well as the stress‐induced hypothalamic inflammatory cytokine responses and corticotropin‐releasing factor (CRF) (Ait‐Belgnaoui et al., 2012).…”

Section: Discussionmentioning

confidence: 99%

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Walter

Vetreno

Crews

2017

Alcoholism Clin & Exp Res

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BackgroundCycles of alcohol and stress are hypothesized to contribute to alcohol use disorders. How this occurs is poorly understood, although both alcohol and stress activate the neuroimmune system—the immune molecules and cells that interact with the nervous system. The effects of alcohol and stress on the neuroimmune system are mediated in part by peripheral signaling molecules. Alcohol and stress both enhance immunomodulatory molecules such as corticosterone and endotoxin to impact neuroimmune cells, such as microglia, and may subsequently impact neurons. In this study, we therefore examined the effects of acute and chronic ethanol (EtOH) on the corticosterone, endotoxin, and microglial and neuronal response to acute stress.MethodsMale Wistar rats were treated intragastrically with acute EtOH and acutely stressed with restraint/water immersion. Another group of rats was treated intragastrically with chronic intermittent EtOH and acutely stressed following prolonged abstinence. Plasma corticosterone and endotoxin were measured, and immunohistochemical stains for the microglial marker CD11b and neuronal activation marker c‐Fos were performed.ResultsAcute EtOH and acute stress interacted to increase plasma endotoxin and microglial CD11b, but not plasma corticosterone or neuronal c‐Fos. Chronic EtOH caused a lasting sensitization of stress‐induced plasma endotoxin, but not plasma corticosterone. Chronic EtOH also caused a lasting sensitization of stress‐induced microglial CD11b, but not neuronal c‐Fos.ConclusionsThese results find acute EtOH combined with acute stress enhanced plasma endotoxin, as well as microglial CD11b in many brain regions. Chronic EtOH followed by acute stress also increased plasma endotoxin and microglial CD11b, suggesting a lasting sensitization to acute stress. Overall, these data suggest alcohol and stress interact to increase plasma endotoxin, resulting in enhanced microglial activation that could contribute to disease progression.

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Section: Discussionmentioning

confidence: 99%

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Walter

Vetreno

Crews

2017

Alcoholism Clin & Exp Res

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“…Presently, the identity of the endogenous lipid antigens that contribute to chronic-plus-binge ethanol-induced hepatic iNKT cell activation is unknown. It is known that chronic ethanol feeding induces gut bacterial overgrowth and increases gut permeability, [29][30][31] which may result in elevated hepatic levels of bacterial products, such as glycosphingolipids, which can induce CD1d-dependent NKT cell activation. 32 Interestingly, a recent study reported that incubation with physiological concentrations of ethanol stimulated NKT cell activation by enhancing CD1d glycolipid loading.…”

Section: Discussionmentioning

confidence: 99%

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

et al. 2015

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“…As discussed in the review, 3 there was a consistent 5-fold to 20-fold increase in endotoxin level following ethanol feeding, despite the variability in the levels of plasma endotoxin measured in different studies. Similarly, a high level of plasma endotoxin was recorded in patients with alcoholic liver disease (ALD) compared to normal subjects when similar extraction methods, lysate, and standards were used.…”

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confidence: 79%

Endotoxemia in alcoholic liver disease

Fujita

2009

Hepatology

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As described in an interesting review by Rao, 1 much evidence derived from numerous experimental studies of alcoholic liver disease (ALD) support the association of endotoxemia with the initiation and progression of ALD. The review focuses on the role of endotoxemia and the mechanisms of gut barrier dysfunction in ALD. The author mentions that endotoxemia is conventionally believed to exist when the plasma endotoxin level rises higher than 2.5 endotoxin units (EU)/mL, and the endotoxin levels in ALD patients, ranging from 8.5 to 206 pg/mL, are 5-to 20-fold higher than those in normal subjects. First, I would like to comment on the determination and interpretation of endotoxemia in the clinical setting. Historically, the rabbit pyrogenic test was introduced to detect the contamination of endotoxins and other toxins in biological preparations in 1940. In the early 1960s, dose-dependent endotoxin-induced coagulation of lysates from the horseshoe crab amoebocyte was found, leading to the development of a new method of quantifying the endotoxin in 1970s, which is now called the limulus amoebocyte lysate (LAL) assay. This assay was quickly approved by the US Food and Drug Administration (FDA) because the LAL test is more sensitive, less time-consuming, more costeffective, and better standardized than the rabbit test. For interpreting the results of the LAL assay, it should be noted that LAL is not prepared for the detection of endotoxemia but is intended only for in vitro diagnostic purposes. Endotoxin antagonists, antibiotics, plasma proteins, and unknown substances in the blood can interfere with or activate the LAL test. The term EU indicates the national standard biological activity in the LAL assay, which was determined by the FDA and other organizations on the basis of the relationship between the LAL assay and the rabbit pyrogenic test. Although the FDA initially defined 1 EU as the endotoxin activity of 200 pg of a reference standard endotoxin, the conversion ratio is variable because it is dependent on the source of the endotoxin used for each assay, ranging from 1 EU to 20 pg to 1 EU to 500 pg. Commercially available LAL kits use a control standard endotoxin because a reference standard endotoxin is very expensive. There are substantial variations in endotoxin potency among the control standard endotoxins. Additionally, substantial variation in the reactivity of lysates from different horseshoe crabs has been observed. Therefore, I would like to ask the author whether it was quite difficult to define endotoxemia and assess the differences in endotoxin levels among the studies.The author concludes that the evidence is clear that alcohol consumption leads to increased intestinal permeability and endotoxemia, which are involved in the pathogenesis of ALD. However, there is no definite clinical evidence showing that improvements in intestinal permeability or anti-endotoxin therapy can ameliorate liver injury in ALD. Also, in an experimental study, ethanol-induced liver damage was not markedly enhanced by the lon...

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Endotoxemia and gut barrier dysfunction in alcoholic liver disease

Cited by 388 publications

References 70 publications

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

Endotoxemia in alcoholic liver disease

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