Leaky Gut in Alcoholic Cirrhosis: A Possible Mechanism for Alcohol-Induced Liver Damage

Keshavarzian, Ali; Holmes, Earle W.; Patel, Milin; Iber, F. L.; Fields, Jeremy Z.; Pethkar, Shardha

doi:10.1111/j.1572-0241.1999.00797.x

Cited by 327 publications

(67 citation statements)

References 33 publications

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“…This in turn can lead to alcoholic cirrhosis and liver failure, which is a causal factor in the development of alcoholic endotoxemia and hepatitis. Keshavarizian [3] found that intestinal barrier dysfunction was observed in alcoholics who also had liver disease. The intestinal barrier is formed by the epithelial cells and the tight junctions (TJs) between them [4], and provides barrier functions between luminal triggers and the host.…”

Section: Introductionmentioning

confidence: 99%

The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury

et al. 2013

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BackgroundThis study aimed to investigate the mechanism of the probiotic VSL#3 in acute alcoholic intestinal injury, and evaluate the effect of VSL#3, glutamine,VSL#3+glutamine and heat-killed VSL#3 therapy in a rat model.MethodsSix- to eight-week-old male wild-type rats were divided into seven groups. To establish the acute alcohol liver disease model, rats received three doses of corn starch dissolved in PBS/40% alcohol administered intra-gastrically every 12 hours. Treatment groups received an intra-gastric dose of VSL#3, Glutamine, heat-killed VSL#3, or VSL#3+Glutamine 30 minutes prior to alcohol administration. The placebo group was treated with PBS prior to alcohol administration. TNFα and endotoxin in plasma was measured by ELISA and Tachypleus Ameboctye Lysate assays, and electron microscopy, Western blotting, and reverse transcription polymerase chain reaction were used to identify the mechanisms of VSL#3 in the regulation of epithelial permeability.ResultsFirst, compared with control group, endotoxin and TNFα in alcohol group was obviously high. At the same time, in VSL#3 group,the expression of endotoxin and TNFα obviously lower than the alcohol group. And the trends of the expression of tight junction proteins in these groups were reversed with the change of endotoxin and TNFα. Second, compared the groups of VSL#3 with glutamine,VSL#3+glutamine and heat-killed VSL#3,we found that both VSL#3 and heat-killed VSL#3, glutamine were as effective as VSL#3+glutamine in the treatment of acute alcohol liver disease, the expression of endotoxin and TNFα were lower than the alcohol group, and tight junction proteins were higher than the alcohol group whereas the expression of tight junction proteins were higher in VSL#3 + glutamine group than either agent alone, but have no significant difference.ConclusionWe conclude that VSL#3 treatment can regulate the ecological balance of the gut microflora, preventing passage of endotoxin and other bacterial products from the gut lumen into the portal circulation and down-regulating the expression of TNFα, which could otherwise down-regulate the expression of tight junction proteins and increase epithelial permeability.

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Section: Introductionmentioning

confidence: 99%

The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury

et al. 2013

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“…In many patients this abnormality persisted for up to 2 weeks after cessation of drinking [25]. Alcoholics with chronic liver disease showed a markedly increased intestinal permeability by the L/M test, whereas the increase in intestinal permeability was slight in alcoholics with no liver disease [26]. Only patients with increased intestinal permeability had an altered fecal microbiota composition: a drastic decrease in the abundance of Ruminococcus , Faecalibacterium , Subdoligranulum , Oscillibacter , and Anaerofilum belonging to the Ruminococcaceae family [27].…”

Section: Alcoholic Liver Diseasementioning

confidence: 99%

Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?

2016

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Background: Increased intestinal permeability due to barrier dysfunction is supposed to cause microbial translocation which may induce low-grade inflammation in various diseases. However, this series of events has not been comprehensively evaluated yet. Summary: Intestinal epithelial barrier dysfunction and increased permeability have been described in patients with inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), alcoholic liver disease, nonalcoholic steatohepatitis (NASH), liver cirrhosis, acute pancreatitis, primary biliary cholangitis (PBC), type 1 and type 2 diabetes, chronic kidney disease, chronic heart failure (CHF), depression, and other diseases. Most clinical reports used either permeability assays of challenge tests or measurement of circulating bacterial markers like endotoxin for assessment of ‘the leaky gut'. The intestinal permeability assessed by the challenge tests has often been related to the changes of tight junction proteins in the epithelium or circulating endotoxin levels. In patients with IBD, alcoholic liver disease, NASH, liver cirrhosis, PBC, obstructive jaundice, severe acute pancreatitis, and CHF, endotoxemia and proinflammatory cytokinemia have been found in addition to increased permeability. In the serum of patients with IBS and depression, antiflagellin antibodies and antilipid A antibodies were detected, respectively, together with increased permeability and proinflammatory cytokinemia. The site of infection, which is localized to the intestine in IBD and IBS, includes various extraintestinal organs in other diseases. The relation of gut dysbiosis to intestinal barrier dysfunction has gradually been clarified. Key Messages: Although no direct cause-and-effect relationship has been confirmed, all clinical and experimental data suggest the importance of intestinal hyperpermeability in the inflammatory changes of various diseases. Increased intestinal permeability is a new target for disease prevention and therapy. Considering the close relationship of ‘the leaky gut' and gut dysbiosis to the major diseases, we can conclude that meticulous dietetic and probiotic approaches to recover healthy microbiota have the potential to make a breakthrough in the management of these diseases tomorrow.

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“…[11][12][13][14][15] Bacteria deconjugate bile acids, 16 and bacterial deconjugation should result in a further reduction in bile acid concentration because unconjugated bile acids are rapidly absorbed by nonionic diffusion. Finally, studies have indicated there is increased small intestinal permeability in cirrhosis, [17][18][19][20] raising the possibility that even conjugated bile acids, which are membrane-impermeable in health, might be absorbed passively. In principle, the combination of decreased conjugated bile acid secretion, increased deconjugation, and passive permeation of conjugated bile acids should lead to a marked decrease in the intraluminal concentration of bile acids.…”

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confidence: 99%

Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats

et al. 2003

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Experiments were performed to test whether conjugated bile acid administration would decrease bacterial overgrowth, bacterial translocation, and endotoxemia in ascitic cirrhotic rats. Cholylsarcosine, a deconjugation-dehydroxylation resistant and cholylglycine, a deconjugation-dehydroxylation susceptible bile acid were used. Rats with CCl 4 -induced cirrhosis and ascites were fed cholylsarcosine, cholylglycine (both at 70 mg/kg/d), or placebo for 2 weeks. Healthy rats, as controls, were treated similarly. In cirrhotic rats receiving placebo, bile secretion from an acute biliary fistula was lower than in healthy rats (27.2 ؎ 6.5 vs. 53.0 ؎ 3.1 L/kg/min; mean ؎ SE, P < .05). The administration of conjugated bile acids to cirrhotic rats normalized bile secretion (cholylsarcosine, 51.8 ؎ 6.29; cholylglycine, 52.72 ؎ 8.9 L/kg/min). Total ileal bacterial content was 6-fold higher in ascitic cirrhotic rats than in healthy rats. Conjugated bile acid administration reduced bacterial content to normal levels. Bacterial translocation was less in cirrhotic animals receiving conjugated bile acids (cholylsarcosine, 33%; cholylglycine, 26%) than in animals receiving placebo (66%). Endotoxemia was decreased in cirrhotic rats by conjugated bile acid feeding (cholylsarcosine, 0.098 ؎ 0.002; cholylglycine 0.101 ؎ 0.007 EU/mL) compared with placebo (0.282 ؎ 0.124, P < .001). Survival was greater in animals receiving conjugated bile acids (cholylsarcosine, 10/15; cholylglycine, 11/15; placebo, 5/15). In conclusion, the administration of conjugated bile acids to ascitic cirrhotic rats increased bile acid secretion, eliminated intestinal bacterial overgrowth, decreased bacterial translocation, decreased endotoxemia, and increased survival. Oral conjugated bile acids may be useful in preventing bacterial translocation, endotoxemia, and spontaneous bacterial perotonitis in cirrhotic patients. (HEPATOLOGY 2003;37:551-557.)

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Leaky Gut in Alcoholic Cirrhosis: A Possible Mechanism for Alcohol-Induced Liver Damage

Abstract: Because only the alcoholics with chronic liver disease had increased intestinal permeability, we conclude that a "leaky" gut may be a necessary cofactor for the development of chronic liver injury in heavy drinkers.

Cited by 327 publications

References 33 publications

The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury

The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury

Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?

Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats

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