Proton pump inhibitor therapy does not increase serum endotoxin activity in patients with cirrhosis

Okada, Yasushi; Namisaki, Tadashi; Sato, Shinya; Moriya, Kyoji; Akahane, Takemi; Kitade, Mitsuteru; Kawaratani, Hideto; Kaji, Kosuke; Takaya, Hiroaki; Sawada, Yasuhiko; Shimozato, Naotaka; Seki, Kazuhiko; Saikawa, Soichiro; Nakanishi, Keisuke; Furukawa, Masanori; Fujinaga, Yukihisa; Kubo, Takuya; Kaya, Daisuke; Tsuji, Yosuke; Ozutsumi, Takahiro; Kitagawa, Koh; Mashitani, Tsuyoshi; Ogawa, Hiroyuki; Ishida, Koji; Mitoro, Akira; Yamao, Junichi; Yoshiji, Hitoshi

doi:10.1111/hepr.13249

Cited by 9 publications

(9 citation statements)

References 33 publications

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“…Previous studies reported that progression of liver cirrhosis was associated with intestinal barrier dysfunction leading to several defense mechanism abnormalities and increase in gut-derived endogenous Et [1,2]. Et was found to be associated with functional liver capacity and to increase with the progression of liver disease [10]. In this study, the risk of ACLF development was increased in patients with Child-Pugh class B disease compared with class A disease, and Et was associated with functional liver capacity.…”

Section: Discussionsupporting

confidence: 53%

“…Previous studies have reported that EA was increased in patients with bacterial sepsis and related to the mortality risk, and that anti-Et treatment decreased EA [9]. Previous studies have also reported that increased EA in cirrhotic patients was associated with progression of liver cirrhosis [10] and EA was increased in patients with ALF [11]. EA associated with bacterial infection and inflammation may be involved in the pathophysiology of ACLF in liver cirrhosis patients.…”

Section: Introductionmentioning

confidence: 96%

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Increased Endotoxin Activity Is Associated with the Risk of Developing Acute-on-Chronic Liver Failure

Takaya

Namisaki

Sato

et al. 2020

JCM

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Acute-on-chronic liver failure (ACLF) leads to systematic inflammatory response syndrome and multiple organ failure. This study investigated the relationship between endotoxin (Et) and ACLF with the aim of determining whether Et activity (EA) is useful as a predictive biomarker of ACLF development and whether rifaximin treatment decreased the risk of ACLF development. Two hundred forty-nine patients with liver cirrhosis were enrolled in this study. Et concentration was determined in the whole blood by a semiquantitative EA assay. Predictive factors of ACLF development and the risk of ACLF development with and without rifaximin treatment were identified by univariate and multivariate analysis using Fine and Gray’s proportional subhazards model. EA level was higher in Child-Pugh class B than in class A patients, and class B patients had an increased risk of ACLF development compared with class A patients. Multivariate analysis showed that EA level was a predictive factor independently associated with ACLF development. Rifaximin decreased EA level and the risk of ACLF development in Child-Pugh class B patients. Et levels were associated with functional liver capacity and were predictive of ACLF development in cirrhotic patients. Rifaximin decreased Et level and the risk of ACLF development in advanced cirrhotic patients.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 96%

Increased Endotoxin Activity Is Associated with the Risk of Developing Acute-on-Chronic Liver Failure

Takaya

Namisaki

Sato

et al. 2020

JCM

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“…Among the 12 patients in the PH group, 11 were taking proton pump inhibitors (PPIs), so the relationship between the ongoing use of PPIs for the treatment of varices was also taken into consideration (12)(13)(14)(15). It has been reported that the partial changes in the gut microbiota caused by PPI usage are similar to the changes caused by the progression of liver cirrhosis, and increased inflow of oral flora to the intestines might create an intestinal environment that is a risk factor for the progression of liver cirrhosis, spontaneous bacterial peritonitis, and hepatic encephalopathy (9,(16)(17)(18)(19). The levels of genera (Lactobacillales, Streptococcus, Selenomonas, Veillonella, Campylobacter, and Haemophilus) have been reported to be high in PPI users (20).…”

Section: Discussionmentioning

confidence: 99%

Exploratory Research on the Relationship between Human Gut Microbiota and Portal Hypertension

et al. 2020

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Objective The relationship between gut microbiota and portal hypertension remains unclear. We investigated the characteristics of the gut microbiota in portal hypertension patients with esophago-gastric varices and liver cirrhosis. Methods Thirty-six patients (12 patients with portal hypertension, 12 healthy controls, and 12 non-cirrhosis patients) were enrolled in this university hospital study. Intestinal bacteria and statistical analyses were performed up to the genus level using the terminal restriction fragment length polymorphism method targeting 16S ribosomal RNA genes, with diversified regions characterizing each bacterium. Results Levels of Lactobacillales were significantly higher (p=0.045) and those of Clostridium cluster IV significantly lower (p=0.014) in patients with portal hypertension than in other patients. This Clostridium cluster contains many butanoic acid-producing strains, including Ruminococcace and Faecalibacterium prausnitzii. Clostridium cluster IX levels were also significantly lower (p=0.045) in portal hypertension patients than in other patients. There are many strains of Clostridium that produce propionic acid, and the effects on the host and the function of these bacterial species in the human intestine remain unknown. Regarding the Bifidobacterium genus, which is supposed to decrease as a result of cirrhosis, no significant decrease was observed in this study. Conclusion In the present study, we provided information on the characteristics of the gut microbiota of portal hypertension patients with esophago-gastric varices due to liver cirrhosis. In the future, we aim to develop probiotic treatments following further analyses that include the species level, such as the intestinal flora analysis method and next-generation sequencers.

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“…Since endotoxemia was first associated with human liver diseases in the 1970s, much attention has been paid to the importance of intestinal Et as a critical cofactor in severe liver diseases [ 2 , 3 ]. Et are frequently detected in patients with liver cirrhosis (LC) who present with no other evidence of Gram-negative infection, indicating that their condition is due to the impaired hepatic clearance of gut-derived Et that are normally absorbed from the gastrointestinal tract [ 4 , 5 ]. Increased Et levels due to increased intestinal permeability and insufficient Et clearance by the hepatic reticuloendothelial system, including macrophages (e.g., Kupffer cells), may lead to a marked increase in liver sensitivity to Et, resulting in spillover of the Et into the systemic circulation, which leads to extrahepatic manifestations consistent with liver injury [ 1 , 2 , 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Et are frequently detected in patients with liver cirrhosis (LC) who present with no other evidence of Gram-negative infection, indicating that their condition is due to the impaired hepatic clearance of gut-derived Et that are normally absorbed from the gastrointestinal tract [ 4 , 5 ]. Increased Et levels due to increased intestinal permeability and insufficient Et clearance by the hepatic reticuloendothelial system, including macrophages (e.g., Kupffer cells), may lead to a marked increase in liver sensitivity to Et, resulting in spillover of the Et into the systemic circulation, which leads to extrahepatic manifestations consistent with liver injury [ 1 , 2 , 3 , 4 , 5 , 6 ]. Increasing levels of Et in patients with LC are associated with hepatic failure, hepatic encephalopathy, and increased mortality [ 5 , 6 , 7 ]; they also trigger the hypercoagulability and cytokine cascade that precede multiple organ failure (MOF) (e.g., acute-on-chronic liver failure (ACLF)) [ 2 , 3 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

ADAMTS13, VWF, and Endotoxin Are Interrelated and Associated with the Severity of Liver Cirrhosis via Hypercoagulability

Takaya

Namisaki

Asada

et al. 2022

JCM

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ADAMTS13 specifically cleaves the multimeric von Willebrand factor (VWF), and an imbalance between ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) levels is associated with the severity of liver cirrhosis (LC). However, the reason for this imbalance in patients with LC is unknown. This study investigated the relationship among ADAMTS13:AC, VWF:Ag, and endotoxin (Et) levels in patients with LC. ADAMTS13:AC and VWF:Ag levels were determined using ELISA, whereas Et levels were estimated using a chromogenic substrate assay. The levels of ADAMTS13 inhibitor (ADAMTS13:INH) were evaluated by measuring the extent that heat-inactivated patient’s plasma reduces the ADAMTS13:AC of the control. The status (degraded, normal, or unusually large [UL]) of the VWF multimer (VWFM) was determined through vertical agarose gel electrophoresis. ADAMTS13:AC, VWF:Ag, and Et levels decreased, increased, and increased, respectively, with the severity of LC. Patients with cirrhosis with high Et levels had lower and higher ADAMTS13:AC and VWF:Ag levels, respectively, than those with low Et levels. Patients with cirrhosis with detectable ADAMTS13:INH had higher Et levels than those with undetectable ADAMTS13:INH. Patients whose VWFM was either normal or UL had higher Et levels than those with degraded VWFM. In conclusion, ADAMTS13, VWF, and Et may be interrelated and associated with the severity of LC via hypercoagulability.

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Proton pump inhibitor therapy does not increase serum endotoxin activity in patients with cirrhosis

Abstract: Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis.

Cited by 9 publications

References 33 publications

Increased Endotoxin Activity Is Associated with the Risk of Developing Acute-on-Chronic Liver Failure

Increased Endotoxin Activity Is Associated with the Risk of Developing Acute-on-Chronic Liver Failure

Exploratory Research on the Relationship between Human Gut Microbiota and Portal Hypertension

ADAMTS13, VWF, and Endotoxin Are Interrelated and Associated with the Severity of Liver Cirrhosis via Hypercoagulability

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