scholarly journals Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice

mBio ◽  
2021 ◽  
Author(s):  
Masahiro Matsui ◽  
Shinya Fukunishi ◽  
Takashi Nakano ◽  
Takaaki Ueno ◽  
Kazuhide Higuchi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Lifestyle Modification ◽  
Community Surveys ◽  
First Line ◽  
Diet And Exercise ◽  
Bile Acid Transporter ◽  
Gut Microbiota Dysbiosis

NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise.

scholarly journals Ileal bile acid transporter inhibitor improves hepatic steatosis by changing the gut microbiota dysbiosis in NAFLD model mice

2020 ◽  
Author(s):  
Masahiro Matsui ◽  
Shinya Fukunishi ◽  
Takashi Nakano ◽  
Takaaki Ueno ◽  
Kazuhide Higuchi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Hepatic Steatosis ◽  
Body Weight Gain ◽  
Alcoholic Fatty Liver ◽  
Fecal Microbiome ◽  
Α Diversity ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Gut Microbiota Dysbiosis

Abstract Background & Aim: Non-alcoholic fatty liver disease (NAFLD) which is characterized by excessive fat deposition in the liver that is not attributable to consumption of alcohol, highly prevalent in all countries. However, therapeutic agents approved for the treatment of NAFLD are lacking. An ileal bile acid transporter inhibitor (IBATi) which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi for NAFLD through modification of the gut microbiota in mice. Results When HFD mice were treated with IBATi, their body weight gain and serum LDL levels were significantly suppressed and NAFLD activity score was significantly decreased. Treatment with IBATi ameliorated the increase of ileal Fgf15 mRNA and the decrease hepatic Cyp7a1 mRNA in HFD mice. The microbial compositions of the feces from these mice were analyzed using 16S rRNA sequencing. The decrease of α-diversity in gut microbiota induced by HFD was recovered by the IBATi treatment. To establish a cause-effect of the improvement efficacy of IBATi for NAFLD, we recolonized antibiotic solution-treated mice reared in SPF conditions by fecal microbiome transplantation (FMT) using stool from the HFD or HFD + IBATi mice. From FMT, the gut microbiota from HFD + IBATi mice prevented hepatic steatosis caused by HFD. Conclusions IBATi improves hepatic steatosis by changing the gut microbiota dysbiosis in NAFLD model mice.

scholarly journals Liver cirrhosis contributes to the disorder of gut microbiota in patients with hepatocellular carcinoma

2020 ◽  
Vol 9 (12) ◽  
pp. 4232-4250 ◽  
Author(s):  
Ruipeng Zheng ◽  
Guoqiang Wang ◽  
Zhiqiang Pang ◽  
Nan Ran ◽  
Yinuo Gu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Gut Microbiota

scholarly journals Gut Microbiota Dysbiosis Associated with Bile Acid Metabolism in Neonatal Cholestasis Disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Meng Li ◽  
Sixiang Liu ◽  
Mingying Wang ◽  
Hongwei Hu ◽  
Jianwen Yin ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Neonatal Cholestasis ◽  
Gut Microbiota Dysbiosis

scholarly journals Role of Gut Microbiota in Bile-Acid Metabolism

2021 ◽  
Author(s):  
Yuji Naito ◽  
Tomohisa Takagi ◽  
Ryo Inoue
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Chronic Constipation ◽  
Bile Acid Metabolism ◽  
Endogenous Factors ◽  
Healthy Longevity ◽  
Bile Acid Transporter ◽  
Acid Metabolites ◽  
Bile Acid Receptor

The role of the gut microbiota in modifying the pathophysiology of various diseases, including neurodegenerative diseases, is increasingly becoming clear. Bile acids have been shown to be endogenous factors that affect gut microbiota, and bile-acid metabolites directly or indirectly affect host physiology and pathophysiology. The development of metagenomic analysis for gut microbiota and systematic bile-acid measurement using LC–MS/MS has triggered a breakthrough for research in this field. Clinically, an inhibitor of the ileal bile-acid transporter (Elobixibat) was used as a therapeutic agent for chronic constipation, which also paved the way for progress in bile-acid signal research. Additionally, this review emphasizes the importance of gut microbiota-bile acid-receptor signals when considering nutritional approaches to promote healthy longevity.

CaboRISE: A phase II study evaluating reduced starting dose and dose escalation of cabozantinib as second-line therapy for advanced HCC in patients with compensated liver cirrhosis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4163-TPS4163
Author(s):  
Jorg Trojan ◽  
Stefan Pluntke ◽  
Florian van Boemmel ◽  
Ursula Ehmer ◽  
Thorsten Oliver Goetze ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Adverse Events ◽  
Dose Escalation ◽  
Discontinuation Rate ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Once Daily ◽  
Starting Dose

TPS4163 Background: The multi-targeted tyrosine kinase inhibitor cabozantinib is approved for the treatment of advanced hepatocellular carcinoma (HCC) in adults, who have previously been treated with sorafenib. In the pivotal phase 3 CELESTIAL trial a significant improvement for OS and PFS was shown for cabozantinib in comparison to placebo treated patients (Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63). However, in 62% of patients a dose reduction of cabozantinib was necessary and the median average daily dose was 35.8 mg. The discontinuation rate due to treatment-related adverse events (TRAEs) was 16% and grade 3-4 TRAEs occurred in 68% of patients. For HCC patients treated with sorafenib in first-line, a reduced starting dose of 200 mg BID was not inferior in terms of OS but showed a trend toward a decreased rate of sorafenib discontinuation(Reiss KA et al. J Clin Oncol 2017; 35:3575-3581). The aim of the CaboRISE trial is to study the effect of a reduced starting dose of cabozantinib on tolerability, safety, and efficacy. Methods: The CaboRISE trial is an open-label, single arm, multicenter phase II trial, including patients with advanced stage hepatocellular carcinoma (HCC) with compensated liver cirrhosis (Child-Pugh A) in second line treatment, after first line treatment with sorafenib or lenvatinib. Forty evaluable patients will be enrolled in the study to receive a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. The objective of the trial is to assess the tolerability of a reduced starting dose of cabozantinib, in order to reduce the treatment discontinuation rates due to treatment-related adverse events below 10%. Primary endpoint is the treatment discontinuation rate due to TRAEs. Secondary endpoints are overall survival, progression free survival at 10 weeks, objective response rate, time on treatment, treatment exposure, toxicity, and quality of life. Study start of the CaboRISE trial was in October 2020. By February 2021, 7 centers across Germany have been initiated and a total of 4 out of 40 planned patients have been enrolled. The study is currently ongoing. This study is financially supported by Ipsen. ClinicalTrials.gov: NCT04522908 EudraCT: 2020-000775-20. Clinical trial information: NCT04522908.

scholarly journals Perinatal High-Salt Diet Induces Gut Microbiota Dysbiosis, Bile Acid Homeostasis Disbalance, and NAFLD in Weanling Mice Offspring

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2135
Author(s):  
Qing Guo ◽  
Yi Tang ◽  
Ying Li ◽  
Ziyuan Xu ◽  
Di Zhang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Lithocholic Acid ◽  
High Salt ◽  
Alcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Tnf Α ◽  
Junction Protein ◽  
Gut Microbiota Dysbiosis

A perinatal high-salt (HS) diet was reported to elevate plasma triglycerides. This study aimed to investigate the hypothesis that a perinatal HS diet predisposed offspring to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of abnormal lipid metabolism, and the possible mechanism. Female C57BL/6 mice were fed a control diet (0.5% NaCl) or HS diet (4% NaCl) during pregnancy and lactation and their offspring were sacrificed at weaning. The perinatal HS diet induced greater variation in fecal microbial beta-diversity (β-diversity) and increased bacteria abundance of Proteobacteria and Bacteroides. The gut microbiota dysbiosis promoted bile acid homeostasis disbalance, characterized by the accumulation of lithocholic acid (LCA) and deoxycholic acid (DCA) in feces. These alterations disturbed gut barrier by increasing the expression of tight junction protein (Tjp) and occludin (Ocln), and increased systemic lipopolysaccharide (LPS) levels and hepatic inflammatory cytokine secretion (TNF-α and IL-6) in the liver. The perinatal HS diet also inhibited hepatic expression of hepatic FXR signaling (CYP7A1 and FXR), thus triggering increased hepatic expression of pro-inflammatory cytokines (TNF-α and IL-6) and hepatic lipid metabolism-associated genes (SREBP-1c, FAS, ACC), leading to unique characteristics of NAFLD. In conclusion, a perinatal HS diet induced NAFLD in weanling mice offspring; the possible mechanism was related to increased bacteria abundance of Proteobacteria and Bacteroides, increased levels of LCA and DCA in feces, and increased expressions of hepatic FXR signaling.

scholarly journals The gut microbiota: A new potential driving force in liver cirrhosis and hepatocellular carcinoma

2017 ◽  
Vol 5 (7) ◽  
pp. 944-953 ◽  
Author(s):  
Marco Sanduzzi Zamparelli ◽  
Alba Rocco ◽  
Debora Compare ◽  
Gerardo Nardone
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Gut Microbiota ◽  
Driving Force

scholarly journals Diagnostic and therapeutic potential of the gut microbiota in patients with early hepatocellular carcinoma

2019 ◽  
Vol 11 ◽  
pp. 175883591984818 ◽  
Author(s):  
Francesca Romana Ponziani ◽  
Alberto Nicoletti ◽  
Antonio Gasbarrini ◽  
Maurizio Pompili
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Gut Microbiota ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Intestinal Flora ◽  
Early Hepatocellular Carcinoma ◽  
Pathological Conditions ◽  
Immunological Alterations

The gut microbiota is involved in the maintenance of the homeostasis of the human body and its alterations are associated with the development of different pathological conditions. The liver is the organ most exposed to the influence of the gut microbiota, and recently important connections between the intestinal flora and hepatocellular carcinoma (HCC) have been described. In fact, HCC is commonly associated with liver cirrhosis and develops in a microenvironment where inflammation, immunological alterations, and cellular aberrations are dramatically evident. Prevention and diagnosis in the earliest stages are still the most effective weapons in fighting this tumor. Animal models show that the gut microbiota can be involved in the promotion and progression of HCC directly or through different pathogenic mechanisms. Recent data in humans have confirmed these preclinical findings, shedding new light on HCC pathogenesis. Limitations due to the different experimental design, the ethnic and hepatological setting make it difficult to compare the results and draw definitive conclusions, but these studies lay the foundations for a pathogenetic redefinition of HCC. Therefore, it is evident that the characterization of the gut microbiota and its modulation can have an enormous diagnostic, preventive, and therapeutic potential, especially in patients with early stage HCC.

Sign in / Sign up

Export Citation Format

Share Document