AIM To determine the efficacy of rifaximin for hepatic encephalopathy(HE) with the linkage of gut microbiome in decompensated cirrhotic patients.METHODS Twenty patients(12 men and 8 women; median ...age, 66.8 years; range, 46-81 years) with decompensated cirrhosis(Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test(NCT)-A. Changes in whole blood endotoxin activity(EA) was analyzed by endotoxinactivity assay. Fecal microbiome was assessed by 16 S ribosome RNA(rR NA) gene sequencing.RESULTS Treatment with rifaximin for 4 wk improved hyperammonemia(from 90.6 ± 23.9 μg/d L to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT(from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced(from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels(r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator(Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups(3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered.CONCLUSION Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.
Sodium‐glucose cotransporter 2 inhibitors (SGLT2‐Is) comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules. Although a recent report demonstrated ...the potential ability of SGLT2‐Is to attenuate cancer growth of SGLT2‐expressing cancer cells, little is known about the effects of SGLT2‐Is on hepatocellular carcinoma (HCC). Here, we investigate the anti‐cancer properties of a SGLT2‐I, canagliflozin, against human liver cancer cells. SGTL2 mRNA and protein expression were detected in Huh7 and HepG2 cells, although not in HLE as well as primary human hepatocytes and hepatic stellate cells. Canagliflozin exerted antiproliferative effects on SGLT2‐expressing Huh7 and HepG2 cells in a dose‐dependent manner by inhibiting glycolytic metabolism including glucose uptake, lactate and intracellular ATP production. This agent also induced G2/M arrest and apoptosis with inhibited phosphorylation of ERK, p38 and AKT and cleavage of caspase3. Xenograft tumor growth assay showed that oral administration of canagliflozin (10 mg/kg/day) significantly reduced subcutaneous tumor burdens in a glycemic status‐independent manner, and attenuated intratumor vascularization in Huh7‐ and HepG2‐derived xenograft tumors in BALB/c nude mice. In vitro, canagliflozin suppressed the increased human umbilical vein endothelial cell (HUVEC) proliferation and tubular formation which were observed in Huh7 or HepG2 co‐cultures. By contrast, canagliflozin had no effect on tumor growth and intratumor angiogenesis in SGLT2‐null HLE‐derived xenograft models. These results indicate that SGLT2‐I therapy is a potential new strategy for the treatment of HCC.
What's new?
Sodium‐glucose cotransporter 2 inhibitors (SGLT2‐Is) comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules. Although recent evidence suggests that SGLT2‐Is can attenuate growth of SGLT2‐expressing cancer cells, little is known about their effects on hepatocellular carcinoma (HCC). Our study shows that the SGLT2‐I canagliflozin directly inhibits the growth of SGLT2‐expressing liver cancers by reducing glucose uptake and inhibiting glycolytic metabolism. Furthermore, canagliflozin attenuates proangiogenic activity in SGLT2‐expressing liver cancers. Because SGLT2‐Is are already used extensively without serious side effects, these agents may emerge as a new therapeutic strategy for HCC patients.
Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of ...patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end‐stage liver disease. Obeticholic acid is an approved second‐line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second‐line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end‐stage liver disease and, consequently, the potential need for additional treatments.
Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, ...induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.
Background
It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have ...proved that anti-IR treatment can alleviate liver fibrosis. Sodium–glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long–Evans Tokushima Otsuka (LETO) rats.
Methods
Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro.
Results
OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs.
Conclusion
In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.
Aim
Although some relationships between gut microbiota and liver diseases have been reported, it remains uncertain whether changes in gut microbiota owing to differences in race, food and living ...environment have similar effects. Response to ursodeoxycholic acid (UDCA) may predict the long‐term prognosis of patients with primary biliary cholangitis (PBC); however, little is known about the significance of the gut microbiome in patients with PBC. We elucidated the relationships among clinical profiles, biochemical response to UDCA and gut microbiome composition in patients with PBC.
Methods
Fecal samples from 76 patients with PBC treated at our hospital were collected; patients whose UDCA intake period was <1 year were excluded. The microbiome structures of patients were determined using 16S ribosomal RNA gene sequencing and were statistically compared with those of healthy subjects. The structures of patients in the UDCA responder (n = 43) and non‐responder (n = 30) groups were compared according to the Nara criteria (reduction rate of gamma‐glutamyl transpeptidase, ≥69%, after 1 year).
Results
Compared with healthy subjects, bacterial diversity was lower in patients with PBC, with a decreased abundance of the order Clostridiales and increased abundance of Lactobacillales. The UDCA non‐responder group had a significantly lower population of the genus Faecalibacterium, known as butyrate‐producing beneficial bacteria (P < 0.05), although no significant differences in gender, body mass index, medicated drugs or other serological data were indicated between these two groups.
Conclusions
Gut dysbiosis with loss of beneficial Clostridiales commensals was observed in patients with PBC. Decrease in Faecalibacterium abundance might predict the long‐term prognosis of patients with PBC.
Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of ...liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.
Although gut-derived lipopolysaccharide (LPS) affects the progression of non-alcoholic steatohepatitis (NASH) pathogenesis, few studies have focused on this relationship to develop treatments for ...NASH.
To explore the effects of combination with rifaximin and lubiprostone on NASH liver fibrosis through the modulation of gut barrier function.
To induce steatohepatitis, F344 rats were fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and received oral administration of rifaximin and/or lubiprostone. Histological, molecular, and fecal microbial analyses were performed. Barrier function in Caco-2 cells were assessed by in vitro assays.
Combination rifaximin/lubiprostone treatment significantly suppressed macrophage expansion, proinflammatory responses, and liver fibrosis in CDAA-fed rats by blocking hepatic translocation of LPS and activation of toll-like receptor 4 signaling. Rifaximin and lubiprostone improved intestinal permeability via restoring tight junction proteins (TJPs) with the intestinal activation of pregnane X receptor and chloride channel-2, respectively. Moreover, this combination increased the abundance of Bacteroides, Lactobacillus, and Faecalibacterium as well as decreased that of Veillonella resulting in an increase of fecal short-chain fatty acids and a decrease of intestinal sialidase activity. Both agents also directly suppressed the LPS-induced barrier dysfunction and depletion of TJPs in Caco-2 cells.
The combination of rifaximin and lubiprostone may provide a novel strategy for treating NASH-related fibrosis.
Background
Dipeptidyl peptidase-4 inhibitor (DPP4-I) is clinically used as a new oral antidiabetic agent. Although DPP4 is reportedly associated with the progression of chronic liver diseases, the ...effect of DPP4-I on liver fibrosis development is still obscure. This study was designed to elucidate the effect of DPP4-I on liver fibrosis development in conjunction with the activated hepatic stellate cells (Ac-HSCs).
Methods
The antifibrotic effect of DPP4-I was assessed in vivo and in vitro using porcine serum-induced experimental liver fibrosis model. DPP4-I, sitagliptin, at a clinically comparable low dose was administered by gavage daily.
Results
DPP4-I significantly attenuated liver fibrosis development along with the suppression of hepatic transforming growth factor (TGF)-β1, total collagen, and tissue inhibitor of metalloproteinases-1 in a dose-dependent manner. These suppressive effects occurred almost concurrently with the attenuation of HSCs activation. Our in vitro studies showed that DPP4-I inhibited platelet-derived growth factor-BB-mediated proliferation of the Ac-HSCs as well as upregulation of TGF-β1 and α1(I)-procollagen at magnitudes similar to those of the in vivo studies. The inhibitory effects of DPP4-I against HSCs proliferation and fibrogenic gene expression are mediated through the inhibition of the phosphorylation of ERK1/2, p38 and Smad2/3, respectively.
Conclusions
DPP4-I markedly inhibits liver fibrosis development in rats via suppression of HSCs proliferation and collagen synthesis. These suppressive effects are associated with dephosphorylation of ERK1/2, p38 and Smad2/3 in the HSCs. Since DPP4-I is widely used in clinical practice, this drug may represent a potential new therapeutic strategy against liver fibrosis in the near future.
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