The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver ...disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.
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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium–glucose ...cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD.
Using a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model.
SGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol.
SGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Vitamin B6 is an important cofactor in fat metabolism and its deficiency has been correlated with nonalcoholic fatty liver disease. However, no study has investigated the efficacy of vitamin B6 ...supplementation in these patients. The aim of this open-label, single-arm, single-center study was to examine the therapeutic effect of vitamin B6 in patients with nonalcoholic fatty liver disease. Twenty-two patients with nonalcoholic fatty liver disease received vitamin B6 (90 mg/day) orally for 12 weeks. Clinical parameters were evaluated, and liver fat and fibrosis were quantified before and after treatment using magnetic resonance imaging-based proton density fat fraction and magnetic resonance elastography. Serum alanine aminotransferase levels, the primary endpoint, did not change significantly after vitamin B6 treatment (93.6 ± 46.9 to 93.9 ± 46.6, p = 0.976). On the other hand, magnetic resonance imaging-based proton density fat fraction, a parameter of hepatic lipid accumulation, was significantly reduced (18.7 ± 6.1 to 16.4 ± 6.4, p<0.001) despite no significant changes in body mass index, even in those not taking vitamin E (n = 17, 18.8 ± 6.9 to 16.7 ± 7.3, p = 0.0012). Vitamin B6 administration significantly ameliorated hepatic fat accumulation. As an inexpensive agent with few side effects, vitamin B6 could be a novel therapeutic agent for the treatment of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It occurs with a prevalence of up to 25%, of which 10-20% cases progress to nonalcoholic steatohepatitis ...(NASH), cirrhosis, and liver cancer. The histopathology of NASH is characterized by neutrophilic infiltration, and endotoxins from gram-negative rods have been postulated as a contributing factor. Elevations in endotoxin levels in the blood can be classified as intestinal and hepatic factors. In recent years, leaky gut syndrome, which is characterized by impaired intestinal barrier function, has become a significant issue. A leaky gut may prompt intestinal bacteria dysbiosis and increase the amount of endotoxin that enters the liver from the portal vein. These contribute to persistent chronic inflammation and progressive liver damage. In addition, hepatic factors suggest that liver damage can be induced by low-dose endotoxins, which does not occur in healthy individuals. In particular, increased expression of CD14, an endotoxin co-receptor in the liver, may result in leptin-induced endotoxin hyper-responsiveness in obese individuals. Thus, elevated blood endotoxin levels contribute to the progression of NASH. The current therapeutic targets for NASH treat steatosis and liver inflammation and fibrosis. While many clinical trials are underway, no studies have been performed on therapeutic agents that target the intestinal barrier. Recently, a randomized placebo-controlled trial examined the role of the intestinal barrier in patients with NAFLD. To our knowledge, this study was the first of its kind and study suggested that the intestinal barrier may be a novel target in the future treatment of NAFLD.
IntroductionThe treatment of diabetes has a significant impact on the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We compared the effectiveness of tofogliflozin, a selective ...sodium-glucose cotransporter 2 inhibitor, and pioglitazone for the treatment of NAFLD patients with type 2 diabetes mellitus.Research design and methodsThis open-label, prospective, single-center, randomized clinical trial recruited NAFLD patients with type 2 diabetes mellitus and a hepatic fat fraction of at least 10% as assessed based on the MRI-proton density fat fraction (MRI-PDFF). Eligible patients were stratified according to hemoglobin A1c (HbA1c), alanine transaminase, and MRI-PDFF levels and randomly assigned (1:1) to receive either 20 mg tofogliflozin or 15–30 mg pioglitazone, orally, once daily for 24 weeks. The primary endpoint was an absolute change in MRI-PDFF at 24 weeks. Efficacy and safety was assessed in all treated patients. This trial was registered in the Japan Registry of Clinical Trials.ResultsOverall, 40 eligible patients were randomly assigned to receive tofogliflozin (n=21) or pioglitazone (n=19). Changes in hepatic steatosis after 24 weeks of treatment were evaluated by MRI-PDFF, which showed a significant decrease in both groups (−7.54% (p<0.0001) and −4.12% (p=0.0042) in the pioglitazone and tofogliflozin groups, respectively). Compared with baseline, the body weight decreased by 2.83±2.86 kg (−3.6%, p=0.0443) in the tofogliflozin group and increased by 1.39±2.62 kg (1.7%, p=0.0002) in the pioglitazone group after 24 weeks. No life-threatening events or treatment-related deaths occurred.ConclusionsTofogliflozin was well tolerated, and it reduced the MRI-PDFF levels in NAFLD patients with type 2 diabetes mellitus.Trial registration numberjRCTs031180159.
IntroductionNon-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related ...to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH.Methods and analysisA total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation.Ethics and disseminationEthics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). The results of this study will be submitted for publication in international peer-reviewed journals, and the key findings will be presented at international scientific conferences. Participants wishing to know the results of this study will be contacted directly on data publication.Trial registration numberThis trial is registered with ClinicalTrials.gov (number: NCT05084404).Protocol versionV.1.1, 19 August 2021.
Opioid-induced constipation (OIC) may occur in patients receiving opioid treatment, decreasing their quality of life (QOL). We compared the effectiveness of magnesium oxide (MgO) with that of ...naldemedine (NAL) in preventing OIC. This proof-of-concept, randomized controlled trial (registration number UMIN000031891) involved 120 patients with cancer scheduled to receive opioid therapy. The patients were randomly assigned and stratified by age and sex to receive MgO (500 mg, thrice daily) or NAL (0.2 mg, once daily) for 12 weeks. The change in the average Japanese version of Patient Assessment of Constipation QOL (JPAC-QOL) from baseline to 2 weeks was assessed as the primary endpoint. The other endpoints were spontaneous bowel movements (SBMs) and complete SBMs (CSBMs). Deterioration in the mean JPAC-QOL was significantly lower in the NAL group than in the MgO group after 2 weeks. There were fewer adverse events in the NAL group than in the MgO group. Neither significant differences in the change in SBMs between the groups nor serious adverse events/deaths were observed. The CSBM rate was higher in the NAL group than in the MgO group at 2 and 12 weeks. In conclusion, NAL significantly prevented deterioration in constipation-specific QOL and CSBM rate compared with MgO.
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Natural history of chronic intestinal pseudo-obstruction (CIPO), a rare disease characterized by episodes of non-mechanical obstruction, is unclear in adults. This study evaluates the clinical course ...of CIPO and palliative care needs of patients.
From October 2010 to September 2021, 74 patients who underwent cine MRI and had a definitive diagnosis of CIPO were prospectively included. We investigated disease etiology and outcomes, age at onset, nutritional status at consultation (body mass index and serum albumin), hydrogen breath test results, and total parenteral nutrition (TPN) during the disease course.
Forty-seven patients (64%) were women, with a mean age of 44 years at onset and 49 years at diagnosis. Primary CIPO was observed in 48 patients (65%). Secondary CIPO was observed in 26 cases (35%), of whom 18 (69%) had scleroderma. The mean body mass index, serum albumin level, and hydrogen breath test positivity rate were 17 kg/m
, 3.8 mg/dL, and 60%, respectively. TPN and invasive decompression therapy were required by 23 (31%) and 18 (24%) patients, respectively. Intestinal sterilization was performed in 51 (69%) patients and was effective in 33 (65%); of these, 28 (85%) were taking metronidazole. Seven (9%) patients used opioids. There were 9 deaths (12%), including 5 (56%) from infection and 2 (22%) from suicide. Of the deaths, 6 (67%) and 4 (44%) underwent TPN management and decompression therapy, respectively. Fifty-one patients (69%) wanted palliative care.
CIPO is a rare, severe, and under-recognized disease. Standardization of treatment strategies, including palliative care and psychiatric interventions, is desired.
IntroductionChronic constipation (CC) is a functional disorder that negatively impacts the quality of life of patients. This is a protocol for a multicentre, 12-week, randomised, double-blind, ...placebo-controlled study to test the efficacy and safety of elobixibat (EXB) versus placebo in patients with CC.Methods and analysisThis will be a multicentre, double-blind, placebo-control, randomised controlled trial. A total of 100 adult patients with CC, diagnosed based on Rome IV criteria, who fulfil the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive EXB (10 mg) or placebo treatment (n=50 per group). Blood tests and stool sampling will be performed 12 weeks following initiation of treatment and questionnaires will be issued to participants. The primary outcome will be the change in complete spontaneous bowel movements after 12 weeks of administration. The secondary outcomes will include the change in Japanese Patient Assessment of Constipation Quality of Life and absolute serum and faecal bile acid.Ethics and disseminationEthics approval has been obtained from Yokohama City University Certified Institutional Review Board before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences.Protocol versionV.3.0, 15 June 2021.Trial registration numberClinicalTrials.gov (number NCT04784780).
Patients taking opioids are known to develop opioid-induced constipation (OIC), which reduces their quality of life. The aim of this study is to compare magnesium oxide with naldemedine and determine ...which is more effective in preventing OIC.
This proof-of-concept, prospective, randomized controlled trial commenced in Japan in March 2018. Initially, a questionnaire-based survey will be conducted targeting adult patients with cancer who concomitantly commenced opioid treatment and OIC prevention treatment. Patients will then be randomly allocated to a magnesium oxide group (500 mg thrice daily) or a naldemedine group (0.2 mg once daily). Each drug will be orally administered for 12 weeks. The primary endpoint is defined as any improvement in scores on the Japanese version of Patient Assessment of Constipation Quality of Life questionnaire (JPAC-QOL) from baseline to 2 weeks of treatment.
The primary endpoint is change in JPAC-QOL score from baseline to 2 weeks of intervention. The key secondary endpoint will be change in spontaneous bowel movements at 2 and 12 weeks of intervention. This study will determine whether magnesium oxide or naldemedine is more effective for the prevention of OIC.
University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000031891. Registered March 25, 2018.
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