Efficacy of 1-kestose supplementation in patients with mild to moderate ulcerative colitis: A randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Ulcerative colitis involves an excessive immune response to intestinal bacteria. Whether administering prebiotic 1-kestose is effective for active ulcerative colitis remains controversial. AIMS: This randomised, double-blind, placebo-controlled pilot trial investigated the efficacy of 1-kestose against active ulcerative colitis. METHODS: Forty patients with mild to moderate active ulcerative colitis were randomly treated with 1-kestose (N = 20) or placebo (maltose, N = 20) orally for 8 weeks in addition to the standard treatment. The Lichtiger clinical activity index and Ulcerative Colitis Endoscopic Index of Severity were determined. Faecal samples were analysed to evaluate the gut microbiome and metabolites. RESULTS: The clinical activity index at week 8 was significantly lower in the 1-kestose group than in the placebo group (3.8 ± 2.7 vs. 5.6 ± 2.1, p = 0.026). Clinical remission and response rates were higher in the 1-kestose group than in the placebo group (remission: 55% vs. 20%, p = 0.048; response: 60% vs. 25%, p = 0.054). The Ulcerative Colitis Endoscopic Index of Severity at week 8 was not significantly different (2.8 ± 1.6 vs. 3.5 ± 1.6, p = 0.145). Faecal analysis showed significantly reduced alpha-diversity in the 1-kestose group, with a decreased relative abundance of several bacteria, including Ruminococcus gnavus group. The short-chain fatty acid levels were not significantly different between the groups. The incidence of adverse events was comparable between the groups. DISCUSSION: Oral 1-kestose is well tolerated and provides clinical improvement for patients with mild to moderate ulcerative colitis through modulation of the gut microbiome.

1-Kestose Supplementation Increases Levels of a 5α-Reductase Gene, a Key Isoallolithocholic Acid Biosynthetic Gene, in the Intestinal Microbiota.

1-Kestose (kestose) is the smallest fructooligosaccharide component and shows a particularly high prebiotic function. Both kestose and the bile acid metabolite isoallolithocholic acid (isoalloLCA) are known to be beneficial for human health, especially in terms of immune homeostasis in the gastrointestinal system; however, the effect of kestose on the levels of microbial isoalloLCA producers remains to be clarified. IsoalloLCA is known to be produced by several members of the phylum Bacteroidota that carry the 5α-reductase (5AR) gene, a key isoalloLCA biosynthetic gene. Thus, we designed a specific primer set to detect the 5AR gene based on the consensus sequences of the genes from several isoalloLCA producers. Using real-time quantitative PCR with this primer set and fecal DNA samples, we compared the 5AR gene level (5ar-level) in the intestinal microbiota of a kestose-supplemented group (n=20) and a placebo group (n=16) before and after intake for 12 wk. The 5ar-level was significantly increased in the kestose-supplemented group (p=0.015), but not in the placebo group (p=0.379), indicating that kestose supplementation increased the 5ar-level in human intestinal microbiota. Our findings suggest that targeting functional gene levels could potentially be used to predict and understand the beneficial prebiotic effects associated with changes in gut microbiota.

Antifibrotic Effects of 1,25(OH)2D3 on Nonalcoholic Steatohepatitis in Female Mice.

BACKGROUND: Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH. AIM: We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)2D3. METHODS: Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)2D3 (0.0008, 0.004, and 0.02 µg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis. RESULTS: Supplementation of 1,25(OH)2D3 in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-ß, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)2D3 groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)2D3 groups. CONCLUSION: Supplementation of 1,25(OH)2D3 may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.

Prognostic Factors Associated with Postprogression Survival in Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib Not Eligible for Second-Line Regorafenib Treatment.

OBJECTIVES: The aim of this study was to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib, who were not eligible for second-line treatment with regorafenib. METHODS: A total of 103 patients with radiological confirmation of progressive disease (PD) were enrolled. RESULTS: The median PPS (n = 67) was 6.1 months. Significant and independent prognostic factors at initial radiological PD associated with good PPS were an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0, the absence of macrovascular invasion (MVI), and time to progression (TTP) ≥4 months. Upon scoring these three variables as good PPS factors, the median PPS in the good PPS score of 3 or 2 group (n = 38) was significantly longer than that in the good PPS score of 1 or 0 group (n = 29) (16.6 vs. 2.9 months; p < 0.0001, respectively). CONCLUSIONS: An ECOG-PS score of 0, the absence of MVI, and TTP ≥4 months at first radiological confirmation of PD may be useful for predicting good PPS in patients with advanced HCC who do not meet the eligibility criteria for the RESORCE trial.

Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction.

4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production. Under TNF-α stimulation, Atractylodin induced the tri-methylation of histone H3 at lysine residue 9, which impaired the binding between NF-κB and the IL-6 promoter on the genomic DNA. Atractylodin inhibited KDM4A but not KDM6A activity. Atractylodin administration attenuated colitis induction. The KDM4A inhibitor ML324 showed similar actions on IL-6 production and colitis induction. We propose the inhibition of KDM4A activity as a strategy to suppress IL-6 production and attenuate colitis induction.

Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

BACKGROUND: For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. AIM: In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. METHODS: Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. RESULTS: Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P<0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. CONCLUSIONS: BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.

Fever within 2 Weeks of Sorafenib Therapy Predicts Favorable Treatment Efficacy in Patients with Advanced Hepatocellular Carcinoma.

OBJECTIVES: The aim of this study was to investigate the relationship between fever within 2 weeks after the start of sorafenib therapy and treatment efficacy in patients with advanced hepatocellular carcinoma (HCC). METHODS: One hundred and two patients with advanced HCC were enrolled in this study. We retrospectively compared patients with fever (more than 38°C) within 2 weeks after the start of sorafenib therapy (fever group, n = 34) and patients without fever (non-fever group, n = 68) in terms of survival, best antitumor response, and change in intratumor blood on contrast-enhanced computed tomography (CE-CT) after 2 weeks of sorafenib therapy. RESULTS: Fever was the only significant and independent predictor of better outcomes (hazard ratio, 0.517; 95% confidence interval, 0.319-0.838; p = 0.0071). In the fever group, the partial response rate, the disease control rate, and the rate of disappearance of arterial tumor enhancement on CE-CT after 2 weeks of sorafenib therapy were significantly higher than those in the non-fever group (38.2 vs. 5.9%, respectively, p = 0.0001; 85.3 vs. 60.3%, respectively, p = 0.0103; 76.5 vs. 35.3%, respectively, p < 0.0001). CONCLUSIONS: Fever within 2 weeks after the start of sorafenib therapy may be a useful predictor of a favorable treatment response in patients with advanced HCC.

S100G expression and function in fibroblasts on colitis induction.

Supplementation with interleukin (IL)-10, an important anti-inflammatory cytokine, has shown disappointing efficacy for inflammatory bowel diseases (IBD). IL-10 may down-regulate the expression of other anti-inflammatory mediators following colitis induction. We used a colitis model characterized by hapten-protein visualization, which indicates the site of hapten-protein formation after colitis induction for histological and gene expression analyses. Under IL-10 deficiency, following colitis induction inflammatory changes were reduced, and S100G expression was elevated. S100G was expressed in fibroblasts, and S100G expression was down-regulated by IL-10. S100G suppressed the production of monocyte chemotactic protein-1 (MCP-1) through the inhibition of NF-κB activation. Therefore, S100G, also known as Calbindin-D9k, may be an important anti-inflammatory mediator in fibroblasts following colitis induction, and down-regulation of S100G expression might be one reason for the insufficient performance of IL-10 supplementation.

Early Clinical Response after 2 Weeks of Sorafenib Therapy Predicts Outcomes and Anti-Tumor Response in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: We evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma. METHODS: Fifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child-Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated. RESULTS: After 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively). CONCLUSIONS: Changes in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma.

Copper Accumulates in Hemosiderins in Livers of Patients with Iron Overload Syndromes.

In biology, redox reactions are essential and sometimes harmful, and therefore, iron metabolism is tightly regulated by cuproproteins. Since the state of copper in iron overload syndromes remains unclear, we investigated whether copper metabolism is altered in these syndromes. Eleven patients with iron overload syndromes participated in this study. The clinical diagnoses were aceruloplasminemia (n=2), hemochromatosis (n=5), ferroportin disease (n=2), and receiving excess intravenous iron supplementation (n=2). Liver specimens were analyzed using a light microscope and transmission electron microscope equipped with an X-ray analyzer. In addition to a large amount of iron associated with oxygen and phosphorus, the iron-rich hemosiderins of hepatocytes and Kupffer cells contained small amounts of copper and sulfur, regardless of disease etiology. Two-dimensional imaging clearly showed that cuproproteins were distributed homogenously with iron complexes within hemosiderins. Copper stasis was unlikely in noncirrhotic patients. The enhanced induction of cuproproteins by excess iron may contribute to copper accumulation in hemosiderins. In conclusion, we have demonstrated that copper accumulates in hemosiderins in iron overload conditions, perhaps due to alterations in copper metabolism.

Cholecystocolonic fistula preoperatively diagnosed by endoscopic ultrasound of the colon.

The patient was a 58-year-old woman. Gallbladder stones and occult blood in feces were detected during a physical check-up, then the patient was referred to Nagoya University Hospital. In this case the fistula was difficult to diagnosed by ultrasound and endoscopic ultrasound (EUS) of the upper intestinal tract because the gallbladder was filled with stones. Barium enema and endoscopic retrograde cholangiopancreatography did not reveal fistula. Curved-linear array EUS of the colon showed fistula.