Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.

Western-style high-fat/high-sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD-induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild-type (WT) and human-like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography-tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD-induced change of gut microbiota inhibited BA deconjugation and 7α-dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human-like hydrophobic BA composition.

Current states of prevention of drug-induced gastroduodenal ulcer in real clinical practice: a cross-sectional study.

Non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA) are the most common causes of drug-induced gastroduodenal ulcer and We investigated preventive treatment with use of concomitant anti-ulcer drugs and the clinical features of gastroduodenal ulcer in cases treated with these drugs. Patients with gastroduodenal ulcer and patients with bleeding were classified into 3 groups: LDA, non-aspirin NSAIDs, and those taking neither aspirin nor NSAIDs. Chronological changes over the past 16 years (1st-5th period) were investigated. The status of prevention of ulcer and clinical features were examined. From January 2002 to December 2018, the ratio of all patients taking NSAIDs and LDA increased significantly until 3rd period (p<0.05), but then started to decrease in 4th period; and the percentage of all patients taking NSAIDs and LDA decreased significantly (p<0.05) until 5th period. Among the 292 patients with gastroduodenal ulcer and the 121 patients with a bleeding ulcer taking NSAIDs and LDA, 16 (5.5%) and 9 (7.4%), respectively, were receiving preventive treatment with concomitant anti-ulcer drugs. The percentages of patients taking LDA and other antiplatelet drugs in patients with bleeding gastroduodenal ulcer were significantly higher than those in patients with non-bleeding. In conclusion, although the percentages of patients with gastroduodenal ulcer taking NSAIDs or LDA have not recently increased in real-world practice, preventive treatment in these patients is still low. This low rate of prevention suggests the need to enlighten physicians about preventive treatment because drug withdrawal of LDA has a high risk of cardiovasculr and cerebrovascular events.

Differences in the Serum 4ß-hydroxycholesterol Levels of Patients with Chronic Hepatitis C Virus (HCV) Infection: A Possible Impact on the Efficacy and Safety of Interferon (IFN)-free Treatment.

Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4ß-hydroxycholesterol (4ßHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4ßHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4ßHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4ßHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4ßHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.