The study aimed to investigate the alterations in gut microbiota among nonobese individuals with nonalcoholic fatty liver disease (NAFLD) and their response to treatment with ursodeoxycholic acid (UDCA). A total of 90 patients diagnosed with NAFLD and 36 healthy subjects were recruited to participate in this study. Among them, a subgroup of 14 nonobese nonalcoholic steatohepatitis (NASH) were treated with UDCA. Demographic and serologic data were collected for all participants, while stool samples were obtained for fecal microbiome analysis using 16S sequencing. In nonobese NAFLD patients, the alpha diversity of intestinal flora decreased (Shannon index, p < 0.05), and the composition of intestinal flora changed (beta diversity, p < 0.05). The abundance of 20 genera, including Fusobacterium, Lachnoclostridium, Klebsiella, etc., exhibited significant changes (p < 0.05). Among them, nine species including Fusobacterium, Lachnoclostridium, Klebsiella, etc. were found to be associated with abnormal liver enzymes and glucolipid metabolic disorders. Among the 14 NASH patients treated with UDCA, improvements were observed in terms of liver enzymes, CAP values, and E values (p < 0.05), however, no improve the glucolipid metabolism. While the alpha diversity of intestinal flora did not show significant changes after UDCA treatment, there was a notable alteration in the composition of intestinal flora (beta diversity, p < 0.05). Furthermore, UCDA treatment led to an improvement in the relative abundance of Alistipes, Holdemanella, Gilisia, etc. among nonobese NASH patients (p < 0.05). Nonobese NAFLD patients exhibit dysbiosis of the intestinal microbiota. UDCA can ameliorate hepatic enzyme abnormalities and reduce liver fat content in nonobese NASH patients, potentially through its ability to restore intestinal microbiota balance.

BACKGROUND: Progressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known.
METHODS: A 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations.
CONCLUSIONS: Owing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.

Cholestasis is bile flow disruption that leads to bile accumulation, which could lead to liver fibrosis. Ursodeoxycholic acid (UDCA) has a hepatoprotective effect. Glutathione (GSH) is an endogenous antioxidant that plays a role in maintaining the function and structure of liver cells. This study aimed to examine the effect of UDCA-GSH combination therapy in multiple doses on liver function in the Sprague-Dawley rats\' liver fibrosis model.
This was a randomised post-testonly study. A total of 28 rats were assigned into four groups: Group 1 is control group (C), samples had bile duct ligation and UDCA monotherapy 20 mg; Group 2, bile duct ligation + UDCA 10 mg + glutathione 10 mg (P1); Group 3, bile duct ligation + UDCA 20 mg + glutathione 15 mg (P2); Group 4, bile duct ligation + UDCA 30 mg + glutathione 20 mg (P3). Serum AST, ALT, ALP activity, total, direct and indirect bilirubin were collected. Shapiro-Wilk test was used for the normality test. All groups\' data were compared using Kruskall-Wallis and Mann-Whitney tests.
There was a significant difference in the ALP level in all rats and between the C and P2 groups. ALP level of all groups decreased significantly compared to the control group. Combination therapy group showed lower bilirubin levels. ALT levels significantly differed between the C-P1, P1-P2, and P1-P3 groups.
UDCA-GSH therapy improves liver function in BDL rats\' models compared to UDCA monotherapy.

Delivery represents a major hurdle to the clinical advancement of oligonucleotide therapeutics for the treatment of disorders such as Duchenne muscular dystrophy (DMD). In this preliminary study, we explored the ability of 2\'-O-methyl-phosphorothioate antisense oligonucleotides (ASOs) conjugated with lipophilic ursodeoxycholic acid (UDCA) to permeate across intestinal barriers in vitro by a co-culture system of non-contacting IEC-6 cells and DMD myotubes, either alone or encapsulated in exosomes. UDCA was used to enhance the lipophilicity and membrane permeability of ASOs, potentially improving oral bioavailability. Exosomes were employed due to their biocompatibility and ability to deliver therapeutic cargo across biological barriers. Exon skipping was evaluated in the DMD myotubes to reveal the targeting efficiency. Exosomes extracted from milk and wild-type myotubes loaded with 5\'-UDC-3\'Cy3-ASO and seeded directly on DMD myotubes appear able to fuse to myotubes and induce exon skipping, up to ~20%. Permeation studies using the co-culture system were performed with 5\'-UDC-3\'Cy3-ASO 51 alone or loaded in milk-derived exosomes. In this setting, only gymnotic delivery induced significant levels of exon skipping (almost 30%) implying a possible role of the intestinal cells in enhancing delivery of ASOs. These results warrant further investigations to elucidate the delivery of ASOs by gymnosis or exosomes.

BACKGROUND: Conflicting evidence exists regarding the effects of ursodeoxycholic acid (UDCA) on coronavirus disease 2019 (COVID-19). This study investigates the association between UDCA administration and COVID-19 infection and its related outcomes in individuals with chronic liver disease (CLD).
METHODS: A customized COVID-19 research database (n = 3,485,376) was created by integrating data from the National Health Insurance Service (NHIS) and the Korea Disease Control and Prevention Agency\'s COVID-19 databases. The study focused on patients diagnosed with COVID-19 in 2021, using the NHIS data from 365 days before diagnosis. To create comparable groups with and without UDCA administration before COVID-19, we used propensity score matching. The primary endpoint was the first confirmed positive result for severe acute respiratory syndrome coronavirus-2. In addition, we identified severe COVID-19-related outcomes. Subgroup analysis were conducted based on the dose of UDCA exposure.
RESULTS: Data from 74,074 individuals with CLD was analyzed. The participants\' average age was 57.5 years, and 52.1% (19,277) of those in each group were male. Those with prior UDCA exposure had a significantly lower risk of COVID-19 infection (adjusted OR: 0.80, 95% CI [0.76-0.85]) compared to the non-UDCA group. Additionally, the UDCA group had a lower risk of severe COVID-19 outcomes (adjusted OR: 0.67, 95% CI [0.46-0.98]). Subgroup analyses indicated that there was a decrease in COVID-19 infection and its related outcomes with increasing UDCA exposure dose.
CONCLUSIONS: Our large observational study highlights the potential use of readily available UDCA as an adjunctive therapy for COVID-19 in individuals with CLD.

OBJECTIVE: Primary biliary cholangitis is a chronic and progressive autoimmune liver disease, whose prognosis can be improved by normalizing alkaline phosphatase and bilirubin. While ursodeoxycholic acid (UDCA) is first line standard of care, approximately 40 % of patients exhibit incomplete response. We aimed to identify prognostic markers for deep response to UDCA therapy at presentation.
METHODS: Data from the Brazilian Cholestasis Study Group cohort were analyzed retrospectively. Patients were assessed for deep response, defined as normal alkaline phosphatase and bilirubin, after 1 year of UDCA treatment. Additionally, the performance of the UDCA response score in predicting deep response was evaluated.
RESULTS: A total of 297 patients were analyzed, with 57.2 % achieving an adequate response according to the Toronto criteria, while 22.9 % reached deep response. Cirrhosis (OR 0.460; 95 % CI 0.225-0.942; p = 0.034) and elevated baseline alkaline phosphatase levels (OR 0.629; 95 % CI 0.513-0.770; p < 0.001) were associated with reduced odds of deep response. The UDCA response score exhibited moderate discrimination power (AUROC = 0.769) but lacked calibration.
CONCLUSIONS: Baseline ALP and liver fibrosis emerge as the most important prognostic factors to predict normalization of alkaline phosphatase and bilirubin after UDCA. The UDCA response score was inadequate for predicting deep response in the Brazilian PBC population.

暂无摘要。

BACKGROUND: Ursodeoxycholic acid (UDCA) slows disease progression among patients with primary biliary cholangitis (PBC), yet not all patients receive this standard-of-care medication. Our study aims to identify reasons why PBC patients did not receive the recommended UDCA treatment.
METHODS: Using medical record data collected by the Fibrotic Liver Disease (FOLD) Consortium for 2006-2016, we identified PBC patients from a single site with no UDCA therapy record. Two independent reviewers used a structured data collection instrument to systematically confirm and record the reasons for the lack of treatment.
RESULTS: Among 494 PBC patients (11% men and 13.2% Black patients) with a median follow-up of 5.2 years, 35 (7%) had never received UDCA (16% men and 24% Black patients). Of these, 18 (51%) had laboratory indications of PBC but were not formally diagnosed. Among the remaining 17 patients with recognized PBC, six were never offered UDCA, seven declined treatment, and four remained untreated despite being offered treatment. We did not find a statistically significant association between the lack of PBC diagnosis and treatment and patients\' age (p = 0.139), gender (p = 0.222), race (p = 0.081), or insurance coverage (p = 0.456), perhaps due to our small sample size.
CONCLUSIONS: Multiple factors influencing the lack of evaluation and treatment in PBC patients were identified at the provider and patient levels. The most common reasons included financial barriers, loss to follow-up, severe decompensated disease at diagnosis, and lack of referral to specialists for further evaluation. Future interventions targeting modifiable provider and patient barriers may improve rates and timeliness of PBC diagnosis and treatment.

UNASSIGNED: An association between gut microbes and cardiovascular disease (CVD) has been established, but the underlying mechanisms remain largely unknown.
UNASSIGNED: We conducted a secondary analysis of the cross-sectional data obtained from the Metabolic Syndrome in Men (METSIM) population-based cohort of 10,194 Finnish men (age = 57.65 ± 7.12 years). We tested the levels of circulating gut microbe-derived metabolites as predictors of CVD, ischemic cerebrovascular accident (CVA), and myocardial infarction (MI). The Kaplan-Meier method was used to estimate the time from the participants\' first outpatient clinic visit to the occurrence of adverse outcomes. The associations between metabolite levels and the outcomes were assessed using Cox proportional hazard models.
UNASSIGNED: During a median follow-up period of 200 months, 979 participants experienced CVD, 397 experienced CVA, and 548 experienced MI. After adjusting for traditional risk factors and correcting for multiple comparisons, higher plasma levels of succinate [quartile 4 vs. quartile 1; adjusted hazard ratio, aHR = 1.30, (confidence interval (CI), 1.10-1.53) p = 0.0003, adjusted p = 0.01] were significantly associated with the risk of CVD. High plasma levels of ursodeoxycholic acid (UDCA) (quartile 3 vs. quartile 1); [aHR = 1.68, (CI, 1.26-2.2); p = 0.0003, adj. p = 0.01] were associated with a higher risk of CVA. Furthermore, as a continuous variable, succinate was associated with a 10% decrease in the risk of CVD [aHR = 0.9; (CI, 0.84-0.97); p = 0.008] and a 15% decrease in the risk of MI [aHR = 0.85, (CI, 0.77-0.93); p = 0.0007].
UNASSIGNED: Gut microbe-derived metabolites, succinate, and ursodeoxycholic acid were associated with CVD, MI, and CVA, respectively. Regulating the gut microbes may represent a potential therapeutic target for modulating CVD and CVA.

BACKGROUND: Cholelithiasis is one of the more common complications following bariatric surgery. This may be related to the rapid weight loss during this period, although the exact mechanism of gallstone formation after bariatric surgery has not been fully elucidated.
METHODS: The present literature review focuses on risk factors, prevention options and the impact of the gut microbiota on the development of gallbladder stones after bariatric surgery.
RESULTS: A potential risk factor for the development of cholelithiasis after bariatric surgery may be changes in the composition of the intestinal microbiota and bile acids. One of the bile acids-ursodeoxycholic acid-is considered to reduce the concentration of mucin proteins and thus contribute to reducing the formation of cholesterol crystals in patients with cholelithiasis. Additionally, it reduces the risk of both asymptomatic and symptomatic gallstones after bariatric surgery. Patients who developed gallstones after bariatric surgery had a higher abundance of Ruminococcus gnavus and those who did not develop cholelithiasis had a higher abundance of Lactobacillaceae and Enterobacteriaceae.
CONCLUSIONS: The exact mechanism of gallstone formation after bariatric surgery has not yet been clarified. Research suggests that the intestinal microbiota and bile acids may have an important role in this.