An Analysis of the Role of the Indigenous Microbiota in Cholesterol Gallstone Pathogenesis

Background and Aims: Cholesterol gallstone disease is a complex process involving both genetic and environmental variables. No information exists regarding what role if any the indigenous gastrointestinal microbiota may play in cholesterol gallstone pathogenesis and whether variations in the microbiota can alter cholesterol gallstone prevalence rates. Methods: Genetically related substrains (BALB/cJ and BALB/cJBomTac) and (BALB/AnNTac and BALB/cByJ) of mice obtained from different vendors were compared for cholesterol gallstone prevalence after being fed a lithogenic diet for 8 weeks. The indigenous microbiome was altered in these substrains by oral gavage of fecal slurries as adults, by cross-fostering to mice with divergent flora at <1day of age or by rederiving into a germ-free state. Results: Alterations in the indigenous microbiome altered significantly the accumulation of mucin gel and normalized gallbladder weight but did not alter cholesterol gallstone susceptibility in conventionally housed SPF mice. Germ-free rederivation rendered mice more susceptible to cholesterol gallstone formation. This susceptibility appeared to be largely due to alterations in gallbladder size and gallbladder wall inflammation. Colonization of germ-free mice with members of altered Schaedler flora normalized the gallstone phenotype to a level similar to conventionally housed mice. Conclusions: These data demonstrate that alterations in the gastrointestinal microbiome may alter aspects of cholesterol gallstone pathogenesis and that in the appropriate circumstances these changes may impact cholesterol cholelithogenesis.National Institutes of Health (U.S.) (Grant T32OD010978)National Institutes of Health (U.S.) (Grant P30ES002109)National Institutes of Health (U.S.) (Grant R01AT004326

Vitamin C supplement use may protect against gallstones: an observational study on a randomly selected population

<p>Abstract</p> <p>Background</p> <p>Animal experiments have shown a protective effect of vitamin C on the formation of gallstones. Few data in humans suggest an association between reduced vitamin C intake and increased prevalence of gallstone disease. The aim of this study was to assess the possible association of regular vitamin C supplementation with gallstone prevalence.</p> <p>Methods</p> <p>An observational, population-based study of 2129 subjects aged 18-65 years randomly selected from the general population in southern Germany was conducted. Abdominal ultrasound examination, completion of a standardized questionnaire, compilation of anthropometric data and blood tests were used. Data were collected in November and December 2002. Data analysis was conducted between December 2005 and January 2006.</p> <p>Results</p> <p>Prevalence of gallstones in the study population was 7.8% (167/2129). Subjects reporting vitamin C supplementation showed a prevalence of 4.7% (11/232), whereas in subjects not reporting regular vitamin C supplementation, the prevalence was 8.2% (156/1897). Female gender, hereditary predisposition, increasing age and body-mass index (BMI) were associated with increased prevalence of gallstones. Logistic regression with backward elimination adjusted for these factors showed reduced gallstone prevalence for vitamin C supplementation (odds ratio, OR 0.34; 95% confidence interval, CI 0.14 to 0.81; P = 0.01), increased physical activity (OR 0.62; 95% CI, 0.42 to 0.94; P = 0.02), and higher total cholesterol (OR 0.65; 95% CI, 0.52 to 0.79; P < 0.001).</p> <p>Conclusion</p> <p>Regular vitamin C supplementation and, to a lesser extent, increased physical activity and total cholesterol levels are associated with a reduced prevalence of gallstones. Regular vitamin C supplementation might exert a protective effect on the development of gallstones.</p

Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array

Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15,241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~ 53,000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P = 5.88 × 10(-7), ß = -0.146) and TTC39B rs686030:C>A (P = 6.95 x 10(-7), ß = 0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), ß = 0.734), ABCG8 rs4299376:G(>)T (P = 2.40 × 10(-18), ß = 0.278), ABCG5 rs6544718:T>C (P = 2.08 × 10(-14), ß = 0.044) and ABCG5 rs6720173:G>C (P = 3.81 × 10(-12), ß(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings

Bulk moduli of F.C.C. alloys

The isothermal bulk moduli B of six f.c.c. alloys, for various compositions are calculated, using the values of the end members. Two simple macroscopic models suggested by Giri and Varotsos are applied. The calculated values are not in agreement with experiment in all cases. We attempt to give an interpretation. Copyright © 1994 WILEY‐VCH Verlag GmbH &amp; Co. KGa

O-127 Higher probability of live birth after testosterone pretreatment in women with poor ovarian response undergoing IVF: a systematic review and meta-analysis

Abstract Study question Does testosterone pretreatment increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin-releasing hormone (GnRH) analogues and gonadotrophins for in-vitro fertilization (IVF)? Summary answer Testosterone pretreatment increases clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF. What is known already Androgens have been shown to stimulate early stages of follicular growth, increase the number of primary, pre-antral and antral follicles as well as increase ovarian sensitivity to follicle stimulating hormone (FSH). Although androgen supplementation has been evaluated in several randomized controlled trials (RCTs) and meta-analyzed in six systematic reviews until today currently no solid conclusions can be drawn regarding its effectiveness. Study design, size, duration A literature search was performed until September 2021 aiming to identify RCTs evaluating testosterone pretreatment in poor responders. Outcome measures included achievement of pregnancy, total dose of gonadotrophins required, duration of stimulation, estradiol levels, endometrial thickness and number of follicles ≥17 mm on the day of triggering final oocyte maturation, number of cumulus–oocyte complexes (COCs) retrieved, embryos transferred, metaphase II (MII) and 2-pronuclei oocytes (2pn) and the proportion of patients having an embryo transfer (ET). Participants/materials, setting, methods Eight RCTs published between 2006 and 2021 were analyzed, including 760 women. Pretreatment with transdermal testosterone gel was performed in all studies with a dose ranging from 10 to 12.5 mg/day for 10 to 56 days. In dichotomous data, estimates were expressed as risk ratio (RR) with 95% confidence intervals (CIs), using the fixed or random effects method. In continuous data, differences were pooled across resulting in a weighted mean difference (WMD) with 95% CI. Main results and the role of chance Testosterone pretreatment was associated with a significantly higher live birth (RR: 2.07, 95%CI: 1.09 to 3.92) and clinical pregnancy rate (RR: 2.25, 95%CI: 1.54) in women with POR undergoing IVF, while there was also a significant increase in the number of COCs retrieved (WMD: +0.88, 95% CI: +0.22 to + 1.54). Significantly less days to complete ovarian stimulation (WMD: -0.81 days, 95% CI: -1.46 to −0.16), a lower total dose of gonadotrophins (WMD: -368.8 IUs, 95% CI: −612.4 to -125.2), a thicker endometrium on the day of triggering final oocyte maturation (WMD: +0.83 mm, 95% CI: +0.13 to + 1.53) and a lower cancellation rate due to poor ovarian response (RR: 0.37, 95%CI: 0.20 to 0.71) were observed. No significant differences were observed in estradiol levels (WMD: -8.12 pg/mL, 95% CI: -118.2 to + 101.96), in the numbers of follicles ≥17 mm on the day of triggering final oocyte maturation (WMD: +0.82, 95%CI: -0.11 to + 1.74), of MII oocytes (WMD: +0.50, 95% CI: -0.17 to + 1.17),  of 2pn oocytes (WMD: +0.49, 95% CI: -0.11 to + 1.10), of embryos transferred (WMD: +0.21, 95%CI: -0.07 to + 0.49) and in the proportion of patients with ET (RR: 1.00, 95% CI: 0.96 to 1.04). Limitations, reasons for caution The definition of poor ovarian response varied among studies and a considerable heterogeneity regarding the type, dose and duration of testosterone pretreatment was present. Although the present study is currently the largest meta-analysis evaluating testosterone pretreatment, the total number of patients is still not large enough to draw solid conclusions. Wider implications of the findings The current study suggests that the probability of pregnancy is increased in poor responders pretreated with transdermal testosterone. This increase, in the absence of other proven beneficial interventions in these patients, justifies the conduction of further relevant RCTs. Trial registration number CRD42021262098 </jats:sec