The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.

CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

Diarrhoea of unknown cause: medical treatment in a stepwise mannerManagement of Idiopathic Diarrhoea Based on Experience of Step-Up Medical Treatment.

The basic principle for the treatment of idiopathic diarrhoea (functional diarrhoea K59.1) is to delay transit through the gut in order to promote the absorption of electrolytes and water. Under mild conditions, bulking agents may suffice. With increasing severity, antidiarrhoeal pharmaceuticals may be added in a stepwise manner. In diarrhoea of unknown aetiology, peripherally-acting opioid receptor agonists, such as loperamide, are first-line treatment and forms the pharmaceutical basis of antidiarrheal treatment. As second-line treatment opium drops have an approved indication for severe diarrhoea when other treatment options fail. Beyond this, various treatment options are built on experience with more advanced treatments using clonidine, octreotide, as well as GLP-1 and GLP-2 analogs which require specialist knowledge the field.

Chronic diarrhoea without an established cause is common.There are a small number of clinical trials, often with a limited number of patients or healthy volunteers.Treatment is often carried out on a trial-and-error basis, with considerable variation in the choice of treatment.There is a paucity of guidelines, and there is a gap in knowledge concerning treatment goals, such as the frequency, consistency and form of stool.The stepwise approach to the treatment of chronic idiopathic diarrhoea described in this article is based on clinical knowledge and experience.

Integration of Metabolomics, Lipidomics, and Proteomics Reveals the Metabolic Characterization of Nonalcoholic Steatohepatitis.

Metabolic dysfunction is associated with nonalcoholic steatohepatitis (NASH) development. However, omics studies investigating metabolic changes in NASH patients are limited. In this study, metabolomics and lipidomics in plasma, as well as proteomics in the liver, were performed to characterize the metabolic profiles of NASH patients. Moreover, the accumulation of bile acids (BAs) in NASH patients prompted us to investigate the protective effect of cholestyramine on NASH. The liver expression of essential proteins involved in FA transport and lipid droplets was significantly elevated in patients with NASH. Furthermore, we observed a distinct lipidomic remodeling in patients with NASH. We also report a novel finding suggesting an increase in the expression of critical proteins responsible for glycolysis and the level of glycolytic output (pyruvic acid) in patients with NASH. Furthermore, the accumulation of branched chain amino acids, aromatic amino acids, purines, and BAs was observed in NASH patients. Similarly, a dramatic metabolic disorder was also observed in a NASH mouse model. Cholestyramine not only significantly alleviated liver steatosis and fibrosis but also reversed NASH-induced accumulation of BAs and steroid hormones. In conclusion, NASH patients were characterized by perturbations in FA uptake, lipid droplet formation, glycolysis, and accumulation of BAs and other metabolites.

Familial hypercholesterolaemia in pregnancy: Australian case series and review.

BACKGROUND: Familial hypercholesterolaemia (FH) is associated with a significant increase in the risk of premature coronary artery disease. Pregnancy is likely a vulnerable time for atherosclerosis progression, with a physiological rise in low-density lipoprotein cholesterol (LDL-C) further exaggerated by the discontinuation of cholesterol-lowering therapy. MATERIALS AND METHODS: A retrospective review was undertaken of 13 women with familial hypercholesterolemia who were managed during pregnancy between 2007 and 2021 by a multidisciplinary team following individualised risk assessment. RESULTS: Overall, pregnancy outcomes were good, with no maternal or fetal complications, including congenital abnormalities, maternal cardiac events or hypertensive complications. Loss of statin treatment time ranged between 12 months and 3.5 years resulting from the accumulation of the preconception, pregnancy and lactation periods and was magnified in women having more than one pregnancy. Of seven women treated with cholestyramine, one developed abnormal liver function with an elevated international normalisation ratio which was corrected with vitamin K. CONCLUSION: Pregnancy is associated with prolonged cessation of cholesterol-lowering therapy, a concern with respect to the risk of coronary artery disease in FH. Continuation of statin therapy up to conception and even during pregnancy in patients at higher risk of cardiovascular disease may be justified, especially with increasing evidence supporting the safety of statin therapy during pregnancy. However, more long-term maternal and fetal data are required for the routine use of statins during pregnancy. Guideline-informed models of care covering family planning and pregnancy should be implemented for all women with FH.

Downregulation of the farnesoid X receptor promotes colorectal tumorigenesis by facilitating enterotoxigenic Bacteroides fragilis colonization.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the world. The downregulation of farnesoid X receptor (FXR) is frequently founded in CRC patients. The current study found that the decreased expression of FXR in colorectal cancer leads to disorders of bile acids (BAs) metabolism. The altered BAs profile shaped distinct intestinal flora and positively regulated secretory immunoglobulin A (sIgA). The dual regulation of BAs and sIgA enhanced adhesion and biofilm formation of enterotoxigenic Bacteroides fragilis (ETBF), which has a colorectal tumorigenesis effect. The abundance of ETBF increased significantly in intestinal mucosa of colitis-associated cancer (CAC) mice, and finally promoted the development of colorectal cancer. This study suggests that downregulation of FXR in CRC results in BAs dysregulation, and BAs have strong effects on sIgA and gut flora. The elevated BAs concentration and altered gut microbiome are risk factors for CRC.

Effects of Bile Acid Modulation by Dietary Fat, Cholecystectomy, and Bile Acid Sequestrant on Energy, Glucose, and Lipid Metabolism and Gut Microbiota in Mice.

Bile acid metabolism, involved with the digestion and absorption of nutrients in the gut, is linked to the gut microbiota community, greatly impacting the host's metabolism. We examined the hypothesis that the modulation of bile acid metabolism by dietary fat contents, gallbladder removal (GBX; cholecystectomy), and bile acid sequestrant (BAS; cholestyramine) treatment could alter energy, glucose, and lipid metabolism through the changes in the gut microbiota. Mice were randomly assigned to the following six groups: (1) Sham GBX surgery (Sham) + low fat/high carbohydrate diet (LFD), (2) Sham + high fat diet (HFD), (3) Sham + HFD + BAS, (4) GBX + LFD, (5) GBX + HFD, and (6) GBX + HFD + BAS. BAS groups received 2% cholestyramine. After an 8-week intervention, energy, glucose, and lipid metabolism, and the gut microbiota community were measured. HFD groups exhibited higher body weight gain than LFD, and GBX increased the weight gain comped to Sham groups regardless of BAS in HFD (p < 0.05). Homeostatic model assessment for insulin resistance (HOMA-IR) was higher in HFD than LFD, and GBX increased it regardless of BAS. Serum lipid profiles were worsened in GBX + HFD compared to Sham + LFD, whereas BAS alleviated them, except for serum HDL cholesterol. Hepatic tumor-necrosis-factor-α (TNF-α) mRNA expression and lipid peroxide contents increased with GBX and BAS treatment compared to Sham and no BAS treatment (p < 0.05). Hepatic mRNA expression of sterol regulatory element-binding transcription factor 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma (PPAR-γ) exhibited the same trend as that of tumor necrosis factor-α (TNF-α). The α-diversity of gut bacteria decreased in GBX + HFD and increased in GBX + HFD + BAS. Akkermentia, Dehalobacterium, SMB53, and Megamonas were high in the Sham + LFD, and Veillonella and Streptococcus were rich in the Sham + HFD, while Oscillospira and Olsenella were high in Sham + HFD + BAS (p < 0.05). GBX + LFD increased Lactobacillus and Sutterella while GBX + HFD + BAS elevated Clostridium, Alistipes, Blautia, Eubacterium, and Coprobacillus (p < 0.05). In conclusion, the modulation of bile acid metabolism influences energy, glucose, and lipid metabolisms, and it might be linked to changes in the gut microbiota by bile acid metabolism modulation.

Prevalence of biliary acid malabsorption in patients with chronic diarrhoea of functional characteristics: a prospective study.

BACKGROUND: Bile acid malabsorption occurs in up to one third of patients with chronic diarrhoea of functional characteristics. The gold standard test for its diagnosis is the 75Selenium homocholic acid taurine (75SeHCAT) test. The aim of this work is to confirm previous data suggesting that bile acid malabsorption, diagnosed by 75Se-HCAT test, is the underlying cause of diarrhoea in a significant proportion of patients previously diagnosed with a functional disorder. In addition, we have analysed the clinical response of bile acid sequestrants in those patients with a bile acid diarrhoea diagnosis. METHODS: This is a prospective, single-centre study including consecutive adult patients diagnosed with chronic diarrhoea of unknown origin and with functional characteristics; systematic rule out of common causes of chronic diarrhoea was performed before bile acid malabsorption evaluation by 75SeHCAT scanning. A retention percentage less than 10% was considered positive. Clinical response to cholestyramine was further evaluated in those patients with a positive diagnosis of bile acid diarrhoea RESULTS: 38 patients (20 male, mean age 37.5 years) were finally included. Twenty (52.6%) patients included had a positive 75SeHCAT test. Median body mass index was significantly higher in those patients. We did not find significant differences in other clinical or biochemical variables 75SeHCAT-positive and 75SeHCAT-negative groups. Only 6 of 17 (35.3%) patients responded to cholestyramine treatment; 10 patients did not have response or withdraw the drug due to adverse events. Logistic regression analysis showed that none of the included variables was a predictor of clinical response to cholestyramine. CONCLUSIONS: Bile acid malabsorption occurs in a high proportion of patients suffering from chronic diarrhoea with functional characteristics. Systematic investigation of bile acid malabsorption should be included in the diagnostic algorithms of patients with chronic watery diarrhoea in the routine clinical practice. Absence of response to cholestyramine does not rule out bile acid diarrhoea.

Case report of one month and 15 days old baby with type V hyperlipoproteinemia (HLP).

BACKGROUND: Most of the patients with type 1 and V hyperlipoproteinemia (HLP) present with symptoms and signs of acute pancreatitis due to marked elevation of triglycerides, but this baby presented with a chest infection, which was later diagnosed as type V HLP on laboratory workup. CASE PRESENTATION: We report a case of a 1 month and 15 days old baby boy, product of 2-nd degree consanguinity admitted to a nearby hospital with complaints of refusal to feed, cough and excessive crying. On examination his heart rate was 102 beats/min, respiratory rate was 55 breaths/min and temperature was within the normal range, provisional diagnosis of Pneumonia was made. His samples were tested at our laboratory, the lipid Profile at age of 1 month 15 days showed total cholesterol (TC) of 1400 mg/dl reference range (RR < 200 mg/dl), triglycerides (TG) of > 885 mg/dl after dilution it was 31,400 mg/dl (RR < 150 mg/dl), High density Cholesterol (HDL) of 35 mg/dl (RR > 40 mg/dl) and low density cholesterol (LDL) of 200 mg/dl (RR < 100 mg/dl). The patient's blood sample was grossly milky and lipemic in appearance. A "Refrigerator test" was performed after overnight storage of the sample in refrigerator at 4 °C, which gave a creamy layer at the top and clear infranatant due to caking of the Chylomicrons. Lipoprotein electrophoresis performed 1 month later showed Chylomicrons of 4.7% (RR 0-2%), Pre-beta lipoproteins of 51.5% (RR 5-22%), beta lipoproteins of 16.5% (RR 39-70%) and alpha of 27.3% (RR 23-53%). Initially he was diagnosed as type 1 HLP, but later on he was correctly diagnosed as type V HLP. Cholestyramine (Questran sachet) powder was started at a dose of 100 mg/kg on t.i.d basis with NAN-1 formula Milk at the age of 1 month and 15 days. On follow up, detailed advices regarding the weaning food was given to the mother (using olive oil in cooking, giving proteins and avoiding heavy fatty meals). His lipid profile was repeated at age of 3 months, which showed some improvement, his TGs were 1986 mg/dl and TC 105 mg/dl. CONCLUSION: There is no universal diagnostic criterion for diagnosing Type V HLP, most likely, due to a scanty literature on this disorder. It stimulated us to report this case so that our findings may help for a timely diagnosis of the affected patients.

Cholestyramine, a Bile Acid Sequestrant, Increases Cecal Short Chain Fatty Acids and Intestinal Immunoglobulin A in Mice.

Bile acid sequestrants are used as medicinal drugs to treat dyslipidemia and type 2 diabetes. We found that cholestyramine, a bile acid sequestrant, increases cecal short-chain fatty acid (SCFA) production and intestinal immunoglobulin A (IgA) in C57BL/6J mice. In a 12-week high-fat diet study, feeding cholestyramine (2% (w/w)) significantly promoted C2-C4 SCFAs in the cecum by approximately 1.6-fold and fecal IgA by 1.8-fold. In an 8-week normal-fat diet study, feeding cholestyramine (1 and 2%) increased the cecal propionic acid content by approx. 2.0-fold. Fecal IgA was also significantly increased at 4 weeks (1%: 1.7-fold; 2%: 2.1-fold) and 8 weeks (1%: 1.8-fold; 2%: 2.0-fold) in the normal-fat diet study. These results indicate that bile acid sequestrants may exert their physiological functions, such as intestinal IgA production, through SCFA-dependent signaling pathways.

INTRAVENOUS LIPID EMULSION TREATMENT REDUCES SYMPTOMS OF BREVETOXICOSIS IN TURTLES (TRACHEMYS SCRIPTA).

Harmful algal blooms (HABs) occur when excess nutrients allow dinoflagellates to reproduce in large numbers. Marine animals are affected by blooms when algal toxins are ingested or inhaled. In the Gulf of Mexico, near annual blooms of Karenia brevis release a suite of compounds (brevetoxins) that cause sea turtle morbidity and mortality. The primary treatment at rehabilitation facilities for brevetoxin-exposed sea turtles is supportive care, and it has been difficult to design alternative treatment strategies without an understanding of the effects of brevetoxins in turtles in vivo. Previous studies using the freshwater turtle as a model species showed that brevetoxin-3 impacts the nervous and muscular systems, and is detoxified and eliminated primarily through the liver, bile, and feces. In this study, freshwater turtles (Trachemys scripta) were exposed to brevetoxin (PbTx-3) intratracheally at doses causing clear systemic effects, and treatment strategies aimed at reducing the postexposure neurological and muscular deficits were tested. Brevetoxin-exposed T. scripta displayed the same behaviors as animals admitted to rehabilitation centers for toxin exposure, ranging from muscle twitching and incoordination to paralysis and unresponsiveness. Two treatment regimes were tested: cholestyramine, a bile acid sequestrant; and an intravenous lipid emulsion treatment (Intralipidt) that provides an expanded circulating lipid volume. Cholestyramine was administered orally 1 hr and 6 hr post PbTx-3 exposure, but this regime failed to increase toxin clearance. Animals treated with Intralipid (100 mg/kg) 30 min after PbTx-3 exposure had greatly reduced symptoms of brevetoxicosis within the first 2 hr compared with animals that did not receive the treatment, and appeared fully recovered within 24 hr compared with toxin-exposed control animals that did not receive Intralipid. The results strongly suggest that Intralipid treatment for lipophilic toxins such as PbTx-3 has the potential to reduce morbidity and mortality in HAB-exposed sea turtles.

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism.

BACKGROUND AND OBJECTIVES: Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. METHODS: Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. RESULTS: Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. CONCLUSIONS: Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.

Determination of Degradation Kinetics and Effect of Anion Exchange Resin on Dissolution of Novel Anticancer Drug Rigosertib in Acidic Conditions.

Rigosertib is a novel anticancer drug in clinical development by Onconova therapeutics, Inc. Currently, it is in pivotal phase III clinical trials for myelodysplastic syndrome (MDS) patients. Chemically, it is a sodium salt of weak acid with low solubility in lower pH solutions. In the preliminary studies, it was found that rigosertib is unstable in acidic conditions and forms multiple degradation products. In this research, drug degradation kinetics of rigosertib were studied in acidic conditions. Rigosertib follows pseudo-first-order general acid catalysis reaction. Cholestyramine, which is a strong anion exchange resin, was used to form complex with drug to improve stability and dissolution in acidic conditions. Drug complex with cholestyramine showed better dissolution profile compared to drug alone. Effect of polyethylene glycol was investigated on the release of drug from the drug resin complex. Polyethylene glycol further improved dissolution profile by improving drug solubility in acidic medium.

Cholestyramine as a promising, strong anion exchange resin for direct capture of genetic biomarkers from raw pancreatic fluids.

The ability to capture cell-free DNA from the gastrointestinal tract, in a minimally invasive manner, could enhance our ability to diagnose gastrointestinal disease, or gain a better understanding of the spatial mapping of the intestinal microbiota. We, therefore, sought to identify a class of capture agents that could directly and efficiently sequester genetic material from intestinal fluids. As a particular case study, we examined the ability to capture DNA from pancreatic secretions, for potential application in enabling the sequestration of early, genetic biomarkers of pancreatic disease. We hypothesized that the cholestyramine series of strong cation exchange resins, which are FDA approved for the treatment of high cholesterol, may be capable of capturing DNA from pancreatic secretions. We identified a particular cholestyramine resin, DOWEX 1 × 2 100-200 mesh, which is able to efficiently capture and purify DNA from pancreatic fluid. Using only 200 µL of pancreatic secretions, we are able to recover 247 ± 182 ng of amplifiable human DNA, giving an estimated pancreatic fluid DNA content of 1.23 ± 0.91 ng/µL. To our knowledge, this is the first demonstration of a material that can effectively capture and purify DNA directly from untreated pancreatic fluids. Thus, our approach could hold high utility for the in vivo capture of DNA and disease biomarkers if incorporated into an appropriate sampling device. Biotechnol. Bioeng. 2017;114: 934-938. © 2016 Wiley Periodicals, Inc.

Use of a Cholestyramine Washout in a Patient With Septic Shock on Leflunomide Therapy: A Case Report and Review of the Literature.

Patients presenting with infections while receiving disease-modifying antirheumatic agents (DMARD) may be predisposed to a higher degree illness due to immunosuppression. This can be particularly problematic in patients who are receiving DMARDs with prolonged pharmacokinetic profiles. Leflunomide is a DMARD that has a prolonged half-life due to enterohepatic recirculation. We report a case of a patient with severe septic shock secondary to a prosthetic joint infection in which therapeutic levels of leflunomide were discovered, despite the patient ceasing therapy several weeks prior to admission. An orogastric cholestyramine washout was given to the patient to expedite the removal of the drug. Serum levels rapidly declined over the next several days, corresponding with resolution of her sepsis. A review of the literature relevant to the incidence of DMARD-related infections was conducted as well as discussion regarding the role of leflunomide drug monitoring and cholestyramine-facilitated removal of the drug in episodes of acute infectious syndromes.

Mutant neurogenin-3 in a Turkish boy with congenital malabsorptive diarrhea.

Congenital diarrheal disorders are caused by disruption in nutrient digestion, absorption, or transport, enterocyte development and functioning, or enteroendocrine functioning. Many additional rare forms of congenital diarrhea are expected to be linked to genes associated with appropriate intestinal fluid and electrolyte balance. Neurogenin-3 mutation, a very rare form of congenital diarrhea, disrupts enteroendocrine cell differentiation and is characterized by malabsorption and the absence of pancreatic islet cells. Diabetes mellitus is typically associated with malabsorptive diarrhea at early onset or at later presentation in neurogenin-3 mutation. Here, we describe the case of an infant with homozygous neurogenin-3 mutation who had severe malabsorptive diarrhea and episodes of hyperchloremic metabolic acidosis after birth. Remarkably, cholestyramine was effective at reducing stool volume and frequency and improved the consistency of the stools; diabetes was not present in this patient.

Clinical characteristics and patterns and predictors of response to therapy in collagenous and lymphocytic colitis.

BACKGROUND: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory disorders of the colon. There is a paucity of data on differences in etiology, natural history, and treatment response between CC and LC. METHODS: Between 2002 and 2013, we identified new diagnoses of CC and LC using the Research Patient Data Registry in a tertiary referral center. We used chi square or Fischer's exact test and Wilcoxon rank-sum tests to compare the differences in clinical characteristics, treatment types, and response rates between LC and CC. RESULTS: Through 2013, we confirmed 131 patients with a new diagnosis of microscopic colitis (MC) (55 LC, 76 CC). Compared to cases of LC, patients with a diagnosis of CC were more likely to be women (86% vs. 69%, p = 0.03), have elevated erythrocyte sedimentation rate (mean 28 vs. 13 mm/h, p = 0.04), and less likely to be diabetic (5% vs. 18%, p = 0.02). Budesonide was the most effective treatment for both CC and LC (94% and 80%, respectively). However, there were no statistically significant differences in response to various treatments according to the type of MC (all p > 0.10). Older age at the time of diagnosis was associated with better response to bismuth subsalicylate (odds ratio: 1.76; 95% confidence interval: 1.21-2.56 for every 5-year increase) for both CC and LC. CONCLUSION: Despite differences in the clinical characteristics, response rates to available treatments appeared to be similar in both LC and CC. Older patients may have a better response to bismuth subsalicylate therapy.

Gestational cholestyramine treatment protects adult offspring of ApoE-deficient mice against maternal-hypercholesterolemia-induced atherosclerosis.

AIM: Perinatal hypercholesterolemia exacerbates the development of atherosclerotic plaques in adult offspring. Here, we aimed to study the effect of maternal treatment with cholestyramine, a lipid-lowering drug, on atherosclerosis development in adult offspring of hypercholesterolemic ApoE-deficient (ApoE-/-) mice. METHODS: ApoE-/- mice were treated with 3% cholestyramine (CTY) during gestation (G). After weaning, offspring (CTY-G) were fed control diet until sacrificed at 25weeks of age. Atherosclerosis development in the aortic root of offspring was assessed after oil-red-o staining, along with some of predefined atherosclerosis regulators such as LDL and HDL by high-performance liquid chromatography (HPLC), and bile acids (BA) and trimethylamine N-oxide (TMAO) by liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: In pregnant dams, cholestyramine treatment resulted in significantly lower plasma total- and LDL-cholesterol as well as gallbladder total BA levels. In offspring, both males and females born to treated dams displayed reduced atherosclerotic plaques areas along with less lipid deposition in the aortic root. No significant change in plasma total cholesterol or triglycerides was measured in offspring, but CTY-G males had increased HDL-cholesterol and decreased apolipoproteins B100 to A-I ratio. This latter group also showed reduced gallbladder total and specifically tauro-conjugated bile acid pools, whereas for CTY-G females, hydrophilic plasma tauro-conjugated BA pool was significantly higher. They also benefited from lower plasma TMAO. CONCLUSION: Prenatal cholestyramine treatment reduces atherosclerosis development in adult offspring of ApoE-/- mice along with modulating the plaques' composition as well as some related biomarkers such as HDL-C, bile acids and TMAO.

Refractory Graves' Disease in an Adolescent Successfully Treated With Cholestyramine and Subsequent Thyroidectomy.

Graves' disease is the most common form of hyperthyroidism in children and adolescents. There are three primary lines of treatment for Graves' disease: antithyroid drugs (ATDs), thyroidectomy, and radioactive iodine. Ideally, patients should be rendered euthyroid before surgery to minimize complications. Here, we report on a 14-year-old girl with severe Graves' disease refractory to conventional treatments despite maximal therapy over 18 months. The patient received two types of ATDs, beta-blockers, and different courses of steroids; however, her thyroid function tests remained high. She was then given an adjunctive four-week course of cholestyramine, to which she responded well and became euthyroid. Subsequently, a thyroidectomy was performed without complications. Cholestyramine is an effective adjunctive treatment for refractory Graves' disease in adolescents.

Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B.

BACKGROUND & AIMS: A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB. METHODS: To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. RESULTS: Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. CONCLUSIONS: R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

Comparison between SeHCAT test and clinical response to cholestyramine in patients with chronic diarrhea and high suspicion of bile acid malabsorption: A single-center prospective study.

OBJECTIVES: We aimed to evaluate the clinical response to cholestyramine in patients with functional chronic diarrhea and a high clinical suspicion of bile-acid diarrhea (BAD) investigated with 75-selenium homocholic acid taurine (SeHCAT) test. METHODS: Adult patients attending our outpatient clinic between January and December 2021 for chronic diarrhea with suspicion of BAD were proposed SeHCAT testing and a therapeutic trial of cholestyramine 4-8 g daily. Clinical response to cholestyramine was evaluated at 1, 3, 6, and 12 months. Clinical and demographic data were analyzed according to SeHCAT test results. RESULTS: Among the 50 patients with chronic diarrhea and clinical suspicion of BAD, 13 (26.0%) refused either SeHCAT testing or cholestyramine therapy. Finally, 37 patients (31 females, age 44 ± 14 years) agreed to undergo SeHCAT and were started on cholestyramine (median follow-up 14 months [interquartile range 6-16 months]). Initial response to cholestyramine was similar in patients with positive and negative SeHCAT test results, but improved over time in those with a positive test result. Long-term response (100% vs 65.2%, P = 0.02) and necessity of maintenance therapy for symptom control were more common in those with positive SeHCAT test result (71.4% vs 26.1%, P = 0.02). However, response to cholestyramine was also frequent in patients with a negative test result. CONCLUSIONS: The SeHCAT test accurately identifies patients with BAD who benefit from long-term cholestyramine treatment. Nevertheless, cholestyramine may be also effective in patients with chronic diarrhea but negative SeHCAT test result.