Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS: We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS: All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION: Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION: Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY: Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING: The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Cholic acid therapy in Zellweger spectrum disorders.

INTRODUCTION: Zellweger spectrum disorders (ZSDs) are characterized by a failure in peroxisome formation, caused by autosomal recessive mutations in different PEX genes. At least some of the progressive and irreversible clinical abnormalities in patients with a ZSD, particularly liver dysfunction, are likely caused by the accumulation of toxic bile acid intermediates. We investigated whether cholic acid supplementation can suppress bile acid synthesis, reduce accumulation of toxic bile acid intermediates and improve liver function in these patients. METHODS: An open label, pretest-posttest design study was conducted including 19 patients with a ZSD. Participants were followed longitudinally during a period of 2.5 years prior to the start of the intervention. Subsequently, all patients received oral cholic acid and were followed during 9 months of treatment. Bile acids, peroxisomal metabolites, liver function and liver stiffness were measured at baseline and 4, 12 and 36 weeks after start of cholic acid treatment. RESULTS: During cholic acid treatment, bile acid synthesis decreased in the majority of patients. Reduced levels of bile acid intermediates were found in plasma and excretion of bile acid intermediates in urine was diminished. In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates. CONCLUSIONS: Oral cholic acid therapy can be used in the majority of patients with a ZSD, leading to at least partial suppression of bile acid synthesis. However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects.

Nutrition before, during, and after surgery increases the arginine:asymmetric dimethylarginine ratio and relates to improved myocardial glucose metabolism: a randomized controlled trial.

BACKGROUND: Nitric oxide (NO) is essential for the optimal perfusion of the heart and its vasculature. NO may be insufficient in surgical patients because its precursor arginine is decreased, and the inhibitor of NO synthesis asymmetric dimethylarginine (ADMA) is increased. Besides arginine, the presence of other amino acids essential for the proper metabolism of cardiac cells may be decreased too. Supplementation of these amino acids with enteral and parenteral nutrition before, during, and after surgery may augment the myocardial and plasma arginine:ADMA ratio and availability of amino acids. Myocardial glucose metabolism and nutritional conditioning may result in a reduction of cardiac injury and support rapid recovery after major surgery. OBJECTIVE: We investigated the effect of nutrition before, during, and after surgery on amino acids and the myocardial arginine:ADMA ratio and its relation to myocardial glucose metabolism. DESIGN: In this trial, 33 patients who were undergoing off-pump coronary artery bypass grafting (CABG) were randomly assigned between enteral, parenteral, or no nutrition (control) from 2 d before, during, and until 2 d after surgery. Both enteral and parenteral solutions were prepared with commercially available products and included proteins or amino acids, glucose, vitamins, and minerals. Concentrations of amino acids including ADMA were analyzed in myocardial tissue and plasma samples. ¹8F-fluorodeoxyglucose positron emission tomography was performed before and after surgery to assess myocardial glucose metabolism. RESULTS: The myocardial arginine:ADMA ratio increased during surgery and was significantly higher in the enteral and parenteral groups than in the control group [median (IQR): 115.0 (98.0-142.2) (P = 0.012), 116.9 (100.3-135.3) (P = 0.004), and 93.3 (82.7-101.1), respectively]. Furthermore, the change in the preoperative to postoperative plasma arginine:ADMA ratio correlated with the change in myocardial glucose metabolism in positron emission tomography (r = 0.427, P = 0.033). CONCLUSION: Enteral or parenteral nutrition before, during, and after CABG may positively influence myocardial glucose metabolism by increasing the plasma and myocardial arginine:ADMA ratio.