Gastrointestinal manifestations after Roux-en-Y gastric bypass surgery in individuals with and without type 2 diabetes

Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity, which improves cardiovascular health and reduces the risk of premature mortality. However, some reports have suggested that RYGB may predispose patients to adverse health outcomes, such as inflammatory bowel disease (IBD) and colorectal cancer. Objectives: The present prospective study aimed to evaluate the impact of RYGB surgery on cardiovascular risk factors and gastrointestinal inflammation in individuals with and without type 2 diabetes (T2D). Setting: University hospital setting in Finland. Methods: Blood and fecal samples were collected at baseline and 6 months after surgery from 30 individuals, of which 16 had T2D and 14 were nondiabetics. There were also single study visits for 6 healthy reference patients. Changes in cardiovascular risk factors, serum cholesterol, and triglycerides were investigated before and after surgery. Fecal samples were analyzed for calprotectin, anti-Saccharomyces cerevisiae immunoglobulin A antibodies (ASCA), active lipopolysaccharide (LPS) concentration, short-chain fatty acids (SCFAs), intestinal alkaline phosphatase activity, and methylglyoxal-hydro-imidazolone (MG-H1) protein adducts formation. Results: After RYGB, weight decreased on average 221.6% (-27.2 +/- 7.8 kg), excess weight loss averaged 51%, and there were improvements in cardiovascular risk factors. Fecal calprotectin levels (P < .001), active LPS concentration (P < .002), ASCA (P < .02), and MG-H1 (P < .02) values increased significantly, whereas fecal SCFAs, especially acetate (P < .002) and butyrate (P < .03) levels, were significantly lowered. Conclusion: The intestinal homeostasis is altered after RYGB, with several fecal markers suggesting increased inflammation; however, clinical significance of the detected changes is currently uncertain. As chronic inflammation may predispose patients to adverse health effects, our findings may have relevance for the suggested association between RYGB and increased risks of incident IBD and colorectal cancer. (C) 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.Peer reviewe

Total fecal IgA levels increase and natural IgM antibodies decrease after gastric bypass surgery

Obesity is associated with low-grade inflammation and increased systemic oxidative stress. Roux-en-Y gastric bypass (RYGB) surgery is known to ameliorate the obesity-induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non-diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA-LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first-line defense against microbes, and their production is markedly altered with RYGB surgery.Peer reviewe

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism

Background and Purpose Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved.Experimental Approach We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis.Key Results Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation.Conclusion and Implications PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia

Analysis of the SYSDIET Healthy Nordic Diet randomized trial based on metabolic profiling reveal beneficial effects on glucose metabolism and blood lipids

Background & aims Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profiles and to associate them with cardiometabolic markers. MethodsDuring 18-24 weeks of intervention, 200 participants with metabolic syndrome were advised at six centres to eat either HND (e.g. whole-grain products, berries, rapeseed oil, fish and low-fat dairy) or CD while being weight stable. Of these 166/159 completers delivered blood/urine samples. Metabolic profiles of fasting plasma and 24 h pooled urine were analysed to identify characteristic diet-related patterns. Principal components analysis (PCA) scores (i.e. PC1 and PC2 scores) were used to test their combined effect on blood glucose response (primary endpoint), serum lipoproteins, triglycerides, and inflammatory markers. ResultsThe profiles distinguished HND and CD with AUC of 0.96 ± 0.03 and 0.93 ± 0.02 for plasma and urine, respectively, with limited heterogeneity between centers, reflecting markers of key foods. Markers of fish, whole grain and polyunsaturated lipids characterized HND, while CD was reflected by lipids containing palmitoleic acid. The PC1 scores of plasma metabolites characterizing the intervention is associated with HDL (β = 0.05; 95% CI: 0.02, 0.08; P = 0.001) and triglycerides (β = -0.06; 95% CI: -0.09, -0.03; P ConclusionsPlasma and urine metabolite profiles from SYSDIET reflected good compliance with dietary recommendations across the region. The scores of metabolites characterizing the diets associated with outcomes related with cardio-metabolic risk. Our analysis therefore offers a novel way to approach a per protocol analysis with a balanced compliance assessment in larger multicentre dietary trials.The study was registered at clinicaltrials.gov with NCT00992641.</p

Xenobiotic-metabolizing cytochrome P450 enzymes in human lung

Abstract The cytochrome P450 (CYP) enzyme system in human lung is an essential component in the pulmonary carcinogenicity of several inhaled xenobiotic compounds. The aim of this study was to elucidate the expression and regulation of xenobiotic-metabolizing CYP enzymes in human lung. To evaluate which of the two is a better surrogate cell model for lung tissue, the expression patterns of CYP enzymes in alveolar macrophages and peripheral blood lymphocytes were clarified by reverse transcriptase-polymerase chain reaction (RT-PCR) and compared to the expression in lung tissue. The pattern of CYP expression in alveolar macrophages was found to closely resemble the expression pattern in human lung tissue, while the pattern in lymphocytes was markedly different. The expression of CYP2B6, CYP2C, CYP3A5, and CYP4B1 mRNAs in alveolar macrophages was demonstrated for the first time. To facilitate mechanistic studies on human pulmonary CYP induction, the A549 lung adenocarcinoma cell line was characterized by RT-PCR, and the CYP expression pattern was found to compare reasonably well to human lung epithelial cells. The induction of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) behaved as predicted, and CYP1B1 and CYP3A5 were also inducible by TCDD and dexamethasone, respectively. TCDD elevated the level of CYP1A1 mRNA (56-fold), while the induction of CYP1B1 mRNA was more modest (2.5-fold). The tyrosine kinase inhibitor genistein and the protein kinase C inhibitor staurosporine blocked CYP1A1 induction by TCDD, but did not affect CYP1B1 induction. The serine/threonine protein phosphatase inhibitor calyculin A and okadaic acid enhanced CYP1B1 induction slightly, but did not alter CYP1A1 induction. The expression of CYP3A forms in human pulmonary tissues was studied with RT-PCR and immunohistochemistry, and both methods established CYP3A5 as the main CYP3A form. CYP3A4 was expressed in only about 20% of the cases. In A549 cells, CYP3A5 was induced about 4-fold by the glucocorticoids budesonide, beclomethasone dipropionate, and dexamethasone. Maximal induction was achieved by concentrations as low as ~100 nM, suggesting that CYP3A5 could be induced in vivo in patients using inhaled glucocorticoids. However, there were no differences in CYP3A5 expression in alveolar macrophages in current glucocorticoid users, ex-users, and non-users. Cigarette smoking had a marked decreasing effect on CYP3A5 levels in alveolar macrophages. The presence and possible induction of CYP3A5 by glucocorticoids in human lung could have consequences for the maintenance of physiological steroid hormone balance in lung and the individual susceptibility to lung cancer of patients using glucocorticoids

PXR and 4β-hydroxycholesterol axis and the components of metabolic syndrome

Abstract Pregnane X receptor (PXR) activation has been found to regulate glucose and lipid metabolism and affect obesity in response to high-fat diets. PXR also modulates vascular tone. In fact, PXR appears to regulate multiple components of metabolic syndrome. In most cases, the effect of PXR action is harmful to metabolic health, and PXR can be hypothesized to play an important role in metabolic disruption elicited by exposure to endocrine-disrupting chemicals. The majority of the data on the effects of PXR activation on metabolic health come from animal and cell culture experiments. However, randomized, placebo-controlled, human trials indicate that the treatment with PXR ligands impairs glucose tolerance and increases 24-h blood pressure and heart rate. In addition, plasma 4β-hydroxycholesterol (4βHC), formed under the control of PXR in the liver, is associated with lower blood pressure in healthy volunteers. Furthermore, 4βHC regulates cholesterol transporters in peripheral tissues and may activate the beneficial reverse HDL cholesterol transport. In this review, we discuss the current knowledge on the role of PXR and the PXR–4βHC axis in the regulation of components of metabolic syndrome

Lääkkeellinen painonhallinta

Tiivistelmä Lihavuuden lääkehoitoa harkitaan elintapahoidon tueksi, kun painoindeksi on ≥ 30 kg/m². Jos potilaalla on lihavuuden liitännäissairauksia, voidaan lääkitystä harkita, kun indeksi on yli 27 kg/m². Lääkevaihtoehtoja ovat orlistaatti, liraglutidi sekä naltreksonin ja bupropionin yhdistelmävalmiste. Myös semaglutidin vaikutuksesta on vahvaa näyttöä. Lääkityksen teho on yksilöllistä. Tehoton lääkitys (paino vähenee &lt; 5 %) tulee lopettaa. Merkittävä painonnousu on tyypillinen ongelma lääkehoidon lopettamisen jälkeen. Lääkehoito pitäisi suunnitella riittävän pitkäaikaiseksi.Summary Pharmacological therapy for obesity and overweight as an adjunct to lifestyle intervention can be considered when the body mass index is ≥ 30 kg/m², or ≥ 27 kg/m² with obesity-related comorbidities. The history of anti-obesity medications is long and often problematic as several medications have been withdrawn due to cardiovascular hazards and mood disorders. There are currently three options for pharmacotherapy in Finland: orlistat, naltrexone–bupropion, and liraglutide. In addition, the diabetes medication semaglutide is currently under evaluation by the European Medicines Agency as a treatment for obesity. The most efficient drugs for weight loss are the GLP-1 agonists liraglutide and especially semaglutide. Orlistat has the most extensive accumulated long term clinical experience of safety, but its efficacy is only modest. Naltrexone–bupropion has moderate efficacy, but several contraindications and drug-drug interactions complicate its use. Cardiovascular safety is established for liraglutide and semaglutide but only in the treatment of diabetes at lower doses than indicated in obesity therapy. The challenges in pharmacotherapy for obesity include the high treatment discontinuation rates, interindividual differences in response to medications, the tendency to regain weight after the drug treatment, and high costs for the patient due to lack of reimbursement. However, liraglutide was recently granted reimbursement for patients with body mass index ≥ 35 kg/m² and prediabetes, with the additional prerequisite of drug treatment for hypertension or dyslipidaemia. Utilization of the current more efficient anti-obesity medications and better access to therapy should lead to improved long-term outcomes, especially when pharmacotherapy is combined with effective lifestyle interventions

Nuclear receptor PXR in drug-induced hypercholesterolemia

Abstract Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug–drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia

CYP-associated drug–drug interactions:a mission accomplished?

Abstract On the basis of official Finnish Medicines Authority (Fimea)-approved drug monographs, less than half of the approved small-molecule drugs between 2007 and 2016 were substrates, inhibitors or inducers of CYP enzymes, predominantly of CYP3A4. No significant unexpected, life-threatening, CYP-associated drug-drug interactions (CYP-DDIs) of newly approved drug entities have been observed in the last 10–15 years. The present analysis seems to suggest that tools to study and predict potentially significant CYP-DDIs are working and efficient

Inhibition and induction of CYP enzymes in humans:an update

Abstract The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena