Marius Trøseid

Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure

Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine‐N‐oxide (TMAO), a microbiota‐dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF.

The role of interleukin-18 in the metabolic syndrome

The metabolic syndrome is thought to be associated with a chronic low-grade inflammation, and a growing body of evidence suggests that interleukin-18 (IL-18) might be closely related to the metabolic syndrome and its consequences. Circulating levels of IL-18 have been reported to be elevated in subjects with the metabolic syndrome, to be closely associated with the components of the syndrome, to predict cardiovascular events and mortality in populations with the metabolic syndrome and to precede the development of type 2 diabetes. IL-18 is found in the unstable atherosclerotic plaque, in adipose tissue and in muscle tissue, and is subject to several regulatory steps including cleavage by caspase-1, inactivation by IL-18 binding protein and the influence of other cytokines in modulating its interaction with the IL-18 receptor. The purpose of this review is to outline the role of IL-18 in the metabolic syndrome, with particular emphasis on cardiovascular risk and the potential effect of life style interventions.

The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls.

Objective Gut microbiota could influence gut, as well as hepatic and biliary immune responses. We therefore thoroughly characterised the gut microbiota in primary sclerosing cholangitis (PSC) compared with healthy controls (HC) and patients with ulcerative colitis without liver disease. Design We prospectively collected 543 stool samples. After a stringent exclusion process, bacterial DNA was submitted for 16S rRNA gene sequencing. PSC and HC were randomised to an exploration panel or a validation panel, and only significant results (p<0.05, QFDR<0.20) in both panels were reported, followed by a combined comparison of all samples against UC. Results Patients with PSC (N=85) had markedly reduced bacterial diversity compared with HC (N=263, p<0.0001), and a different global microbial composition compared with both HC (p<0.001) and UC (N=36, p<0.01). The microbiota of patients with PSC with and without IBD was similar. Twelve genera separated PSC and HC, out of which 11 were reduced in PSC. However, the Veillonella genus showed a marked increase in PSC compared with both HC (p<0.0001) and UC (p<0.02). Using receiver operating characteristic analysis, Veillonella abundance yielded an area under the curve (AUC) of 0.64 to discriminate PSC from HC, while a combination of PSC-associated genera yielded an AUC of 0.78. Conclusions Patients with PSC exhibited a gut microbial signature distinct from both HC and UC without liver disease, but similar in PSC with and without IBD. The Veillonella genus, which is also associated with other chronic inflammatory and fibrotic conditions, was enriched in PSC.

Gut microbiota diversity predicts immune status in HIV-1 infection.

Objective:HIV-1 infection is characterized by altered intestinal barrier, gut microbiota dysbiosis, and systemic inflammation. We hypothesized that changes of the gut microbiota predict immune dysfunction and HIV-1 progression, and that antiretroviral therapy (ART) partially restores the microbiota composition. Design:An observational study including 28 viremic patients, three elite controllers, and nine uninfected controls. Blood and stool samples were collected at baseline and for 19 individuals at follow-up (median 10 months) during ART. Methods:Microbiota composition was determined by 16S rRNA sequencing (Illumina MiSeq). Soluble markers of microbial translocation and monocyte activation were analyzed by Limulus Amebocyte Lysate assay or ELISA. Results:Several alpha-diversity measures, including number of observed bacterial species and Shannon index, were significantly lower in viremic patients compared to controls. The alpha diversity correlated with CD4+ T-cell counts and inversely with markers of microbial translocation and monocyte activation. In multivariate linear regression, for every age and sex-adjusted increase in the number of bacterial species, the CD4+ T-cell count increased with 0.88 (95% confidence interval 0.35–1.41) cells/&mgr;l (P = 0.002). After introduction of ART, microbiota alterations persisted with further reduction in alpha diversity. The microbiota composition at the genus level was profoundly altered in viremic patients, both at baseline and after ART, with Prevotella reduced during ART (P < 0.007). Conclusions:Gut microbiota alterations are closely associated with immune dysfunction in HIV-1 patients, and these changes persist during short-term ART. Our data implicate that re-shaping the microbiota may be an adjuvant therapy in patients commencing successful ART.

Elevated plasma levels of lipopolysaccharide and high mobility group box-1 protein are associated with high viral load in HIV-1 infection : reduction by 2-year antiretroviral therapy

Objective:To investigate plasma levels of high mobility group box-1 protein (HMGB1), a marker of tissue necrosis and immune activation, as well as lipopolysaccharide (LPS), a marker of bacterial translocation, in HIV-1-infected patients. Design:We studied 32 HIV-1-positive patients who had responded to antiretroviral therapy with undetectable viremia after 2 years, 10 nonresponders and 19 healthy controls. Methods:HMGB1 was analyzed by ELISA, and LPS by Lamilus colometric assay. Nonparametric statistics were applied. Results:In naive HIV-1 patients, HMGB1 and LPS were elevated as compared with controls (P < 0.001). LPS levels were higher in African and Oriental patients compared with whites (P = 0.007). Notably, viral load was two-fold higher in patients with LPS, and HMGB1 was above median as compared with other patients (P = 0.005). This association was largely driven by African patients, who had a five-fold increased viral load in the presence of elevated LPS and HMGB1. After 2 years of effective antiretroviral therapy, LPS was reduced to the same median level as in the control group (P < 0.001), and HMGB1 was also reduced (P = 0.001), whereas no reductions were seen in nonresponders. Conclusion:The new findings are the association of elevated plasma levels of LPS and HMGB1 with high viral load, as well as the normalized levels of LPS, and the reduction of HMGB1 after 2 years of effective antiretroviral therapy. As LPS and HMGB1 tend to form immunologically active complexes in vitro, we propose that such complexes may be involved in the immune activation and pathogenesis of HIV-1 infection.

Plasma Lipopolysaccharide Is Closely Associated With Glycemic Control and Abdominal Obesity: Evidence from bariatric surgery

OBJECTIVE It is of vital importance to elucidate the triggering factors of obesity and type 2 diabetes to improve patient care. Bariatric surgery has been shown to prevent and even cure diabetes, but the mechanism is unknown. Elevated levels of lipopolysaccharide (LPS) predict incident diabetes, but the sources of LPS are not clarified. The objective of the current study was to evaluate the potential impact of plasma LPS on abdominal obesity and glycemic control in subjects undergoing bariatric surgery. RESEARCH DESIGN AND METHODS This was a prospective observational study involving a consecutive sample of 49 obese subjects undergoing bariatric surgery and 17 controls. Main assessments were plasma LPS, HbA1c, adipose tissue volumes (computed tomography), and quantified bacterial DNA in adipose tissue compartments. RESULTS Plasma levels of LPS were elevated in obese individuals compared with controls (P < 0.001) and were reduced after bariatric surgery (P = 0.010). LPS levels were closely correlated with HbA1c (r = 0.56; P = 0.001) and intra-abdominal fat volumes (r = 0.61; P < 0.001), but only moderately correlated with subcutaneous fat volumes (r = 0.33; P = 0.038). Moreover, there was a decreasing gradient (twofold) in bacterial DNA levels going from mesenteric via omental to subcutaneous adipose tissue compartments (P = 0.041). Finally, reduced LPS levels after bariatric surgery were directly correlated with a reduction in HbA1c (r = 0.85; P < 0.001). CONCLUSIONS Our findings support a hypothesis of translocated gut bacteria as a potential trigger of obesity and diabetes, and suggest that the antidiabetic effects of bariatric surgery might be mechanistically linked to, and even the result of, a reduction in plasma levels of LPS.

Interleukin-18 is a strong predictor of cardiovascular events in elderly men with the metabolic syndrome. Synergistic effect of inflammation and hyperglycemia

OBJECTIVE—The aim of this study was to investigate the role of inflammatory markers as potential predictors of cardiovascular events in subjects with and without the metabolic syndrome. RESEARCH DESIGN AND METHODS—This was a post hoc analysis from the Diet and Omega-3 Intervention Trial (DOIT), comprising 563 elderly men with (n = 221) and without (n = 342) metabolic syndrome. Circulating inflammatory markers were measured. RESULTS—During 3 years, 68 cardiovascular events were recorded. In the total population, C-reactive protein (CRP) (P < 0.001), interleukin-18 (IL-18) (P = 0.008), and IL-6 (P = 0.003) were elevated in subjects with events. In subjects with metabolic syndrome, IL-18 was the strongest predictor (adjusted odds ratio 2.9 [95% CI 1.1–7.8]). In subjects without metabolic syndrome, only CRP seemed to be an independent predictor (3.3 [1.5–7.3]). There was a significant interaction between fasting glucose and IL-18 (P = 0.008) and IL-6 (P = 0.024) but not CRP. Elevated fasting glucose (>6.2 mmol/l) markedly increased the predictive power of inflammatory markers (IL-18: 5.5 [1.4–21.1], IL-6: 3.5 [1.0–11.8], and CRP: 3.5 [1.0–11.9]). For IL-18, there was a stepwise increase in event rate by quartiles of fasting glucose. CONCLUSIONS—IL-18 was an independent predictor of cardiovascular events in subjects with metabolic syndrome and even more so in the presence of elevated fasting glucose. Our findings suggest a mutually potentiating effect of hyperglycemia and inflammation in cardiovascular risk prediction.

Serum levels of interleukin-18 are reduced by diet and n-3 fatty acid intervention in elderly high-risk men.

Inflammation plays a central role in the development and progression of atherosclerosis, and inflammatory markers have been reported to predict cardiovascular events. Mediterranean-like diet and very long chain omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation have been reported to reduce the risk of cardiovascular mortality and morbidity, but the mechanisms are not fully clarified. The aims of the present study were to investigate the effect of such interventions on serum levels of inflammatory markers, and potential associations with changes in serum fatty acids and anthropometric measures. This was a randomized 2 x 2 factorial-designed trial comparing the effect of 3 years of dietary counseling, n-3 PUFA supplementation (2.4 g/d), or both on different measures of atherosclerosis in elderly high-risk men (N = 563). Levels of interleukin-18 (IL-18) were decreased by diet (-10.5% vs baseline, P = .012 compared with no diet) and by n-3 PUFA supplementation (-9.9% vs baseline, P = .008 compared with placebo). Other measured inflammatory markers were not affected. Changes in IL-18 were significantly correlated to changes in triglycerides (r = 0.20, P < .001), eicosapentaenoic acid (r = -0.14, P = .030), docosahexaenoic acid (r = -0.14, P = .034), body mass index (r = 0.16, P < .001), and waist circumference (r = 0.12, P = .007). In conclusion, levels of IL-18 were significantly reduced by Mediterranean-like diet and n-3 PUFA supplementation. However, the changes correlated only weakly to changes in triglycerides, serum fatty acids, and anthropometric measures. The cardioprotective effects of both interventions might thus in part be explained by reduced levels of IL-18, but probably beyond changes in serum fatty acids and body composition.

Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction.

Objective:Microbial translocation has been suggested to be a driver of immune activation and inflammation. It is hypothesized that microbial translocation may be related to dyslipidemia, insulin resistance, and the risk of coronary heart disease in HIV-infected individuals. Design:Cross-sectional study of 60 HIV-infected patients on combination antiretroviral therapy with viral suppression >2 years and 31 healthy age-matched controls. Methods:Lipopolysaccharide (LPS) was analyzed by limulus amebocyte lysate colorimetric assay. Lipids, including cholesterol, low-density lipoprotein (LDL), and triglycerides, were measured. Glucose metabolism was determined using an oral glucose tolerance test. Body composition was determined using whole-body dual-energy x-ray absorptiometry scans and magnetic resonance imaging. The Framingham risk score was used to assess risk of cardiovascular disease and myocardial infarction. Results:HIV-infected patients had higher level of LPS compared with controls (64 pg/mL vs. 50 pg/mL, P = 0.002). Likewise, HIV-infected patients had higher triglycerides, LDL, and fasting insulin as well as evidence of lower insulin sensitivity compared with controls. Among HIV-infected patients, high LPS was associated with a higher level of triglycerides and LDL and with lower insulin sensitivity. Importantly, among HIV-infected patients, high LPS was associated with a higher Framingham risk score. Conclusions:HIV-infected patients with suppressed viral replication had increased level of microbial translocation as measured by LPS. LPS was associated with cardiometabolic risk factors and increased Framingham risk score. Hence, the gastrointestinal mucosal barrier may be a potential therapeutic target to prevent dyslipidemia and future cardiovascular complications in HIV infection.

Dried blood spots can expand access to virological monitoring of HIV treatment in resource-limited settings

The global scale-up of antiretroviral treatment in past years has, unfortunately, not been accompanied by adequate strengthening of laboratory capacity. Monitoring of treatment with HIV viral load and resistance testing, as recommended in industrialized countries, is rarely available in resource-limited settings due to high costs and stringent requirements for storage and transport of plasma. Consequently, treatment failure usually passes unnoticed until severe symptoms occur, when resistance mutations have accumulated and second-line drug options are restricted. Dried blood spots (DBS) are easy to collect and store, and can be a convenient alternative to plasma. Recently, a number of studies have demonstrated the feasibility and reliability of using DBS to monitor viral load and genotypic resistance. Moreover, several African countries have already started to use DBS for paediatric HIV screening. In the absence of point-of-care assays, the WHO should encourage virological monitoring on DBS in antiretroviral treatment programmes in resource-limited settings.