Association of the Kynurenine Pathway of Tryptophan Metabolism With Human Immunodeficiency Virus-Related Gut Microbiota Alterations and Visceral Adipose Tissue Accumulation.

BACKGROUND: The aim of the study was to investigate the association between human immunodeficiency virus (HIV)-related gut microbiota changes, alterations in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism, and visceral adipose tissue in the context of HIV infection. METHODS: Three hundred eighty-three people with HIV (PWH) were included from the Copenhagen comorbidity in HIV infection (COCOMO) study. Gut microbiota composition was analyzed by 16S ribosomal ribonucleic acid sequencing. Plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by single-slice computed tomography (CT) scan (4th lumbar vertebra). RESULTS: The HIV-related gut microbiota alterations were associated with lower Trp (ß -.01; 95% confidence interval [CI], -0.03 to -0.00) and higher Kyn-to-Trp ratio (ß 0.03; 95% CI, 0.01-0.05), which in turn was associated with higher VAT-to-SAT ratio (ß 0.50; 95% CI, 0.10-0.90) and larger VAT area (ß 30.85; 95% CI, 4.43-57.28). In mediation analysis, the Kyn-to-Trp ratio mediated 10% (P = .023) of the association between the VAT-to-SAT ratio and HIV-related gut microbiota. CONCLUSIONS: Our data suggest HIV-related gut microbiota compositional changes and gut microbial translocation as potential drivers of high Kyn-to-Trp ratio in PWH. In turn, increased activity in the Kyn pathway of Trp metabolism was associated with larger visceral adipose tissue area. Taken together, our findings suggest a possible role for this pathway in the gut-adipose tissue axis in the context of HIV infection.

Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement.

BACKGROUND: A high proportion of COVID-19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 and the renin-angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID-19 patients. METHODS: Plasma levels of a gut leakage marker (LPS-binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL-1ß, IL-18 and their regulatory proteins) were measured at three time points (day 1, 3-5 and 7-10) in 39 hospitalized COVID-19 patients and related to cardiac involvement. RESULTS: Compared to controls, COVID-19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT-pro-BNP levels, whereas IL-18, IL-18BP and IL-1Ra were associated with higher troponin levels. CONCLUSION: Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut-heart axis in COVID-19.

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

OBJECTIVES: 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. DESIGN: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored. RESULTS: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005). CONCLUSIONS: TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.

Markers of microbial translocation predict hypertension in HIV-infected individuals.

OBJECTIVES: The aim of the study was to test the hypothesis that microbial translocation, quantified by levels of lipopolysaccharide (LPS) and subsequent monocyte activation [soluble (sCD14)], is associated with hypertension in HIV-infected individuals. METHODS: In this exploratory substudy, 42 patients were recruited from a larger, longitudinal HIV-infected cohort study on blood pressure. LPS and sCD14 levels were measured retrospectively at the time of nadir CD4 cell count, selecting untreated HIV-infected patients with both advanced immunodeficiency and preserved immunocompetence at the time of nadir. Patients with later sustained hypertension (n = 16) or normotension (n = 26) throughout the study were identified. LPS was analysed using the Limulus Amebocyte Lysate colorimetric assay (Lonza, Walkersville, MD) and sCD14 using an enzyme-linked immunosorbent assay (ELISA). Nonparametric statistical tests were applied. RESULTS: In the HIV-infected patients [median (interquartile range) age 42 (32-46) years; 79% male and 81% Caucasian], LPS and sCD14 levels were both negatively correlated with nadir CD4 cell count. Plasma levels of LPS (P < 0.001) and sCD14 (P = 0.024) were elevated in patients with later hypertension compared with patients with normotension. There was a stepwise increase in the number of patients with hypertension across tertiles of LPS (P = 0.001) and sCD14 (P = 0.007). Both LPS and sCD14 were independent predictors of elevated blood pressure after adjustment for age and gender. For each 10-unit increase in LPS (range 66-272 pg/ml), the increment in mean blood pressure in the first period of blood pressure recording was 0.86 (95% confidence interval 0.31-1.41) mmHg (P = 0.003). CONCLUSIONS: As LPS and sCD14 were both independently associated with elevated blood pressure, microbial translocation may be linked to the development of hypertension.

Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency.

Common variable immunodeficiency (CVID) patients have reduced gut microbial diversity compared to healthy controls. The reduced diversity is associated with gut leakage, increased systemic inflammation and ten "key" bacteria that capture the gut dysbiosis (dysbiosis index) in CVID. Rifaximin is a broad-spectrum non-absorbable antibiotic known to reduce gut leakage (lipopolysaccharides, LPS) in liver disease. In this study, we explored as a 'proof of concept' that altering gut microbial composition could reduce systemic inflammation, using CVID as a disease model. Forty adult CVID patients were randomized, (1:1) to twice-daily oral rifaximin 550 mg versus no treatment for 2 weeks in an open-label, single-centre study. Primary endpoints were reduction in plasma/serum levels of soluble (s) CD14, sCD25, sCD163, neopterin, CRP, TNF, LPS and selected cytokines measured at 0, 2 and 8 weeks. Secondary endpoint was changes in intra-individual bacterial diversity in stool samples. Rifaximin-use did not significantly change any of the inflammation or gut leakage markers, but decreased gut microbial diversity compared with no treatment (p = 0.002). Importantly, the gut bacteria in the CVID dysbiosis index were not changed by rifaximin. The results suggest that modulating gut microbiota by rifaximin is not the chosen intervention to affect systemic inflammation, at least not in CVID.

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.

p24 antigen detection on dried blood spots is a feasible and reliable test for infant HIV infection in rural Tanzania.

The difficulty of diagnosing HIV in infants is a major obstacle to early antiretroviral therapy (ART) in resource-limited settings. As serological tests are unreliable during the first 18 months of life, and the cost and complexity of polymerase chain reaction (PCR)-based assays limit their access in resource-limited settings, p24 antigen detection has emerged as an alternative diagnostic tool. In this study, the performance of an ultrasensitive p24 antigen assay on dried blood spots was evaluated under field conditions in rural Tanzania. Specimens were stored and shipped at tropical room temperature, and analysed within six weeks. In total, 27 consecutive children aged <18 months and exposed to vertical HIV transmission were enrolled. Overall sensitivity and specificity was 100% (95% confidence interval [CI], 47.8-100) and 95.5% (95% CI, 77.2-99.9), respectively. Our findings suggest that detection of p24 antigen on dried blood spots can be a reliable and feasible diagnostic tool for infant HIV infection in rural resource-limited settings.

Comparison of biochemical, functional and structural aspects of arterial wall properties in elderly men.

OBJECTIVE: A variety of methods are available to assess arterial wall properties. The aim of this study was to investigate the relationship between some of the biochemical, functional and structural measurements of arterial wall characteristics. MATERIAL AND METHODS: The study comprised 563 elderly men at high risk of coronary heart disease. Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, von Willebrand factor (vWF) and tissue-type plasminogen activator antigen (tPAag) were compared with pulse wave velocity (PWV) measured by finger photoplethysmography and intima-media thickness (IMT) and plaque score of the common carotid artery. RESULTS: Levels of ICAM-1 were significantly correlated with plaque score (r = 0.17, p<0.001). Levels of vWF were significantly correlated with plaque score (r = 0.11, p = 0.009) and PWV (r = 0.12, p = 0.007), and levels of tPAag were significantly correlated with PWV (r = 0.16, p<0.001). These associations, although generally weak, remained statistically significant after adjustment for relevant cardiovascular risk factors. PWV did not correlate significantly with IMT or plaque score. CONCLUSIONS: The limited intercorrelation between biochemical, functional and structural measurements of arterial wall properties observed in the present population indicate that the various methods reflect different aspects of the atherosclerotic process.

Changes in serum levels of E-selectin correlate to improved glycaemic control and reduced obesity in subjects with the metabolic syndrome.

OBJECTIVE: Inflammation plays an essential role in the atherosclerotic process. Cellular adhesion molecules (CAMs) such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are involved in the rolling, adhesion and extravasation of monocytes and T-lymphocytes into the atherosclerotic plaque. In the present study the effect of physical exercise and pravastatin (40 mg daily) on serum levels of CAMs and a possible role of adipose tissue in regulating serum levels of CAMs were investigated. MATERIAL AND METHODS: The study was designed as an unmasked randomized 2x2 factorial trial of 12 weeks duration in 32 subjects with the metabolic syndrome. Changes from baseline were studied, and correlations between changes in CAMs, anthropometric measures, regional fat distribution, glycaemic control and the adipocytokine tumour necrosis factor-a (TNF-a) and adiponectin were investigated. RESULTS: No significant changes in CAMs were observed in any of the intervention groups. However, when examining the whole study population regardless of intervention, changes in serum E-selectin were significantly correlated to changes in body mass index (r=0.48, p=0.006), waist circumference (r=0.48, p=0.006), fasting glucose (r=0.43, p=0.02) and HbA1c (r=0.45, p=0.01), but not to changes in visceral fat, subcutaneous fat, TNF-a or adiponectin. CONCLUSION: Changes in glycaemic control and obesity, rather than regional fat distribution, seem to influence the levels of E-selectin in subjects with the metabolic syndrome.

[Parvovirus B19 as a cause of acute arthritis]. / Parvovirus B19 som årsak til akutt artritt.

Parvovirus B19 is known to cause erythema infection (fifth disease), acute and chronic arthritis, aplastic crises in chronic hemolytic anemia, chronic anemia in the immunocompromised host and hydrops fetalis. We present two patients with acute arthritis due to parvovirus infection. Both had symmetrical synovitis in wrists and ankles. Patient 1 presented with fever and rash before joint symptoms occurred; patient 2 had joint symptoms only. Arthritis due to parvovirus is usually self-limited, but may develop into a chronic disease similar to rheumatoid arthritis. Parvovirus should be considered one of the differential diagnoses while dealing with acute or chronic arthritis.