Genomic repertoires linked with pathogenic potency of arthritogenic Prevotella copri isolated from the gut of patients with rheumatoid arthritis.

OBJECTIVES: Prevotella copri is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of P. copri in the intestine. This study investigated the pathogenicity of RA patient-derived P. copri (P. copri RA) compared with healthy control-derived P. copri (P. copri HC). METHODS: We obtained 13 P. copri strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of P. copri RA and P. copri HC were compared. To analyse the arthritis-inducing ability of P. copri, we examined two arthritis models (1) a collagen-induced arthritis model harbouring P. copri under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under P. copri-monocolonised conditions. Finally, to evaluate the ability of P. copri to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by P. copri RA and P. copri HC. RESULTS: Comparative genomic analysis revealed no apparent differences in the core gene contents between P. copri RA and P. copri HC, but pangenome analysis revealed the high genome plasticity of P. copri. We identified a P. copri RA-specific genomic region as a conjugative transposon. In both arthritis models, P. copri RA-induced more severe arthritis than P. copri HC. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by P. copri RA. CONCLUSION: Our findings reveal the genetic diversity of P. copri, and the genomic signatures associated with strong arthritis-inducing ability of P. copri RA. Our study contributes towards elucidation of the complex pathogenesis of RA.

Epithelial miR-215 negatively modulates Th17-dominant inflammation by inhibiting CXCL12 production in the small intestine.

MicroRNAs are a class of non-coding short-chained RNAs that control cellular functions by downregulating their target genes. Recent research indicates that microRNAs play a role in the maintenance of gut homeostasis. miR-215 was found to be highly expressed in epithelial cells of the small intestine; however, the involvement of miR-215 in gut immunity remains unknown. Here, we show that miR-215 negatively regulates inflammation in the small intestine by inhibiting CXCL12 production. Mice lacking miR-215 showed high susceptibility to inflammation induced by indomethacin, accompanied by an increased number of Th17 cells in the lamina propria of the small intestine. Our findings provide a rationale for targeting miR-215 as a therapeutic intervention for inflammatory conditions in the small intestine.

TRPM5 Negatively Regulates Calcium-Dependent Responses in Lipopolysaccharide-Stimulated B Lymphocytes.

B cells produce high amounts of cytokines and immunoglobulins in response to lipopolysaccharide (LPS) stimulation. Calcium signaling cascades are critically involved in cytokine production of T cells, and the cytosolic calcium concentration is regulated by calcium-activated monovalent cation channels (CAMs). Calcium signaling is also implicated in B cell activation; however, its involvement in the cytokine production of LPS-stimulated B cells remains less well characterized. Here, we show that the transient receptor potential melastatin 5 channel (TRPM5), which is one of the CAMs, negatively modulates calcium signaling, thereby regulating LPS-induced proliferative and inflammatory responses by B cells. LPS-stimulated B cells of Trpm5-deficient mice exhibit an increased cytosolic calcium concentration, leading to enhanced proliferation and the production of the inflammatory cytokines interleukin-6 and CXCL10. Furthermore, Trpm5-deficient mice show an exacerbation of endotoxic shock with high mortality. Our findings demonstrate the importance of TRPM5-dependent regulatory mechanisms in LPS-induced calcium signaling of splenic B cells.

Relationship of Central Venous Pressure to Body Fluid Volume Status and Its Prognostic Implication in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Although central venous pressure (CVP) is a surrogate measure of preload in patients with acute decompensated heart failure (ADHF), it is a multifactorial index influenced not only by fluid volume status, but also by cardiac pump function and other factors. We aimed to elucidate the individual pathophysiological factors of CVP elevation in patients with ADHF by assessing the relationship between CVP and extracellular fluid volume status (EVS). METHODS AND RESULTS: We quantified EVS in 100 patients with ADHF with the use of bioelectrical impedance analysis. CVP was also measured at the same time point. Subjects were categorized into tertiles according to their CVP-EVS ratios, and patient characteristics and clinical outcomes were compared among these tertiles. The upper-tertile group had a higher incidence of impaired right ventricular pump function, whereas the lower-tertile group had higher incidences of severe inflammation, hypoalbuminemia, and renal dysfunction. Patients in both the upper and lower tertiles had a significantly higher cardiac event rate than those in the middle tertile. CONCLUSIONS: The combined assessment of CVP and EVS provides insight into both the total volume status and distribution of body fluid in ADHF patients, and it may have applications in guiding decongestive therapy and improving prognostic predictions.

Non-Ischemic Heart Failure With Reduced Ejection Fraction Is Associated With Altered Intestinal Microbiota.

BACKGROUND: Research suggests that heart failure with reduced ejection fraction (HFrEF) is a state of systemic inflammation that may be triggered by microbial products passing into the bloodstream through a compromised intestinal barrier. However, whether the intestinal microbiota exhibits dysbiosis in HFrEF patients is largely unknown.Methods and Results:Twenty eight non-ischemic HFrEF patients and 19 healthy controls were assessed by 16S rRNA analysis of bacterial DNA extracted from stool samples. After processing of sequencing data, bacteria were taxonomically classified, diversity indices were used to examine microbial ecology, and relative abundances of common core genera were compared between groups. Furthermore, we predicted gene carriage for bacterial metabolic pathways and inferred microbial interaction networks on multiple taxonomic levels.Bacterial communities of both groups were dominated by the Firmicutes and Bacteroidetes phyla. The most abundant genus in both groups wasBacteroides. Although α diversity did not differ between groups, ordination by ß diversity metrics revealed a separation of the groups across components of variation.StreptococcusandVeillonellawere enriched in the common core microbiota of patients, whileSMB53was depleted. Gene families in amino acid, carbohydrate, vitamin, and xenobiotic metabolism showed significant differences between groups. Interaction networks revealed a higher degree of correlations between bacteria in patients. CONCLUSIONS: Non-ischemic HFrEF patients exhibited multidimensional differences in intestinal microbial communities compared with healthy subjects.

A novel scoring system to predict delirium and its relationship with the clinical course in patients with acute decompensated heart failure.

BACKGROUND: Delirium is known to be a poor prognostic factor in patients with acute decompensated heart failure (ADHF). The purpose of this study was to determine predictors of delirium on admission of ADHF patients, and to establish a scoring formula to identify patients at high risk for delirium. METHODS AND RESULTS: We recorded the Intensive Care Delirium Screening Checklist (ICDSC) score in 120 ADHF patients during their stay in the coronary care unit (CCU). Patients with a highest ICDSC score of 4 or more were diagnosed with delirium. We examined independent candidate predictors of delirium using multivariate logistic regression analysis and developed the following scoring formula, the delirium prediction score (DPS), using independent predictors of delirium and their regression coefficients: DPS=inferior vena cava diameter+C-reactive protein (and additionally +10 for patients with a history of cerebral infarction). Receiver operating curve analysis indicated that evaluation using this scoring system at the time of admission was able to predict delirium with high accuracy (C-statistic: 0.885). In addition, the calculated scores had significantly positive correlations with duration of CCU stay and overall length of hospital stay. CONCLUSIONS: We established a novel scoring system to predict on admission the likelihood of development of delirium in ADHF patients; this system also predicts prolongation of intensive care and hospital stay.

Transtubular Potassium Concentration Gradient as a Surrogate Measure of Arterial Underfilling in Acute Decompensated Heart Failure.

BACKGROUND: The monitoring of tissue hypoperfusion and the subsequent neurohumoral activation (ie, arterial underfilling) during decongestion is important for the management of acute decompensated heart failure (ADHF). The transtubular potassium concentration gradient (TTKG) has been reported to be a marker of renal aldosterone bioactivity. This study tested the hypothesis that TTKG can be a surrogate of arterial underfilling in patients with ADHF. METHODS AND RESULTS: We measured TTKG at discharge in 100 ADHF patients. The primary outcome measure was the occurrence of tissue hypoperfusion events (defined according to the "Cold Modified 2014" definition criteria) within 1 month after discharge. The secondary outcome measure was the occurrence of cardiac death or ADHF readmission within 3 months after discharge. On receiver operating characteristic curve analysis, TTKG predicted tissue hypoperfusion events with high accuracy (C-statistic, 0.889) for a cut-off of 6.0. Multivariate Cox regression analyses demonstrated independent relationships between TTKG and both the primary and secondary outcomes. CONCLUSIONS: TTKG has utility as a surrogate of arterial underfilling, and spot TTKG at discharge may be a prognostic marker in ADHF patients. (Circ J 2016; 80: 1965-1970).

Quantitative Assessment of Fluid Accumulation Using Bioelectrical Impedance Analysis in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Acute decompensated heart failure (ADHF) is generally considered to be a problem of fluid volume overload, therefore accurately quantifying the degree of fluid accumulation is of critical importance in assessing whether adequate decongestion has been achieved. The aim of this study was to develop and validate a method to quantify the degree of fluid accumulation in patients with ADHF. METHODS AND RESULTS: Using multi-frequency bioelectrical impedance analysis (BIA), we measured extracellular water (ECW) volume in 130 ADHF patients on admission and at discharge. We also predicted optimal ECW volume using original equations based on data from 60 control subjects without the signs of HF. Measured/predicted (M/P) ratio of ECW in ADHF patients was observed to decrease from 1.26±0.25 to 1.04±0.17 during hospitalization (P<0.001). The amount of ECW volume reduction was significantly correlated with reduction in body weight (r=0.766, P<0.001). On multivariate analysis, higher M/P ratio of ECW at discharge was associated with increased risk of ADHF readmission or cardiac death within 6 months after discharge. CONCLUSIONS: Multi-frequency BIA-measured ECW was found to offer valuable information for analyzing the pathophysiology of ADHF, and may be a useful guide in the management of this disease.

Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases.

Synaptic activity induces changes in the number of dendritic spines. Here, we report a pathway of regulated endocytosis triggered by arcadlin, a protocadherin induced by electroconvulsive and other excitatory stimuli in hippocampal neurons. The homophilic binding of extracellular arcadlin domains activates TAO2beta, a splice variant of the thousand and one amino acid protein kinase 2, cloned here by virtue of its binding to the arcadlin intracellular domain. TAO2beta is a MAPKKK that activates the MEK3 MAPKK, which phosphorylates the p38 MAPK. Activation of p38 feeds-back on TAO2beta, phosphorylating a key serine required for triggering endocytosis of N-cadherin at the synapse. Arcadlin knockout increases the number of dendritic spines, and the phenotype is rescued by siRNA knockdown of N-cadherin. This pathway of regulated endocytosis of N-cadherin via protocadherin/TAO2beta/MEK3/p38 provides a molecular mechanism for transducing neuronal activity into changes in synaptic morphologies.