Markers Of Bacterial Translocation Research Articles

Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis.

Bacterial translocation-induced inflammation and immune dysfunction are recognised factors contributing to the pathogenesis of primary biliary cholangitis (PBC). However, the specific involvement of interferons (IFNs) and soluble checkpoints (sol-CRs) in shaping the immune landscape in PBC patients remains unexplored. Furthermore, the influence of ursodeoxycholic acid (UDC) on these immune mediators is unknown. Twenty-eight cytokines and 14 sol-CRs were quantified by Luminex assays in plasma samples from 64 PBC patients and 10 healthy controls (HCs). D-lactate was measured as a marker of bacterial translocation. The PBC subgroups were: 24 UDC responders (UDCRs), 18 UDC non-responders (UDCNRs) and 22 patients with end-stage cirrhotic PBC (ESPBC). Soluble herpes virus entry mediator (HVEM) was upregulated in the UDCR subgroup compared to the HC group (p = 0.0404), with increased significance in the ESPBC subgroup (p < 0.0001). There was a progressive increase in several sol-CRs, particularly soluble CD80, LAG3 and CD137 in ESPBC patients. IFN-gamma was higher in the ESPBC subgroup compared to the UDCR subgroup. Elevated IFN-gamma in the UDCNR subgroup compared to UDCR was more significant on excluding patients with cirrhosis (p = 0.0056). Patients with ESPBC expressed several pro-inflammatory cytokines including IL-6, TNF-alpha and CXCL10 compared to the HC group. IFN-lambda-3, but not IFN-lambda-2, was elevated in the ESPBC subgroup compared to all other subgroups. D-lactate levels were equally elevated in all PBC subgroups compared to the HC group. This study provides valuable insights into the immune landscape of PBC, highlighting potential biomarkers and cytokine signatures associated with disease severity and treatment response. Further investigation into the mechanistic roles may pave the way for more targeted therapeutic interventions in PBC management.

Serum Interleukin-6 Levels may be a Key Determinant of 6-week Further Decompensation Risk in Patients With Cirrhosis and Acute Variceal Bleed: A Proof of Concept Study.

Limited data exist on the role of systemic inflammation and gut barrier dysfunction in acute variceal bleed (AVB). We studied inflammatory markers and changes in the intestinal barrier in patients with AVB and assessed if these can be used to identify a higher risk subgroup with regard to outcomes. In this prospective observational study, patients with cirrhosis and AVB presenting at a tertiary care center were stratified by whether or not they developed acute decompensation (AD) over 6 weeks follow-up. Utility of systemic inflammatory markers (interleukin-6 [IL-6], C-reactive protein), endotoxinemia (serum IgM/IgG anti-endotoxin antibodies), and duodenal epithelial tight junction proteins (TJPs) by immunohistochemistry (IHC) for tight-junction proteins (claudin-2,-4, zonula occludens-1(ZO-1), junctional adhesion molecule (JAM)) was assessed to predict the outcomes. These parameters were compared with a pre-existing cohort of patients with cirrhosis and no recent variceal bleed and with those without cirrhosis (dyspepsia with no endoscopic pathology). A nomogram was developed from multivariate model to predict 6-wk AD in patients with AVB. Patients with AVB(n= 66) (age:46.4±11.7 years; etiology: alcohol/NASH/HBV/HCV [48.5%/12.1%/12.1%/7.6%]) were included. Twenty-four (36.3%) patients developed 6-wk AD. Patients with 6-wk AD had higher serum IL-6 (median: 156.14pg/ml [IQR: 136.12-170.52] vs 58.28pg/ml [31.70-110.67]; P < 0.001) and Child score (median: 9 [6.75-10.25] vs 7 [6-9]; P= 0.042) at baseline. Serum endotoxinemia and duodenal epithelial TJP were similar. A nomogram combining CTP and IL-6 was generated that predicted 6-wk AD with optimism-corrected c-statistic of 0.87. Comparison with non-bleeder cirrhosis (n= 52) (7.57 [5.48-9.87]) and dyspepsia controls (n= 53) (5.72 [4.40-6.45]; P < 0.001) also identified significant elevation of serum IL-6, not entirely explainable by derangements in TJP and bacterial translocation markers. 6-wk AD rates in patients with cirrhosis and AVB can be predicted using combination of Child score and serum IL-6.

Progressive systemic inflammation precedes decompensation in compensated cirrhosis

Background & AimsSystemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation. MethodsThis study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n=164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed inflammation markers (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]). ResultsIL-6, CD163, and vWF were higher (p<0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p<0.05) at 1-year in CSPH patients, with a greater rise in those who developed decompensation. CD163 was higher (p<0.01) in patients who decompensated at baseline and 1- and 2-year. FABP was elevated (p<0.01) in CSPH patients compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p<0.01). LPS was higher (p<0.01) in CSPH patients than in those with subclinical PH and controls and increased at 1-year regardless of decompensation development. ConclusionsInflammation and bacterial products are present in the systemic circulation in compensated cirrhosis with CSPH. Progressive inflammation precedes the first decompensation.

Elevated lipopolysaccharide binding protein in Alzheimer's disease patients with APOE3/E3 but not APOE3/E4 genotype.

The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood. In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA. LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS). These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.

Plasma citrulline concentration and plasma LPS detection among critically ill patients a prospective observational study

PurposeGut can be a source of sepsis but sepsis itself can induce gut dysfunction. We aimed to study whether plasma citrulline, a marker of enterocyte mass, was correlated with plasma lipopolysaccharide, a potential marker of bacterial translocation among critically ill patients. Materials and methodsCritically ill patients admitted to the ICU. Plasma citrulline and plasma LPS concentration and activity were measured at ICU admission. Patients were compared according to the presence of sepsis at ICU admission. Results109 critically ill patients, with SOFA score 8 [6–12], were prospectively included. Sixty six patients (61%) had sepsis at ICU admission. There was no correlation between plasma citrulline concentration and plasma LPS concentration or activity. However, sepsis at ICU admission was associated with a lower plasma citrulline concentration (13.4 μmol.L−1 vs 21.3 μmol.L−1, p = 0.02). Plasma LPS activity was significantly higher among patients with abdominal sepsis compared to patients with extra-abdominal sepsis (1.04 EU/mL vs 0.63, p = 0.01). ConclusionsPlasma citrulline is not associated with the level of plasma LPS but is strongly decreased among septic patients. Detection of LPS is ubiquitous among critically ill patients but abdominal sepsis is associated with increased plasma LPS activity compared to extra-abdominal sepsis.

ADAMTS13 and Von Willebrand Factor Levels in Patients with Chronic hepatitis C: Relations to Hemostatic Imbalance and Bacterial Infection

Abstract Background Liver cirrhosis is in close association with bacterial translocation as a result of alteration of intestinal barrier. In response to inflammation, the endothelial cells release the content of WPBs, VWF in the extracellular portion. The aim of the study was to assess the levels of ADAMTS13 and their impact on the prothrombotic function of VWF in patients with chronic hepatitis C with or without SBP. Patients and methods 75 individuals were the study population, 60 patients with CLD classified into: Child A (n = 15), Child B (n = 15) and Child C (n = 30) the latter is further classified into Child C (n = 15) and Child C patients with SBP (n = 15); healthy controls (n = 15). This study was performed at Theodor Bilharz Research Institute (TBRI), Imbaba, Giza. Determination of CRP by fixed time nephelometry. Determination of LBP, VWF, ADAMTS13 and D-dimer by magnetic multiplexed flowcytometry based immunoassay Luminex®. Results VWF levels were significantly increased (p &amp;lt; 0.01) in different groups of patients with CLD compared to controls. A similar significant increase (p &amp;lt; 0.01) was also noticed in Child C patients with SBP compared to other study groups. ADAMTS13 antigen levels were significantly decreased (p &amp;lt; 0.01) in different groups of patients with CLD compared to controls. D-dimer levels were significantly increased (p &amp;lt; 0.01) in different groups of patients with CLD compared to controls. Conclusion The levels of VWF correlated with the systemic inflammatory and bacterial translocation markers. ADAMTS13 levels were decreased in cases of systemic inflammatory process that accompanies SBP, leading to increased VWF levels.

Disrupted epithelial permeability as a predictor of severe COVID-19 development.

An impaired epithelial barrier integrity in the gastrointestinal tract is important to the pathogenesis of many inflammatory diseases. Accordingly, we assessed the potential of biomarkers of epithelial barrier dysfunction as predictive of severe COVID-19. Levels of bacterial DNA and zonulin family peptides (ZFP) as markers of bacterial translocation and intestinal permeability and a total of 180 immune and inflammatory proteins were analyzed from the sera of 328 COVID-19 patients and 49 healthy controls. Significantly high levels of circulating bacterial DNA were detected in severe COVID-19 cases. In mild COVID-19 cases, serum bacterial DNA levels were significantly lower than in healthy controls suggesting epithelial barrier tightness as a predictor of a mild disease course. COVID-19 patients were characterized by significantly elevated levels of circulating ZFP. We identified 36 proteins as potential early biomarkers of COVID-19, and six of them (AREG, AXIN1, CLEC4C, CXCL10, CXCL11, and TRANCE) correlated strongly with bacterial translocation and can be used to predict and discriminate severe cases from healthy controls and mild cases (area under the curve (AUC): 1 and 0.88, respectively). Proteomic analysis of the serum of 21 patients with moderate disease at admission which progressed to severe disease revealed 10 proteins associated with disease progression and mortality (AUC: 0.88), including CLEC7A, EIF4EBP1, TRANCE, CXCL10, HGF, KRT19, LAMP3, CKAP4, CXADR, and ITGB6. Our results demonstrate that biomarkers of intact or defective epithelial barriers are associated with disease severity and can provide early information on the prediction at the time of hospital admission.

Bacterial translocation markers and toll-like receptors in biliary atresia following successful portoenterostomy.

The gut-liver axis may contribute to pathophysiology of cholestatic liver disorders like biliary atresia (BA) by bacterial translocation (BT). Toll-like receptors (TLR) are pattern recognition receptors known to activate innate immunity and secretion of inflammatory cytokines. Herein, we examined BT-associated biomarkers and TLRs in relation to liver injury after successful portoenterostomy (SPE) in BA. Serum levels of lipopolysaccharide-binding protein (LBP), CD14, LAL, TNF-α, IL-6 and FABP2 along with liver expression of TLRs (TLR1, TLR4, TLR7 and TLR9), LBP and CD14 were measured during median 4.9 (1.7-10.6) years follow-up after SPE in 45 BA patients. Serum LBP, CD14, TNF-α and IL-6 all increased after SPE whereas LAL and FABP-2 remained unchanged. Serum LBP correlated positively with CD14 and markers of hepatocyte injury and cholestasis, but not with Metavir fibrosis stage, transcriptional markers for fibrosis (ACTA2) or ductular reaction. Serum CD14 concentration was significantly higher in patients with portal hypertension than without. While liver expression of TLR4 and LBP remained low, TLR7 and TLR1 showed marked BA-specific increases, and TLR7 correlated with Metavir fibrosis stage and ACTA2. BT does not seem to play a significant role in liver injury after SPE in our series of BA patients.

THU-307 - Longitudinal assessment of plasma immune and bacterial translocation markers in biliary atresia

THU-307 - Longitudinal assessment of plasma immune and bacterial translocation markers in biliary atresia

Association between gut permeability, brain volume, and cognition in healthy participants and patients with schizophrenia spectrum disorder.

The barrier function of the gut is important for many organs and systems, including the brain. If gut permeability increases, bacterial fragments may enter the circulation, giving rise to increased systemic inflammation. Increases in bacterial translocation are reflected in higher values of blood markers, including lipopolysaccharide binding protein (LBP) and soluble cluster of differentiation 14 (sCD14). Some pioneer studies showed a negative association between bacterial translocation markers and brain volumes, but this association remains scarcely investigated. We investigate the effect of bacterial translocation on brain volumes and cognition in both healthy controls and patients with a schizophrenia spectrum disorder (SSD). Healthy controls (n=39) and SSD patients (n=72) underwent an MRI-scan, venipuncture and cognition assessments. We investigated associations between LBP and sCD14 and brain volumes (intracranial volume, total brain volume, and hippocampal volume) using linear regression. We then associated LBP and sCD14 to cognitive function using a mediation analysis, with intracranial volume as mediator. Healthy controls showed a negative association between hippocampal volume and LBP (b=-0.11, p=.04), and intracranial volume and sCD14 (b=-0.25, p=.07). Both markers were indirectly associated with lower cognitive functioning in healthy controls (LBP: b=-0.071, p=.028; sCD14: b=-0.213, p=.052), mediated by low intracranial volume. In the SSD patients, these associations were markedly less present. These findings extend earlier studies suggesting that increased bacterial translocation may negatively affect brain volume, which indirectly impacts cognition, even in this young healthy group. If replicated, this finding stresses the importance of a healthy gut for the development and optimal functioning of the brain. Absence of these associations in the SSD group may indicate that other factors such as allostatic load, chronic medication use and interrupted educational carrier had larger impact and attenuated the relative contribution of bacterial translocation.

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial

Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P=0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Wellcome Trust and Department of Health and Social Care.

Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response

BackgroundExperimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD).MethodsPatients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement and absence of acute decompensation or infections were included (n = 249). Serum biomarkers of BT (lipopolysaccharide [LPS], lipoteichoic acid [LTA], bacterial DNA [bactDNA]), systemic inflammation and markers of circulatory dysfunction were assessed. T-cell subsets in intestinal biopsies (n = 7 ACLD, n = 4 controls) were analyzed by flow cytometry.ResultsPatients had a median HVPG of 18 (12–21) mmHg and 56% had decompensated ACLD. LPS (0.04 [0.02–0.06] vs. 0.64 [0.30–1.06] EU/mL), LTA (4.53 [3.58–5.97] vs. 43.2 [23.2–109] pg/mL), and detection of bactDNA (≥ 5 pg/mL; 5% vs. 41%) were markedly higher in patients with ACLD than healthy controls (n = 40; p < 0.001) but were similar between different clinical stages of compensated and decompensated ACLD and displayed no meaningful correlation with HVPG and systemic hemodynamics. TNF-α and IL-10 correlated with LPS (Spearman’s rs = 0.523, p < 0.001/rs = 0.143, p = 0.024) but not with LTA. Presence of bactDNA was associated with higher LPS (0.54 [0.28–0.95] vs. 0.88 [0.32–1.31] EU/mL, p = 0.001) and TNF-α (15.3 [6.31–28.1] vs. 20.9 [13.8–32.9] pg/mL). Patients with ACLD exhibited a decreased CD4:CD8-ratio and increased TH1-cells in the intestinal mucosa as compared to controls. During a median FU of 14.7 (8.20–26.5) months, bacterial antigens did not predict decompensation or liver-related death (in contrast to HVPG, IL-6, and MAP) as well as infections at 24 months.ConclusionBT occurs already in early ACLD stages and triggers a systemic inflammatory response via TNF-α and IL-10. Interestingly, BT markers showed no clear correlation with portal hypertension and circulatory dysfunction in patients with stable ACLD.Clinical trial numberNCT03267615.

Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial.

Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3-15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p=0.006), lower white cell counts throughout hospital stay (p<0.001) and reduced plasma procalcitonin (p=0.009) and interlukin-8 levels (p=0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. Wellcome Trust and Department of Health and Social Care.

The influence of bacterial translocation and systemic inflammation on the nutrition, skeletal muscles, and survival of patients with liver cirrhosis

Annotation. Malnutrition and sarcopenia are common prognosis-modifying complications of liver cirrhosis (LC). Bacterial translocation and systemic inflammation may be involved in the development of nutritional and muscle insufficiency in LC. The aim of the study was to assess the relationship between serum markers of bacterial translocation and systemic inflammation with nutrition, skeletal muscle, and survival in patients with decompensated LC. 74 patients (age 55.3±11.4 years) were included in the study. Nutritional status was assessed using the Patient-Generated Subjective Global Assessment (PG-SGA). Skeletal muscle mass was assessed using the Skeletal Muscle Index (SMI), and muscle strength was assessed by handgrip strength. The level of lipopolysaccharide-binding protein (LBP), interleukin-6 (Interleukin-6, IL-6), and C-reactive protein (C Reactive Protein, CRP) in blood serum was determined by enzyme immunoassay (ELISA). Statistical data processing was performed in SPSS22. It was found that serum LBP, IL-6, and CRP levels moderately correlated with PG-SGA (r= 0.549, 0.434, and 0.453, respectively, p˂0.005), SMI (r= -0.517, -0.518, and -0.468, respectively, p˂0.005), and handgrip strength (r= -0.338, -0.427, and -0.423, respectively, p˂0.005), and predicted severe malnutrition (AUC (LBP) = 0.746; AUC (IL-6) = 0.672; AUC (CRP) = 0.745, p˂0.05) and sarcopenia (AUC (LBP) = 0.861; AUC (IL-6) = 0.789; AUC (CRP) = 0.744, p˂0.01). 42 patients died from LC complications during the follow-up (Me 367 (82-569) days). In the Kaplan-Meier analysis, the mortality of patients with high levels of LBP (more than 33.4 pg/ml), IL-6 (more than 7.68 pg/ml), and CRP (more than 5.52 mg/l) were significantly higher than that of patients with conditionally low levels. Further studies are needed to determine whether correction of bacterial translocation and systemic inflammation can improve nutritional, skeletal muscle status, and survival in patients with decompensated LC.

Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Evaluation of the definition of hyperdynamic circulation in patients with cirrhosis and ascites.

The aim of this study was to evaluate potential criteria for defining hyperdynamic circulation in patients with cirrhosis according to the severity of ascites and its association with the activation of vasoactive systems and markers of systemic inflammation. Cross-sectional studyof patients with cirrhosis and right heart catheter measurement from two different academic centers. We evaluated systemic vascular resistance (SVR)/cardiac output (CO) according to ascites severity. The first substudy evaluated the possible definition, the second validated the findings, and the third evaluated the possible mechanisms. Comparisons were performed by means of t test, Mann-Whitney U test, and analysis of variance. Finally, linear regression curves were adjusted to evaluate the relationship between CO and SVR according to the severity of ascites and compensated or decompensated stage of cirrhosis. The study included 721 patients (substudy 1, n=437; substudy 2, n=197; substudy 3, n=87). Hyperdynamic circulation (HC), defined by absolute cutoffs, had no association with the presence or severity of ascites in the first two cohorts. No association was observed between HC with renin, aldosterone, or markers of bacterial translocation. Comparison of linear regression curves showed a shift of the CO-SVR relationship to the left in patients with refractory ascites (p < 0.001) compared to patients without ascites as well as to patients with decompensated cirrhosis (p=0.002). Conclusion: HC according to the traditional concept of high CO and low SVR is not always present in ascites. Evaluation of the CO-SVR relationship according to the severity of ascites shows a shift to the left, suggesting that the presence of HC would be defined by this shift, independent of absolute values.

Circulating (1 → 3)-β-D-Glucan as an immune activation marker decreased after ART in people living with HIV.

BackgroundPlasma level of polysaccharide (1 → 3)-β-D-Glucan (βDG), as a diagnostic marker of invasive fungal infection has been reported to be elevated in people living with HIV (PLWH). We assessed the association of circulating βDG to inflammation and systemic immune activation and the effect of antiretroviral therapy (ART) on βDG in PLWH.MethodPlasma and peripheral blood monocular cell samples from 120 PLWH naive to ART and after 1 year's ART were collected. Plasma levels of βDG, markers of bacterial translocation, gut damage, and cellular immune activation were quantified.ResultThe plasma βDG levels were negatively correlated with CD4+ T cells count (r = −0.25, p = 0.005) and positively with HIV viral load (r = 0.28, p = 0.002) before ART. It was also positively correlated with immune activation markers, including PD-1 expression on CD4+ T cell (r = 0.40, p = 0.01) and CD8+ T cell (r = 0.47, p = 0.002), as well as HLADR+CD38+ co-expression on CD8+ T cell (r = 0.56, p = 0.0002), but not with the plasma levels of LPS (r = 0.02, p = 0.84), LPS binding protein (LBP, r = 0.11, p = 0.36), soluble LPS receptor sCD14 (r = 0.04, p = 0.68), intestinal fatty acid binding protein (IFABP, r = −0.12, p = 0.18), and regenerating islet-derived protein 3α (REG3α, r = 0.18, p = 0.06). After 1 year's ART, the levels of βDG were significantly decreased compared to that in pre-ART (1.31 ± 0.24 Log10 pg/ml vs. 1.39 ± 0.18 Log10 pg/ml, p < 0.001).ConclusionThe level of plasma βDG was associated with cellular immune activation and decreased after ART in PLWH, suggesting it could serve as a biomarker of immune activation and efficacy monitoring.

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling.

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation — measured as β-glucan, a fungal cell wall polysaccharide — in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2–negative controls. The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Integrase Inhibitors Partially Restore Bacterial Translocation, Inflammation and Gut Permeability Induced by HIV Infection: Impact on Gut Microbiota.

IntroductionHuman immunodeficiency virus (HIV) infection can be considered a chronic disease thanks to the extended use of antiretroviral treatment (ART). In this context, low-grade chronic inflammation related to gut microbiota (GM) dysbiosis and bacterial translocation (BT) among other factors has been observed despite the use of ART. In addition, different ART regimens have demonstrated differential impacts on GM. However, the role of novel integrase strand transfer inhibitors (INSTIs) has not been investigated yet. The aim of this study was to analyse the effects of INSTIs in first-line of treatment on markers of BT, inflammation, cardiovascular risk, gut permeability and GM composition and derived short-chain fatty acids.MethodsTwenty-six non-HIV-infected volunteers and 30 HIV-infected patients (15 naïve and 15 under INSTIs regimen) were recruited. Blood samples were extracted to analyse biochemical parameters and markers of BT, inflammation, cardiovascular risk, gut permeability and bacterial metabolism. GM composition was analysed using 16S rRNA gene sequencing.ResultsOur results showed that HIV infection increased BT, inflammation, cardiovascular risk and gut permeability, whereas INSTIs counteracted these effects. Regarding GM, the reduction in bacterial richness induced by HIV infection was restored by INSTIs. Beta diversity revealed that HIV-infected people were separated from the control group independently of treatment.ConclusionsCurrent antiretroviral regimens based on INSTIs are able to reverse the impact of HIV infection on BT, systemic inflammation, gut permeability and bacterial diversity/richness, reaching similar levels to those observed in an uninfected/control population. These results suggest a protective role of INSTIs in disease progression, subsequent immune activation and in the development of future age-related complications such as cardiovascular events.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00654-4.

Determinants of Leaky Gut and Gut Microbiota Differences in Children With Autism Spectrum Disorder and Their Siblings.

Leaky gut hypothesis is one of the well-known theory which tries to explain etiology of Autism Spectrum Disorder (ASD). Unfortunately there is still a gap of evidence to investigate the corner points of the hypothesis. The aim of this study was to investigate the determinants of leaky gut in children with ASD, their siblings and healthy controls. Intestinal microbiota was found to be similar between ASD and sibling groups. Biological markers of bacterial translocation showed a significant difference in the sibling group, whereas the marker indicating local inflammation was not different between the groups. The findings from this study did not support the role of Gut microbiota or leaky gut on the etiology of autism.