Plasma Lipopolysaccharide Levels Research Articles

Enhanced Antioxidative Capacity Transfer between Sow and Fetus via the Gut-Placenta Axis with Dietary Selenium Yeast and Glycerol Monolaurate Supplementation during Pregnancy.

This study aims to investigate the impact of dietary supplementation with selenium yeast (SeY) and glycerol monolaurate (GML) on the transfer of antioxidative capacity between the mother and fetus during pregnancy and its underlying mechanisms. A total of 160 sows with similar body weight and parity of 3-6 parity sows were randomly and uniformly allocated to four groups (n = 40) as follows: CON group, SeY group, GML group, and SG (SeY + GML) group. Animal feeding started from the 85th day of gestation and continued to the day of delivery. The supplementation of SeY and GML resulted in increased placental weight and reduced lipopolysaccharide (LPS) levels in sow plasma, placental tissues, and piglet plasma. Furthermore, the redox balance and inflammatory markers exhibited significant improvements in the plasma of sows fed with either SeY or GML, as well as in their offspring. Moreover, the addition of SeY and GML activated the Nrf2 signaling pathway, while downregulating the expression of pro-inflammatory genes and proteins associated with inflammatory pathways (MAPK and NF-κB). Vascular angiogenesis and nutrient transportation (amino acids, fatty acids, and glucose) were upregulated, whereas apoptosis signaling pathways within the placenta were downregulated with the supplementation of SeY and GML. The integrity of the intestinal and placental barriers significantly improved, as indicated by the increased expression of ZO-1, occludin, and claudin-1, along with reduced levels of DLA and DAO with dietary treatment. Moreover, supplementation of SeY and GML increased the abundance of Christensenellaceae_R-7_group, Clostridium_sensus_stricto_1, and Bacteroidota, while decreasing levels of gut microbiota metabolites LPS and trimethylamine N-oxide. Correlation analysis demonstrated a significant negative relationship between plasma LPS levels and placental weight, oxidative stress, and inflammation. In summary, dietary supplementation of SeY and GML enhanced the transfer of antioxidative capacity between maternal-fetal during pregnancy via gut-placenta axis through modulating sow microbiota composition.

Brain abscess – A rare confounding factor for diagnosis of post-traumatic epilepsy after lateral fluid-percussion injury

ObjectiveTo assess the prevalence of brain abscesses as a confounding factor for the diagnosis of post-traumatic epilepsy (PTE) in a rat model of lateral fluid-percussion-induced (FPI) traumatic brain injury (TBI). MethodsThis retrospective study included 583 rats from 3 study cohorts collected over 2009–2022 in a single laboratory. The rats had undergone sham-operation or TBI using lateral FPI. Rats were implanted with epidural and/or intracerebral electrodes for electroencephalogram recordings. Brains were processed for histology to screen for abscess(es). In abscess cases, (a) unfolded cortical maps were constructed to assess the cortical location and area of the abscess, (b) the abscess tissue was Gram stained to determine the presence of gram-positive and gram-negative bacteria, and (c) immunostaining was performed to detect infiltrating neutrophils, T-lymphocytes, and glial cells as tissue biomarkers of inflammation. In vivo and/or ex vivo magnetic resonance images available from a subcohort of animals were reviewed to evaluate the presence of abscesses. Plasma samples available from a subcohort of rats were used for enzyme-linked immunosorbent assays to determine the levels of lipopolysaccharide (LPS) as a circulating biomarker for gram-negative bacteria. ResultsBrain abscesses were detected in 2.6% (15/583) of the rats (6 sham, 9 TBI). In histology, brain abscesses were characterized as vascularized encapsulated lesions filled with neutrophils and surrounded by microglia/macrophages and astrocytes. The abscesses were mainly located under the screw electrodes, support screws, or craniectomy. Epilepsy was diagnosed in 60% (9/15) of rats with an abscess (4 sham, 5 TBI). Of these, 67% (6/9) had seizure clusters. The average seizure frequency in abscess cases was 0.436 ± 0.281 seizures/d. Plasma LPS levels were comparable between rats with and without abscesses (p > 0.05). SignificanceAlthough rare, a brain abscess is a potential confounding factor for epilepsy diagnosis in animal models of structural epilepsies following brain surgery and electrode implantation, particularly if seizures occur in sham-operated experimental controls and/or in clusters.

Low-grade endotoxemia and risk of recurrent thrombosis in primary antiphospholipid syndrome. The multicenter ATHERO-APS study

IntroductionLow-grade endotoxemia is associated with systemic inflammation, enhanced oxidative stress and cardiovascular events in different clinical settings, but its possible role as “second hit” in patients with primary antiphospholipid syndrome (PAPS) has never been investigated. PurposeTo evaluate the relationship between plasma lipopolysaccharide (LPS) levels, oxidative stress markers and risk of thrombosis in the prospective multicenter ATHERO-APS study. MethodsBaseline LPS, soluble NADPH-oxidase 2-derived peptide (sNOX-dp), H2O2 production, hydrogen peroxide breakdown activity (HBA), and nitric oxide (NO) bioavailability were compared in 97 PAPS, 16 non-thrombotic aPL carriers and 21 controls (CTRL) matched for age and sex. Correlations among laboratory variables were explored by Rho Spearman's correlation (rS). Cox-regression analysis was performed to assess the association between LPS and risk for a composite outcome of cardiovascular death, venous and arterial thromboembolism. ResultsIn the whole cohort (median age 51 years (IQR 43–60), 72 % female), PAPS demonstrated higher levels of LPS, sNOX-dp and H2O2 and lower levels of NO and HBA compared to non-thrombotic aPL carriers and CTRL. LPS levels were inversely correlated with HBA (rS: −0.295, p = 0.001) and NO (rS: −0.322, p < 0.001) and directly correlated with sNOX-dp (rS:0.469, p < 0.001) and H202 (rS:0.282, p < 0.001). PAPS showed higher levels of LPS, sNOX-dp and H2O2 and lower levels of NO and HBA compared to aPL carriers and CTRL. After a 4.7 years follow-up of, 11 composite outcomes were reported in PAPS (2.5 per 100 patient-years) while none was observed in aPL carriers. On Cox-regression analysis, patients with LPS above the median (>23.1 pg/ml) had a 5-fold increased risk of composite outcome compared to those with LPS below the median, after adjustment for sex, age, diabetes, and global antiphospholipid syndrome score. ConclusionLow-grade endotoxemia is associated with an increased oxidative stress and a higher risk of thrombosis in PAPS. Its prognostic value in carriers needs to be investigated in larger cohorts.

Red Rice Seed Coat Targeting SPHK2 Ameliorated Alcoholic Liver Disease via Restored Intestinal Barrier and Improved Gut Microbiota in Mice.

Alcoholic liver disease (ALD), leading to the most common chronic liver diseases, is increasingly emerging as a global health problem, which is intensifying the need to develop novel treatments. Herein, our work aimed to estimate the therapeutic efficacy of red rice (Oryza sativa L.) seed coat on ALD and further uncover the underlying mechanisms. Red rice seed coat extract (RRA) was obtained with citric acid-ethanol and analyzed via a widely targeted components approach. The potential targets of RRA to ALD were predicted by bioinformatics analysis. Drunken behavior, histopathological examination, liver function, gut microbiota composition and intestinal barrier integrity were used to assess the effects of RRA (RRAH, 600 mg/kg·body weight; RRAL, 200 mg/kg·body weight) on ALD. Oxidative stress, inflammation, apoptosis associated factors and signaling pathways were measured by corresponding kits, Western blot and immunofluorescence staining. In ALD model mice, RRA treatment increased sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate (S1P) levels, improved gut microbiota composition, restored intestinal barrier, decreased lipopolysaccharide (LPS) levels in plasma and the liver, cut down Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-κB) pathways, alleviated liver pathological injury and oxidative stress, attenuated inflammation and apoptosis and enhanced liver function. To sum up, RRA targeting SPHK2 can ameliorate ALD by repairing intestinal barrier damage and reducing liver LPS level via the TLR4/NF-κB pathway and intestinal microbiota, revealing that red rice seed coat holds potential as a functional food for the prevention and treatment of ALD.

Hemorrhagic transformation in patients with large-artery atherosclerotic stroke is associated with the gut microbiota and lipopolysaccharide.

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00032/figure1/v/2023-11-20T171125Z/r/image-tiff Hemorrhagic transformation is a major complication of large-artery atherosclerotic stroke (a major ischemic stroke subtype) that worsens outcomes and increases mortality. Disruption of the gut microbiota is an important feature of stroke, and some specific bacteria and bacterial metabolites may contribute to hemorrhagic transformation pathogenesis. We aimed to investigate the relationship between the gut microbiota and hemorrhagic transformation in large-artery atherosclerotic stroke. An observational retrospective study was conducted. From May 2020 to September 2021, blood and fecal samples were obtained upon admission from 32 patients with first-ever acute ischemic stroke and not undergoing intravenous thrombolysis or endovascular thrombectomy, as well as 16 healthy controls. Patients with stroke who developed hemorrhagic transformation (n = 15) were compared to those who did not develop hemorrhagic transformation (n = 17) and with healthy controls. The gut microbiota was assessed through 16S ribosomal ribonucleic acid sequencing. We also examined key components of the lipopolysaccharide pathway: lipopolysaccharide, lipopolysaccharide-binding protein, and soluble CD14. We observed that bacterial diversity was decreased in both the hemorrhagic transformation and non-hemorrhagic transformation group compared with the healthy controls. The patients with ischemic stroke who developed hemorrhagic transformation exhibited altered gut microbiota composition, in particular an increase in the relative abundance and diversity of members belonging to the Enterobacteriaceae family. Plasma lipopolysaccharide and lipopolysaccharide-binding protein levels were higher in the hemorrhagic transformation group compared with the non-hemorrhagic transformation group. lipopolysaccharide, lipopolysaccharide-binding protein, and soluble CD14 concentrations were associated with increased abundance of Enterobacteriaceae. Next, the role of the gut microbiota in hemorrhagic transformation was evaluated using an experimental stroke rat model. In this model, transplantation of the gut microbiota from hemorrhagic transformation rats into the recipient rats triggered higher plasma levels of lipopolysaccharide, lipopolysaccharide-binding protein, and soluble CD14. Taken together, our findings demonstrate a noticeable change in the gut microbiota and lipopolysaccharide-related inflammatory response in stroke patients with hemorrhagic transformation. This suggests that maintaining a balanced gut microbiota may be an important factor in preventing hemorrhagic transformation after stroke.

Treatment with Ligilactobacillus murinus lowers blood pressure and intestinal permeability in spontaneously hypertensive rats

One feature of hypertension is a microbial imbalance with increased intestinal permeability. In this study, we examined whether an alteration in the microbiota affects blood pressure and intestinal permeability in spontaneously hypertensive rats (SHRs). We performed a 16S metagenome analysis of feces from 10- to 15-week-old SHRs using a synthetic long-read sequencing approach, and found a candidate for the microbiome treatment, Ligilactobacillus murinus (L. murinus), that was robustly decreased. Oral administration of L. murinus to SHRs for 2 weeks significantly inhibited blood pressure elevation and improved endothelium-dependent vasodilation but did not attenuate enhanced vascular contraction in SHR mesenteric arteries. The proximal colon of SHRs exhibited increased intestinal permeability with decreased levels of the tight junction protein claudin 4, morphological changes such as decreased intestinal crypts and elevated TNF-α levels, which was reversed by treatment with L. murinus. Consistent with these intestinal phenotypes, plasma lipopolysaccharides levels were elevated in SHR but decreased following L. murinus administration. We concluded that oral administration of L. murinus to SHRs exerts protective effects on intestinal permeability via restoration of claudin 4 expression and reversal of morphologic disorder, which may improve low-grade endotoxemia and thus reduce development of hypertension via recovery of endothelial vasodilating functions.

Design of Antioxidant Nanoparticle, which Selectively Locates and Scavenges Reactive Oxygen Species in the Gastrointestinal Tract, Increasing The Running Time of Mice.

Excess reactive oxygen species (ROS) produced during strong or unfamiliar exercise cause exercise-induced gastrointestinal syndrome (EIGS), leading to poor health and decreased exercise performance. The application of conventional antioxidants can neither ameliorate EIGS nor improve exercise performance because of their rapid elimination and severe side effects on the mitochondria. Hence, a self-assembling nanoparticle-type antioxidant (RNPO ) that is selectively located in the gastrointestinal (GI) tract for an extended time after oral administration is developed. Interestingly, orally administered RNPO significantly enhances the running time until exhaustion in mice with increasing dosage, whereas conventional antioxidants (TEMPOL) tends to reduce the running time with increasing dosage. The running (control) and TEMPOL groups show severe damage in the GI tract and increased plasma lipopolysaccharide (LPS) levels after 80 min of running, resulting in fewer red blood cells (RBCs) and severe damage to the skeletal muscles and liver. However, the RNPO group is protected against GI tract damage and elevation of plasma LPS levels, similar to the nonrunning (sedentary) group, which prevents damage to the whole body, unlike in the control and TEMPOL groups. Based on these results, it is concluded that continuous scavenging of excessive intestinal ROS protects against gut damage and further improves exercise performance.

Anthocyanin-Rich Butterfly Pea Flower Extract Ameliorating Low-Grade Inflammation in a High-Fat-Diet and Lipopolysaccharide-Induced Mouse Model.

This study aimed to explore the enhancive effects of butterfly pea flower (BF) extracts on metabolic and immune homeostasis in a low-grade inflammation mouse model. The BF extract was found to contain mainly anthocyanins among other flavonoids. BF supplementation alleviated metabolic endotoxemia by lowering the plasma glucose, lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α) levels and restored lipid metabolism and the balance between Treg and Th17 cells, thereby inhibiting the dysfunctional liver and abdominal white adipose tissues. BF extract increased the tight junction protein expression and reduced the expression of proinflammatory cytokines, therefore sustaining the colonic mucosa structure. Furthermore, BF extracts reshaped the gut microbiota structure characterized by significantly promoted SCFA-producing gut microbiota such as Akkermansia and Butyricicoccaceae. Additionally, BF extracts enhanced fecal primary bile acid (BA) levels and modulated bile acid signaling in the liver and ileum to facilitate BA synthesis for the restoration of lipid metabolism. In summary, anthocyanin-enriched BF extracts alleviated the profound negative dietary alterations and helped maintain the metabolic health by modulating the various aspects of the gut microenvironment and enhancing hepatic bile acid synthesis.

Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice.

Two independent experiments were performed with three groups each (sepsis control, sepsis, and sepsis with apoE23 treatment) to investigate the anti-inflammatory effect of apolipoprotein 23 (apoE23) in a mouse model of sepsis induced by S. typhimurium. Survival rates; plasma level variations in tumor necrosis factor (TNF)-α, interleukin (IL)-6, and lipopolysaccharide (LPS); S. typhimurium colony-forming units in the spleen tissue; and mRNA and protein expression levels of low-density lipoprotein receptor (LDLR), LDLR-related protein (LRP), syndecan-1, and scavenger receptor B1 were evaluated in the livers of mice from the three groups. Results found that the survival rate of septic mice treated with apoE23 was 100% within 48 h, while it was only 40% in septic mice without apoE23 treatment (P < 0.001). The plasma LPS, TNF-α, and IL-6 levels and the S. typhimurium load in mice in the apoE23-treated group were significantly lower than those in septic mice (P < 0.05). Moreover, apoE23 restored the downregulated expression of LDLR and LRP in the liver tissue of septic mice. So apoE23 exhibits an anti-inflammatory effect in the mouse model of S. typhimurium-induced sepsis. Further studies are required to understand the mechanisms underlying the anti-inflammatory effects of apoE23.

Plasma lipopolysaccharide elevations in cattle associated with early-stage infection by Fasciola hepatica.

Fasciolosis is an endemic zoonotic parasitic disease with significant impacts on human health and both animal health and production. Early post-infection impacts on the host remain unclear. The objective of this study was to determine the changes, if any, to levels of endotoxin in cattle plasma in response to early-stage infection with Fasciola hepatica. Thirty-six (36) commercial bred cattle were experimentally infected with approximately 400 viable metacercariae. Plasma lipopolysaccharide (endotoxin) levels were examined on 24 occasions from 0 h before infection to 336 h after infection using the Limulus Amoebocyte Lysate chromogenic end point assay and compared with that of six (6) uninfected control animals. Peak lipopolysaccharide levels in infected animals were reached at 52 h after infection and returned to pre-infection levels at time 144 h after infection. Infected animals had significantly elevated lipopolysaccharide levels between 24 and 120 h after infection when compared to uninfected animals. The mean change in endotoxin units (EU)/mL over time after infection was statistically significant in infected animals. Elevations of lipopolysaccharide occurred in all infected animals suggesting a possible repeatable and titratable endotoxemia conducive to therapeutic agent model development.

In HIV-infected patients, intestinal bacteria-derived products interfere with CD4&lt;sup&gt;+&lt;/sup&gt;T cell regeneration

Despite successful suppression of viral replication by antiretroviral drugs there is no significant increase in the number of peripheral CD4+T lymphocytes in some HIV-infected patients (immune nonresponse to therapy). One of the crucial factors for immunodeficiency aggravation is immune activation developing in response to the bacterial products entry into the bloodstream through the damaged intestinal barrier. Additionally, the intestinal microflora produces various solutes that accumulate in the blood and exhibit toxic properties. This work aimed to evaluate the effect of intestinal microbial products (para-cresol sulfate and indoxyl sulfate) on the number of CD4+T lymphocytes in HIV-infected patients receiving antiretroviral therapy. The object of the study was the peripheral blood of HIV-infected subjects with different immune system restoration efficiency during the therapy. Uninfected donors were enrolled as healthy controls. Plasma concentrations of IL-6 (p = 0.012), IP-10 (p = 0.0004), and sCD14 (p = 0.003) in HIV-infected immune nonresponders were increased compared with those in individuals with effective restoration of CD4+Tcells (immune responders). Although both groups of HIV-positive subjects did not differ in plasma lipopolysaccharide and I-FABP levels, para-cresol sulfate (p = 0.001) and indoxyl sulfate (p = 0.042) concentrations were increased in immune non-responders. In vitro experiments showed a negative dose-dependent effect of para-cresol sulfate and indoxyl sulfate on the viability and mitotic activity of CD4+T lymphocytes. Thus, in HIV-infected patients with impaired regeneration of CD4+T lymphocytes during antiretroviral therapy, a higher level of systemic inflammation is noted than in subjects responding to treatment with an increase in the number of CD4+T cells. The severity of the intestinal barrier damage and the load of bacterial components released into the bloodstream are approximately the same in HIV-infected individuals with different efficiency of immune recovery in response to treatment. Simultaneously, the blood plasma of immune non-responders is significantly enriched with microbial products of intestinal origin: para-cresol sulfate and indoxyl sulfate. The significant decrease in the proliferative capacity of CD4+T cells stimulated in vitro and the induction of their death in the presence of these toxins may be a reason for the ineffective restoration of the number of CD4+T lymphocytes in HIV-infected individuals receiving antiretroviral therapy.

Influence of Intestinal Barrier on Alleviating an Increase in Blood Pressure by Sodium Alginate Intake in 2-Kidney, 1-Clip Renovascular Hypertensive Rats.

Sodium alginate (SALG) is a substance derived from brown seaweed that has been shown to reduce blood pressure (BP). However, its effects on renovascular hypertension caused by 2-kidney, 1-clip (2K1C) are not yet clear. Previous research suggests that hypertensive rats have increased intestinal permeability, and that SALG improves the gut barrier in inflammatory bowel disease mouse models. Therefore, the goal of this study was to determine whether the antihypertensive effects of SALG involve the intestinal barrier in 2K1C rats. Rats were fed either a 1.0% SALG diet or a control diet for six weeks after being subjected to 2K1C surgery or a sham operation. The systolic BP was measured weekly, and the mean arterial BP was measured at the end of the study. Intestinal samples were taken for analysis, and plasma lipopolysaccharide (LPS) levels were measured. The results showed that BP in 2K1C rats was significantly higher than in SHAM rats when fed CTL, but not when fed SALG. The gut barrier in 2K1C rats was improved by SALG intake. Plasma LPS levels also differed depending on the animal model and diet. In conclusion, dietary SALG may alleviate 2K1C renovascular hypertension by altering the gut barrier.

Assessment of Intestinal Permeability and Inflammation Bio-Markers in Patients with Rheumatoid Arthritis.

Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers.

Impacts of plasma microbial lipopolysaccharide translocation on B cell perturbations and anti-CD4 autoantibody production in people with HIV on suppressive antiretroviral therapy

Background. Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear.Methods. Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG–producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro.Results. Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro.Conclusion. Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.

The Prebiotic Effects of an Extract with Antioxidant Properties from Morus alba L. Contribute to Ameliorate High-Fat Diet-Induced Obesity in Mice.

Obesity is a global health issue, in which modifications in gut microbiota composition have a key role. Different therapeutic strategies are being developed in combination with diet and exercise, including the use of plant extracts, such as those obtained from Morus alba L. leaves. Recent studies have revealed their anti-inflammatory and antioxidant properties. The aim of the present work was to evaluate whether the beneficial effects of M. alba L. leaf extract in high-fat diet-induced obesity in mice is correlated with its impact on gut microbiota. The extract reduced body weight gain and attenuated lipid accumulation, as well as increased glucose sensitivity. These effects were associated with an amelioration of the obesity-associated inflammatory status, most probably due to the described antioxidant properties of the extract. Moreover, M. alba L. leaf extract mitigated gut dysbiosis, which was evidenced by the restoration of the Firmicutes/Bacteroidota ratio and the decrease in plasma lipopolysaccharide (LPS) levels. Specifically, the extract administration reduced Alistipes and increased Faecalibaculum abundance, these effects being correlated with the beneficial effects exerted by the extract on the obesity-associated inflammation. In conclusion, anti-obesogenic effects of M. alba L. leaf extract may be mediated through the amelioration of gut dysbiosis.

Role of enterocyte Enpp2 and autotaxin in regulating lipopolysaccharide levels, systemic inflammation, and atherosclerosis

Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr−/− mice standard mouse chow supplemented with unsaturated LPA or lysophosphatidylcholine qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet (WD). Here, we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species and oxidized phospholipids (OxPLs) in jejunum mucus. To determine the role of intestinal autotaxin, enterocyte-specific Ldlr−/−/Enpp2 KO (intestinal KO) mice were generated. In control mice, the WD increased enterocyte Enpp2 expression and raised autotaxin levels. Ex vivo, addition of OxPL to jejunum from Ldlr−/− mice on a chow diet induced expression of Enpp2. In control mice, the WD raised OxPL levels in jejunum mucus and decreased gene expression in enterocytes for a number of peptides and proteins that affect antimicrobial activity. On the WD, the control mice developed elevated levels of lipopolysaccharide in jejunum mucus and plasma, with increased dyslipidemia and increased atherosclerosis. All these changes were reduced in the intestinal KO mice. We conclude that the WD increases the formation of intestinal OxPL, which i) induce enterocyte Enpp2 and autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of reactive oxygen species that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma lipopolysaccharide levels that promote systemic inflammation and enhance atherosclerosis.

Hydrogen inhalation ameliorates hepatic inflammation and modulates gut microbiota in rats with high-fat diet-induced non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a multisystem metabolic disease associated with gut microflora dysbiosis and inflammation. Hydrogen (H2) is a novel and effective antiinflammatory agent. The present study was aimed to clarify the effects of 4% H2 inhalation on NAFLD and its mechanism of action. Sprague-Dawley rats were fed a high-fat diet for 10 weeks to induce NAFLD. Rats in treatment group inhaled 4% H2 each day for 2 h. The protective effects on hepatic histopathology, glucose tolerance, inflammatory markers, and intestinal epithelial tight junctions were assessed. Transcriptome sequencing of liver and 16 S-seq of cecal contents were also performed to explore the related mechanisms of H2 inhalation. H2 improved the hepatic histological changes and glucose tolerance, decreased the liver function parameters of plasma alanine aminotransferase and aspartate aminotransferase, and relieved liver inflammation. Liver transcriptomic data suggested that H2 treatment significantly downregulated inflammatory response genes, and the lipopolysaccharide (LPS)/Toll-like receptor (TLR) 4/nuclear transcription factor kappa B (NF-κB) signaling pathway might be involved, and the expressions of critical proteins were further validated. Meanwhile, the plasma LPS level was significantly decreased by the H2 intervention. H2 also improved the intestinal tight junction barrier by enhancing the expressions of zonula occludens-1 and occluding. Based on 16S rRNA sequencing, H2 altered the composition of gut microbiota, improving the relative abundance of Bacteroidetes-to-Firmicutes. Collectively, our data show that H2 could prevent NAFLD induced by high-fat diet, and the anti-NAFLD effect is associated with the modulation of gut microbiota and inhibition of LPS/TLR4/NF-κB inflammatory pathway.

Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity.

The implications of maternal overnutrition on offspring metabolic and neuroimmune development are well-known. Increasing evidence now suggests that maternal obesity and poor dietary habits during pregnancy and lactation can increase the risk of central and peripheral metabolic dysregulation in the offspring, but the mechanisms are not sufficiently established. Furthermore, despite many studies addressing preventive measures targeted at the mother, very few propose practical approaches to treat the damages when they are already installed. Here we investigated the potential of cannabidiol (CBD) treatment to attenuate the effects of maternal obesity induced by a cafeteria diet on hypothalamic inflammation and the peripheral metabolic profile of the offspring in Wistar rats. We have observed that maternal obesity induced a range of metabolic imbalances in the offspring in a sex-dependant manner, with higher deposition of visceral white adipose tissue, increased plasma fasting glucose and lipopolysaccharides (LPS) levels in both sexes, but the increase in serum cholesterol and triglycerides only occurred in females, while the increase in plasma insulin and the homeostatic model assessment index (HOMA-IR) was only observed in male offspring. We also found an overexpression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα), interleukin (IL) 6, and interleukin (IL) 1β in the hypothalamus, a trademark of neuroinflammation. Interestingly, the expression of GFAP, a marker for astrogliosis, was reduced in the offspring of obese mothers, indicating an adaptive mechanism to in utero neuroinflammation. Treatment with 50 mg/kg CBD oil by oral gavage was able to reduce white adipose tissue and revert insulin resistance in males, reduce plasma triglycerides in females, and attenuate plasma LPS levels and overexpression of TNFα and IL6 in the hypothalamus of both sexes. Together, these results indicate an intricate interplay between peripheral and central counterparts in both the pathogenicity of maternal obesity and the therapeutic effects of CBD. In this context, the impairment of internal hypothalamic circuitry caused by neuroinflammation runs in tandem with the disruptions of important metabolic processes, which can be attenuated by CBD treatment in both ends.

Hepatic pIgR-mediated secretion of IgA limits bacterial translocation and prevents ethanol-induced liver disease in mice

ObjectiveAlcohol-associated liver disease is accompanied by microbial dysbiosis, increased intestinal permeability and hepatic exposure to translocated microbial products that contribute to disease progression. A key strategy to generate immune protection...

Mangiferin alleviates trimethylamine-N-oxide (TMAO)-induced atherogenesis and modulates gut microbiota in mice.

Trimethylamine-N-oxide (TMAO), originating from dietary trimethylamine-containing nutrients such as choline, has been recognized as a risk factor for atherosclerosis. Mangiferin is a bioactive xanthone initially extracted from mango (Mangifera indica). The present study aimed to investigate the effect of mangiferin on TMAO-induced atherogenesis in mice fed a high-choline diet. Female ApoE-/- mice were randomly divided into three groups and fed either a control diet, a high-choline diet with 1% free choline, or an experimental diet with 1% free choline plus 0.5% mangiferin for 15 weeks. Our results showed that a high-choline diet elevated plasma TMAO levels, accelerated atherogenesis, promoted cholesterol accumulation, and reduced the generation of short-chain fatty acids (SCFAs) by gut microbes. Mangiferin alleviated inflammation, and lowered plasma total cholesterol levels by facilitating the elimination of neutral and acidic sterols in feces, resulting in a 16.7-29.0% reduction in aortic atherosclerotic lesions. Notably, mangiferin could favorably remodel the composition of the gut microbiota by fostering the growth of the beneficial taxa Akkermansia, Parabacteroides, and Bifidobacteriaceae, while reducing the relative abundance of the pathogenic genus Helicobacter. This modulation led to a decrease in plasma lipopolysaccharide levels, enhanced the production of total SCFAs by gut microbes, and reduced susceptibility to atherosclerosis. In conclusion, mangiferin exhibited its ability to alleviate TMAO-induced atherosclerosis through its anti-inflammatory, cholesterol-lowering, and gut microbial modulatory activities.