Elevated Lipopolysaccharide Levels Research Articles

Osteoporosis in postmenopausal women is associated with disturbances in gut microbiota and migration of peripheral immune cells

BackgroundPostmenopausal osteoporosis (PMO) results from a reduction in bone mass and microarchitectural deterioration in bone tissue due to estrogen deficiency, which may increase the incidence of fragility fractures. In recent years, the “gut-immune response-bone” axis has been proposed as a novel potential approach in the prevention and treatment of PMO. Studies on ovariectomized murine model indicated the reciprocal role of Th17 cells and Treg cells in the aetiology of osteoporosis. However, the relationship among gut microbiota, immune cells and bone metabolic indexes remains unknown in PMO.MethodsA total of 77 postmenopausal women were recruited for the study and divided into control (n = 30), osteopenia (n = 19), and osteoporosis (n = 28) groups based on their T score. The frequency of Treg and Th17 cells in lymphocytes were analyzed by flow cytometry. The serum levels of interleukin (IL)-10, 17 A, 1β, 6, tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) were determined via enzyme-linked immunosorbent assay. Additionally, 16S rRNA gene V3-V4 region sequencing analysis was performed to investigate the gut microbiota of the participants.ResultsThe results demonstrated decreased bacterial richness and diversed intestinal composition in PMO. In addition, significant differences of relative abundance of the gut microbial community in phylum and genus levels were found, mainly including increased Bacteroidota, Proteobacteria, and Campylobacterota, as well as reduced Firmicutes, Butyricicoccus, and Faecalibacterium. Intriugingly, in the osteoporosis group, the concentration of Treg cells and associated IL-10 in peripheral circulation was negatively regulated, while other chronic systemic proinflammatory cytokines and Th17 cells showed opposite trends. Moreover, significantly elevated plasma lipopolysaccharide (LPS) in patients with osteoporosis indicated that disrupted intestinal integrity and permeability. A correlation analysis showed close relationships between gut bacteria and inflammation.ConclusionsCollectively, these observations will lead to a better understanding of the relationship among bone homeostasis, the microbiota, and circulating immune cells in PMO. The elevated LPS levels of osteoporosis patients which not only indicate a breach in intestinal integrity but also suggest a novel biomarker for assessing osteoporosis risk linked to gut health.

Intergenerational neurotoxicity of polystyrene nanoplastics in offspring mice is mediated by dysfunctional microbe-gut-brain axis

Nanoplastics (NPs) are ubiquitous in daily life, posing potential risks to the environment and human. While their negative effects on parental organisms have been extensively studied, intergenerational effects are still in the early stages of investigation. Here, we aimed to investigate the impact of maternal exposure to an environmentally relevant level of polystyrene NPs (PSNPs, 100 nm) during gestation and lactation (∼32 days, 50 μg/mouse/day) on neurotoxicity mediated by the microbe-gut-brain axis in offspring mice. Maternal PSNPs exposure significantly increased brain TNF-α level and microglia by 1.43 and 1.48 folds respectively, compared to control, accompanied by nuclear pyknosis and cell vacuolization in cortex and hippocampus. Targeted neurotransmitter metabolomics analysis revealed dysregulation in dopamine and serotonin metabolism. Specifically, dopamine levels increased significantly from 0.007 ng/L to 0.015 ng/L, while N-acetylseroton and 3,4-dihydroxyphenylacetic acid decreased significantly from 0.002 and 0.929 ng/L to 0.001 and 0.680 ng/L, respectively. Through a combination of 16S rRNA sequencing and biochemical analysis, we discovered that maternal PSNPs exposure led to a depletion of anti-inflammatory bacteria and an enrichment of pro-inflammatory bacteria resulting in intestinal barrier damage, elevated levels of lipopolysaccharide in blood, and subsequent activation of neuroinflammation. Meanwhile, gut bacteria dysbiosis interfered with communication between gut and brain by dysregulating neurotransmitter synthesis, as evidenced by significant associations between neurotransmitter-related bacteria (Akkermansia, Family_XIII_AD3011_group, Lachnoclostridium) and dopamine/serotonin related metabolites. Furthermore, transcriptional alterations in dopamine and serotonin related pathways were observed in the enteric nervous system, suggesting abnormal signal transduction from gut to brain contributes to neurotoxicity. This study provides new insights into NPs-induced neurotoxicity within the context of microbe-gut-brain axis and highlights the risk of cerebral dysfunction in offspring with maternal NPs exposure.

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

ObjectiveMedication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation.Materials and methodsThe study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels.ResultsSerum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores.ConclusionWe have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH.Graphical

Mechanisms of LPS–induced epithelial mesenchymal transition in bEECs

High-concentrate diets cause subacute ruminal acidosis, resulting in increased blood lipopolysaccharide (LPS) levels in cows. We found that the peak LPS in cows fed with high-concentrate diets coincides the period of embryo implantation in a large-scale dairy farm. As epithelial-mesenchymal transition (EMT) should be tightly regulated during normal embryo implantation in cows, we speculated that increased LPS may cause abnormal EMT, thereby inhibiting embryo implantation in cows. To confirm that elevated LPS levels induce abnormal EMT in cows, we treated bovine endometrial epithelial cells (bEECs) with LPS for 48 h and analyzed the protein levels of ZEB1, a major EMT-related transcription factor, which is positively regulated by the TGFβ/SMAD3 pathway. In addition, we analyzed the changes in expression of three EMT-related genes (E-cadherin, N-cadherin, and Vimentin), and examined the morphology and migratory ability of the cells. The results showed that elevated LPS levels increased protein expression of ZEB1, vimentin, and N-cadherin, and reduced that of E-cadherin. Elevated LPS also increased bEECs migration rate, and induced the cells to acquire a mesenchymal phenotype. Furthermore, benzyl butyl phthalate (BBP)-induced ZEB1 overexpression significantly decreased E-cadherin levels and increased N-cadherin levels. As LPS treatment also decreased the expression of Bta-miR-200b, we further found that Bta-miR-200b targets to the 3′UTR of ZEB1 through the confirmation of dual-luciferase reporter system. And the increased level of Bta-miR-200b by mimic enhanced the expression of E-cadherin and yet inhibited the expression of N-cadherin in protein, which exactly opposite to the results induced by LPS. In conclusion, LPS induced EMT in bEECs by upregulating ZEB1, while Bta-miR-200b could inhibit the occurrence of EMT by binding ZEB1 3′UTR. These results provide a new insight for low reproductive rate of dairy cows under the background of high-concentrate diets.

The Endotoxin Hypothesis of Parkinson's Disease.

The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The molecular basis for dysfunctional bacterial lipopolysaccharide-mediated immune receptor activation by SARS-CoV-2 spike.

SARS-CoV-2 has caused hundreds of millions of COVID-19 infections worldwide. While COVID-19 presents with various clinical manifestations, severe COVID-19 disease causes dysregulated host immune reactions that trigger onset of sepsis and acute respiratory distress syndrome. Accumulating evidence suggests that lipopolysaccharide (LPS) derived from the outer membranes of Gram-negative bacteria plays an instrumental role in the progression of such inflammatory states. Patients with pre-existing conditions such as diabetes, hypertension, and obesity are at higher risk to develop severe COVID-19 disease and tend to have significantly elevated blood LPS levels. LPS serves as a signal of bacterial infection upon recognition by Toll-like receptor (TLR4) of the innate immune system, but this can also result in over-amplified immune reactions and sepsis. Here, we present the results of molecular simulations and free-energy calculations, supported by in vitro and in vivo assays and hydrogen-deuterium exchange mass spectrometry experiments, which reveal the molecular mechanism by which the envelope spike glycoprotein of SARS-CoV-2 augments hyperinflammation by acting as a conduit in the TLR4 pathway. LPS was found to bind to several conserved pockets on spike across S1 and S2 subunits. S1 affinity for LPS was comparable to that of CD14, a co-receptor used by immune cells to transfer LPS to TLR4. Cell-based assays and reporter mice experiments showed that low concentrations of spike and LPS synergistically induce a strong pro-inflammatory response, thus pinpointing spike's capacity to “boost” innate immune activation. Finally, the loss of a high-affinity binding site in the Omicron spike led to a reduction of its “boosting” capacity, which may translate to the less severe inflammation observed in patients infected with this variant. Collectively, our findings highlight the potential impact of elevated LPS levels and Gram-negative bacterial coinfections in severe COVID-19 complications.

Implications of Indirect Biomarkers of Intestinal Permeability in the Stools of Newborns and Infants with Perinatal Risk Factors for Intestinal Colonization Disorders and Infant Feeding Patterns.

Background: The intestinal microbiota of pregnant women and factors disturbing the microbial balance of their gastrointestinal tract during the perinatal period may be the cause of dysbiosis and thus intestinal permeability syndrome in their children. The purpose of this study was to analyze the implications of intestinal permeability parameters in the stools of newborns and infants with perinatal risk factors for intestinal colonization disorders (the route of delivery, antibiotic therapy in the neonatal period and the abandonment of breastfeeding). Methods: The study included 100 mother–child pairs. All children were born from uncomplicated and term pregnancies (between 37 and 42 weeks of gestation). In order to determine the parameters of dysbiosis and intestinal permeability, we determined the concentrations of zonulin and occludin in stool samples taken from all children at 0 (i.e., at birth), 3, 6 and 12 months of age. Elevated levels of lipopolysaccharide (LPS) are associated with metabolic diseases and its presence may be indicative of TJ injury and the onset of leaky gut syndrome. To indirectly determine the presence of endotoxemia, the concentrations of lipopolysaccharide were also measured in stool samples taken from all children at 0, 3, 6 and 12 months of age. We analyzed the relationship between the markers studied and perinatal risk factors for impaired intestinal colonization, including the mode of delivery, the method of feeding, and a family history of allergy. Results: During the first 3 months of infant life, higher concentrations of fecal occludin and zonulin were most often accompanied by higher values of fecal LPS. Similarly, higher concentrations of zonulin were accompanied by higher values of occludin. There were no significant differences in the stool concentrations of the studied markers during the first year of life between children born by caesarean section and those born naturally. In addition, the method of feeding had no significant effect on the changes in the concentrations of the determined fractions. Antibiotic therapy was associated only with an increase in the fecal occludin concentration after birth, without any effect on zonulin, occludin or LPS levels. The use of probiotic therapy in infants resulted in a decrease in only LPS concentrations at 3 months of age, with no effect on zonulin or occludin concentrations at 0, 6 and 12 months. Conclusions: Perinatal factors related to intestinal permeability are important during the first 3 months of infant life. However, we found that the mode of delivery had no influence on the parameters of infant intestinal leakage during the first year of life. In addition, the mode of infant feeding—breast or exclusively formula—did not significantly affect the changes in the concentrations of LPS, zonulin or occludin in the stools of children. A short-term increase in occludin concentrations after delivery in the stools of children from mothers undergoing antibiotic therapy indicates a negative but reversible influence of intrapartum antibiotics on the intestinal integrity of children in the perinatal period. Probiotic therapy seems to have a positive effect on reducing endotoxemia in children during the first 3 months of life. The presence of LPS at 3 months did not affect intestinal tightness at any of the later measured periods of the infants’ lives.

Local free fatty acids trigger the expression of lipopolysaccharide-binding protein in murine white adipose tissue.

Although lipopolysaccharide (LPS)-binding protein (LBP) is an acute-phase protein mainly produced by hepatocytes, it has also been proposed to be a pro-inflammatory adipokine. Obesity and the consumption of a high-fat diet (HFD) are reportedly associated with elevated levels of LPS in plasma and free fatty acids (FFAs) in white adipose tissue (WAT). We examined whether circulating LPS or local FFAs are responsible for the HFD-induced increase of LBP in WAT. Male C57BL/6J mice were fed either a normal-fat diet (NFD) or an HFD. The mRNA levels in the liver and mesenteric WAT (mWAT), total FFA content in mWAT, and LBP and LPS concentrations in plasma were determined. The Lbp mRNA level in mWAT was higher in mice fed the HFD than in those fed the NFD for 3, 7, or 28 days or 14 weeks, whereas the hepatic Lbp mRNA level did not differ between the groups. The Lbp mRNA level in mWAT was also increased by the HFD in germ-free mice, which do not have gut microbiota, the source of LPS. The plasma LPS level did not show a significant correlation with the mWAT Lbp mRNA level. The total FFA content in mWAT was higher in mice fed the HFD than in those fed the NFD and positively correlated with the Lbp mRNA level. Supplementation with palmitic acid increased the Lbp mRNA level in 3T3-L1 adipocytes. We propose that local FFAs, but not circulating LPS, are the trigger for increased Lbp expression in mWAT of mice fed the HFD.

Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake.

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors.

Arsenic exposure induces intestinal barrier damage and consequent activation of gut-liver axis leading to inflammation and pyroptosis of liver in ducks

Arsenic is an important hazardous metalloid commonly found in polluted soil, rivers and groundwater. However, few studies exist regarding the effect of arsenic trioxide (ATO) on the gut-liver axis and consequent hepatotoxicity in waterfowl. Here, we investigated the influence of ATO on duck intestines and livers, and explored the role of the gut-liver axis in ATO-induced hepatotoxicity and intestinal toxicity. Our results demonstrated that ATO-exposure induced intestinal damage, liver inflammatory cell infiltration and vesicle steatosis. Additionally, the intestinal microbiota community in ATO-exposed ducks displayed significantly decreased α-diversity and an altered bacterial composition. Moreover, ATO-exposure markedly reduced the expression of intestinal barrier-related proteins (Claudin-1, MUC2, ZO-1 and Occludin), resulting in increased intestinal permeability and elevated lipopolysaccharide levels. Simultaneously, ATO-exposure also upregulated pyroptosis-related index levels in the liver and jejunum, and increased pro-inflammatory cytokine production (IFN-γ, TNF-α, IL-18, and IL-1β). Our further mechanistic studies showed that ATO-induced liver and jejunum inflammation were provoked by the activation of the LPS/TLR4/NF-κB signaling pathway and NLRP3 inflammasome. In summary, these results manifested that ATO exposure can cause liver and jejunal inflammation and pyroptosis, and the indirect gut-liver axis pathway may play an essential role in the potential mechanism of ATO-induced hepatotoxicity.

Gut Microbiota Dysbiosis and Elevated Lipopolysaccharide Serum Levels Are Associated with Venous Thromboembolism in Pediatric Patients

Background: Pediatric venous thromboembolism (VTE) is a burgeoning clinical problem. As such, there is an urgent need to identify modifiable host factors to prevent VTE and its long-term adverse effects. The gut microbiome, which can influence host physiology and is implicated in the pathogenesis of several disease states, is one such potentially modifiable host factor. Gut microbiota dysbiosis is an imbalance in the composition of the gut microbiota that often manifests as an overabundance of gram-negative bacteria. Lipopolysaccharide (LPS), the glycolipid on the outer membrane of gram-negative bacteria and a heat stable endotoxin, can cross the gut epithelial barrier into the systemic circulation, where it leads to the activation of inflammatory and coagulation pathways. The association of gut microbiota dysbiosis and VTE has not been fully explored. Objective/Hypothesis: The aims of this study were to determine if patients who develop VTE have 1) a distinct microbiota signature with an expansion of gram-negative bacteria, 2) increased systemic levels of LPS and 3) hypercoagulability as compared to controls without VTE. Methods: In this case-control study, we obtained plasma and fecal samples on newly diagnosed VTE pediatric patients and age-matched controls. Gut microbiome profiling was performed on fecal gDNA (16S rRNA sequencing, V4 region; QIIME2 software for gut microbiota taxonomic composition determination). We measured LPS levels using a sandwich ELISA assay (Cusabio) and hypercoagulability using endogenous thrombin potential (ETP) on thrombin generation assay (Calibrated automated thrombogram) on plasma samples. Results: 31 VTE patients were enrolled, of which 18 had fecal samples, and 22 had plasma samples. The median age of VTE cases was 11.0 years (range 1.0 to 19.0 years) of which 51% had underlying medical comorbidities and 48% had antibiotic exposure 30 days prior to the VTE episode. 5 controls were enrolled with a median age of 14.0 years (range 1.0 to 14.0 years). VTE cases had significant enrichment of commensal gram-negative bacteria Bacteroidetes (median 44% relative abundance compared to 21% in controls, p=0.006, Mann-Whitney) and depletion of commensal gram-positive Actinobacteria (median of 2% vs. 10% in controls, p=0.04, Mann-Whitney). Taxonomic differential abundance by linear analysis coupled with effective side measurements (LEfSe) further confirmed these findings by identifying two specific Bacteroidetes species as being enriched in patients with VTE: Bacteroides stercoris and Bacteroides vulgatus (p= 0.01 and 0.02 respectively, Kruskal-Wallis). VTE patients had significantly higher plasma levels of LPS (n=22; mean, 64.30 ng/mL; +SEM 10.17ng/mL) compared to controls (n=5; mean, 14.75ng/mL; +SEM 6.18ng/mL; p=0.03, t-test). Furthermore, VTE cases had increased ETP (n=15; mean, 1922nM.min; +SEM 144.5nM.min) compared to controls (n=5; mean, 1293nM.min; +SEM 78.11nM.min; p=0.02, t-test). Conclusion: We present the first description of elevated LPS levels, hypercoagulability, and a concomitant gut microbiota enrichment of commensal gram-negative bacteria in pediatric patients experiencing an acute VTE episode. Our findings suggest that enrichment of commensal gram-negative bacteria in pediatric patients and LPS gut translocation could play a role in hypercoagulability and the development of VTE. Disclosures Koh: Mesoblast: Consultancy; Prolacta: Consultancy; Merck: Research Funding; Novartis: Research Funding.

Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis.

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.

Lower levels of leptin are associated with severity parameters in visceral leishmaniasis patients.

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, and if untreated may be fatal. It affects important organs of the immune system and is characterized by a specific immunosuppression, along with intense cellular activation and cytokine storm. Moreover, VL is now recognized as a systemic inflammatory response syndrome (SIRS), in which multiple cytokines and other pro-inflammatory molecules are released. The action of these inflammatory mediators may be considered risk factors for poor prognosis and death. Leptin, a hormone derived from adipose tissue, has been described with several immunoregulatory functions in vitro and in vivo Leishmania infection models, particularly for enhancing the macrophage microbicidal mechanisms. Considering that evaluation of immunologic parameters that may be associated with this clinical scenario may help to decrease VL lethality, we evaluated whether leptin is associated with VL pathogenesis. Thirty-one patients were recruited in the active phase of VL, of which 22 were followed up until one month after therapy (1mpt). Except for creatinine levels, all clinical parameters were altered in active VL patients, especially leucocyte counts and albumin and hemoglobin levels. Also, elevated levels of lipopolysaccharide (LPS), immunoglobulins (Ig)G1 and G3 anti-Leishmania and interleukins (IL)-6 and -10 were higher than in healthy individuals. In contrast, active VL patients presented diminished serum leptin levels and positive correlation with leukocytes counts and hemoglobin and albumin levels. After 1mpt, VL patients showed a significant increase in leptin levels, reaching values similar to healthy volunteers. As expected, only LPS levels remained elevated after 1mpt. These findings suggest that leptin levels are affected in Leishmania infection and the correlation with important parameters associated with the prognosis of VL points to the involvement of this molecule in VL immunopathogenesis. Additional studies are needed to evaluate the possibility of leptin as a prognostic marker of VL.

Rusty Microglia: Trainers of Innate Immunity in Alzheimer's Disease.

Alzheimer's disease, the most common form of dementia, is marked by progressive cognitive and functional impairment believed to reflect synaptic and neuronal loss. Recent preclinical data suggests that lipopolysaccharide (LPS)-activated microglia may contribute to the elimination of viable neurons and synapses by promoting a neurotoxic astrocytic phenotype, defined as A1. The innate immune cells, including microglia and astrocytes, can either facilitate or inhibit neuroinflammation in response to peripherally applied inflammatory stimuli, such as LPS. Depending on previous antigen encounters, these cells can assume activated (trained) or silenced (tolerized) phenotypes, augmenting or lowering inflammation. Iron, reactive oxygen species (ROS), and LPS, the cell wall component of gram-negative bacteria, are microglial activators, but only the latter can trigger immune tolerization. In Alzheimer's disease, tolerization may be impaired as elevated LPS levels, reported in this condition, fail to lower neuroinflammation. Iron is closely linked to immunity as it plays a key role in immune cells proliferation and maturation, but it is also indispensable to pathogens and malignancies which compete for its capture. Danger signals, including LPS, induce intracellular iron sequestration in innate immune cells to withhold it from pathogens. However, excess cytosolic iron increases the risk of inflammasomes' activation, microglial training and neuroinflammation. Moreover, it was suggested that free iron can awaken the dormant central nervous system (CNS) LPS-shedding microbes, engendering prolonged neuroinflammation that may override immune tolerization, triggering autoimmunity. In this review, we focus on iron-related innate immune pathology in Alzheimer's disease and discuss potential immunotherapeutic agents for microglial de-escalation along with possible delivery vehicles for these compounds.

Microbiota modulation by eating patterns and diet composition: impact on food intake.

There is accumulating evidence that the gut microbiota and its composition dynamics play a crucial role in regulating the host physiological functions and behavior. Diet composition is the primary modulator of bacterial richness and abundance in the gastrointestinal (GI) tract. Macronutrient (fat, sugar, and protein) and fiber contents are especially important in determining microbiota composition and its effect on health outcomes and behavior. In addition to food composition, time of intake and eating patterns have recently been shown to significantly affect gut bacterial makeup. Diet-driven unfavorable microbiota composition, or dysbiosis, can lead to an increased production of proinflammatory by-products such as lipopolysaccharide (LPS). Increased inflammatory potential is associated with alteration in gut permeability, resulting in elevated levels of LPS in the bloodstream, or metabolic endotoxemia. We have found that a chronic increase in circulating LPS is sufficient to induce hyperphagia in rodents. Chronic LPS treatment appears to specifically impair the gut-brain axis and vagally mediated satiety signaling. The vagus nerve relays information on the quantity and quality of nutrients in the GI tract to the nucleus of solitary tract in the brain stem. There is evidence that microbiota dysbiosis is associated with remodeling of the vagal afferent pathway and that normalizing the microbiota composition in rats fed a high-fat diet is sufficient to prevent vagal remodeling. Taken together, these data support a role for the microbiota in regulating gut-brain communication and eating behavior. Bacteria-originating inflammation may play a key role in impairment of diet-driven satiety and the development of hyperphagia.

Taurine and tea polyphenols combination ameliorate nonalcoholic steatohepatitis in rats

BackgroundNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease, for which there is currently no safe and effective drug for therapy. In this study, we explored the effects of taurine, tea polyphenols (TPs), or a combination thereof, on NASH rats.MethodsRats were divided into a normal group, a high-fat diet induced model group and a treatment group (including taurine, TPs, or taurine + TPs treatment for 8 weeks). Twelve weeks later, all rats were sacrificed, and serum transaminase, lipid and lipopolysaccharide levels and hepatic oxidative stress levels were determined. Histological changes were evaluated.ResultsIn NASH rats, hepatocyte damage, lipid disturbance, oxidative stress and elevated lipopolysaccharide levels were confirmed. Taurine treatment alleviated hepatocyte damage and oxidative stress. TPs treatment improved lipid metabolism and increased hepatic antioxidant activity. The therapeutic effects of taurine + TPs treatment on hepatocyte damage, lipid disturbance, and oxidative stress were superior to those of taurine and TPs treatment, respectively. Taurine, TPs and their combination all decreased serum lipopolysaccharide levels in NASH rats, but the combination of the compounds caused these levels to decrease more significantly than taurine or TPs treatment alone.ConclusionTaurine combined with TPs treatment could relieve NASH by alleviating hepatocyte damage, decreasing oxidative stress and improving lipid metabolism and gut flora disturbance partly. Taurine and TPs combination may act as a new effective medicine for treating NASH patients.

Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis.

The increased risks conferred by inflammatory bowel disease (IBD) to the development of colorectal cancer gave rise to the term "colitis-associated cancer" and the concept that inflammation promotes colon tumorigenesis. A condition more common than IBD is low-grade inflammation, which correlates with altered gut microbiota composition and metabolic syndrome, both present in many cases of colorectal cancer. Recent findings suggest that low-grade inflammation in the intestine is promoted by consumption of dietary emulsifiers, a ubiquitous component of processed foods, which alter the composition of gut microbiota. Here, we demonstrate in a preclinical model of colitis-induced colorectal cancer that regular consumption of dietary emulsifiers, carboxymethylcellulose or polysorbate-80, exacerbated tumor development. Enhanced tumor development was associated with an altered microbiota metagenome characterized by elevated levels of lipopolysaccharide and flagellin. We found that emulsifier-induced alterations in the microbiome were necessary and sufficient to drive alterations in major proliferation and apoptosis signaling pathways thought to govern tumor development. Overall, our findings support the concept that perturbations in host-microbiota interactions that cause low-grade gut inflammation can promote colon carcinogenesis. Cancer Res; 77(1); 27-40. ©2016 AACR.

Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralis Infection.

Microbial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic Strongyloides stercoralis infection, we measured the plasma levels of LPS and other microbial translocation markers, acute-phase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN]) S. stercoralis infections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of S. stercoralis infection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (α-2 macroglobulin [α-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1β) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of S. stercoralis infection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that S. stercoralis infection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic S. stercoralis infection and is associated with an inflammatory response.

Toll-like receptor-mediated signaling cascade as a regulator of the inflammation network during alcoholic liver disease.

Chronic abuse of alcohol leads to various histological abnormalities in the liver. These are conditions collectively known as alcoholic liver disease (ALD). Currently, ALD is considered to be one of the major causes of death worldwide. An impaired intestinal barrier with related endotoxemia is among the various pathogenetic factors. This is mainly characterized by circulating levels of lipopolysaccharide (LPS), considered critical for the onset of intra-hepatic inflammation. This in turn promotes hepatocellular damage and fibrosis in ALD. Elevated levels of LPS exert their effects by binding to Toll-like receptors (TLRs) which are expressed by all liver-resident cells. The activation of TLR signaling triggers an overproduction and release of some cytokines, which promote an autocatalytic cascade of other pro-inflammatory signals. In this review, we provide an overview of the mechanisms that sustain LPS-mediated activation of TLR signaling, reporting current experimental and clinical evidence of its role during inflammation in ALD.

Plasma Lipopolysaccharide Is Closely Associated With Glycemic Control and Abdominal Obesity

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