Plasma Lipopolysaccharide Research Articles

A triad of gut dysbiosis, dysregulated immunity, and 'leaky' gut characterize HCMV associated neonatal cholestasis.

Gut microbiome dysbiosis and related immune dysfunction have been associated with the pathogenesis of Human Cytomegalovirus (HCMV) infection in infants with neonatal cholestasis (NC) as previously reported by us. However, the interaction of a perturbed microbiome, HCMV infection, and dysregulated immunity leading to exacerbation of disease severity has not been investigated so far. In this study, we examined the association of gut microbiome, host inflammatory and homeostatic markers that are likely to govern increased pathogenesis of NC in HCMV infected IgM positive infants (N = 15) compared to IgM negative (N = 15) individuals. Stool samples of HCMV infected infants and age-matched healthy controls (N = 10) were assessed for gut bacteria-derived metabolites like short-chain fatty acids (SCFAs), Lipopolysaccharide (LPS), cytokines and markers of gut barrier integrity. Data were correlated with previously determined gut microbiome composition and frequency of immune cell subsets. Finally, validation of clinical potential was undertaken by principal component analysis (PCA) of integrated data to delineate the spectrum of clinical pathology. Significantly lower levels of SCFAs and elevated fecal levels of soluble inflammatory mediators were observed in IgM positive HCMV infected infants. Further, increased plasma LPS levels and markers of gut permeability, suggestive of microbial translocation due to a 'leaky gut' were observed in HCMV infected IgM positive group. PCA of integrated data revealed clearly disparate profiles representative of IgM positive, IgM negative, and uninfected healthy states. Our results suggest the utility of an integrated approach involving dysregulated microbiome-immune axis for gaining a better understanding of pathogenesis associated with HCMV infection in NC.

Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring

Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females. These findings underscore the persistent influence of maternal obesity on the offspring's health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.

Effect of the Mediterranean diet on the fecal long-chain fatty acid composition and intestinal barrier integrity: An exploratory analysis of the randomized controlled LIBRE trial.

We recently showed that adherence to the Mediterranean diet increased the proportion of plasma omega-3 polyunsaturated fatty acids (n-3 PUFAs), which was associated with an improved intestinal barrier integrity. In the present exploratory analysis, we assessed fecal fatty acids in the same cohort, aiming to investigate possible associations with intestinal barrier integrity. Women from the LIBRE randomized controlled trial, characterized by an impaired intestinal barrier integrity, followed either a Mediterranean diet (intervention group, IG, n=33) or a standard diet (control group, CG, n=35). At baseline (BL), month 3 (V1), and month 12 (V2), plasma lipopolysaccharide binding protein (LBP), fecal zonulin, and fecal fatty acids were measured. In the IG, fecal proportions of palmitoleic acid (16:1, n-7) and arachidonic acid (20:4, n-6) decreased, while the proportion of linoleic acid (18:2, n-6) and alpha linoleic acid (18:3, n-3) increased (BL-V1 and BL-V2, all P<0.08). In the CG, fecal proportions of palmitic acid and arachidic acid increased while the proportion of linoleic acid decreased (BL-V1, all P<0.05). The decrease in the proportion of palmitoleic acid correlated with the decrease in plasma LBP (∆V1-BL r=0.72, P<0.001; ∆V2-BL r=0.39, P<0.05) and correlated inversely with adherence to the Mediterranean diet (Mediterranean diet score; ∆V1-BL r=-0.42, P=0.03; ∆V2-BL r=-0.53, P=0.005) in the IG. Our data show that adherence to the Mediterranean diet induces distinct changes in the fecal fatty acid composition. Furthermore, our data indicate that the fecal proportion of palmitoleic acid, but not fecal n-3 PUFAs, are associated with intestinal barrier integrity in the IG.

Gastrointestinal permeability and kidney injury risk during hyperthermia in young and older adults.

We tested whether older adults, compared with young adults, exhibit greater gastrointestinal permeability and kidney injury during heat stress. Nine young (32±3 years) and nine older (72±3 years) participants were heated using a model of controlled hyperthermia (increasing core temperature by 2°C via a water-perfused suit). Gastrointestinal permeability was assessed using a multi-sugar drink test containing lactulose, sucrose and rhamnose. Blood and urine samples were assayed for markers of intestinal barrier injury [plasma intestinal fatty acid binding protein (I-FABP), plasma lipopolysaccharide binding protein (LBP) and plasma soluble cluster of differentiation 14 (sCD14)], inflammation (serum cytokines), kidney function (plasma creatinine and cystatin C) and kidney injury [urine arithmetic product of IGFBP7 and TIMP-2 (TIMP-2 × IGFBP7), neutrophil gelatinase-associated lipocalin and kidney injury molecule-1]. The lactulose-to-rhamnose ratio was increased in both young and older adults (group-wide: Δ0.11±0.11), but the excretion of sucrose was increased only in older adults (Δ1.7±1.5). Young and older adults showed similar increases in plasma LBP (group-wide: Δ0.65±0.89µg/mL), but no changes were observed for I-FABP or sCD14. Heat stress caused similar increases in plasma creatinine (group-wide: Δ0.08±0.07mg/dL), cystatin C (group-wide: Δ0.16±0.18mg/L) and urinary IGFBP7×TIMP-2 [group-wide: Δ0.64±0.95 (pg/min)2] in young and older adults. Thus, the level of heat stress used herein caused modest increases in gastrointestinal permeability, resulting in a mild inflammatory response in young and older adults. Furthermore, our data indicate that older adults might be more at risk for increases in gastroduodenal permeability, as evidenced by the larger increases in sucrose excretion in response to heat stress. Finally, our findings show that heat stress impairs kidney function and elevates markers of kidney injury; however, these responses are not modulated by age.

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.

Visceral adiposity in postmenopausal women is associated with a pro-inflammatory gut microbiome and immunogenic metabolic endotoxemia

BackgroundObesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed “metabolic endotoxemia.” We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women.MethodsFifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm2) and n = 25 with high VAT area (177.5 ± 31.3 cm2). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks.ResultsWomen in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet.ConclusionsIncreased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms.7yVbQmTTfsF9b4Af3tznWNVideo

Thermally processed rice starch impacts glucose homeostasis in mice to different degrees via disturbing gut microbial structure and intestinal barrier function

Long-term intake of thermally processed starch-based foods may impact glucose homeostasis, but the consistency of the effects of various thermal treatments and the reasons are not clear. In this study, thermal treatments, especially boiling, damaged the crystal structure and inter-molecular hydrogen bonds of starch-based blends, thus decreasing the structural order and stability. These thermally treated starch-based blends increased the appetite of mice, promoted food digestion, and enhanced postprandial glucose response. Normal C57BL/6J mice were treated with boiled, baked, and fried starch-based diets for ten weeks. Compared to the baked and fried starch-based diets, the boiled starch-based diet significantly (p < 0.05) elevated random blood glucose levels and disrupted insulin homeostasis, primarily due to the remarkable decrease in gut microbial diversity. Both baked and fried starch-based diets resulted in relatively high intestinal epithelial permeability (plasma lipopolysaccharide increased by 28.67 % and 21.85 %, respectively). They adversely affected islet β-cell function and evoked glucose metabolism disorder. Overall, results demonstrate a clear connection among the thermal processing of starch-based diets, disruption of intestinal homeostasis, and adverse glucose metabolism. This study lays a theoretical foundation for the formulation of food processing strategies to mitigate the adverse effects of thermally treated food on glucose homeostasis.

Fibroblast growth factor 21 improves insulin sensitivity by modulating the bile acid-gut microbiota axis in type Ⅱ diabetic mice

BackgroundFibroblast growth factor 21 (FGF21) is an important regulator of glycolipid metabolism. However, whether the gut microbiota is related to the anti-diabetic and obesity effects of FGF21 remains unclear. MethodsOur research used KO/KO db/db male mice and streptozotocin (STZ)-induced to simulate the construction of two type II diabetic mellitus (T2DM) models, and detected impaired glucose tolerance in the model by using the ipGTT and ITT assays, and collected feces from the model mice for sequencing of the intestinal flora and the content of short-chain fatty acids. H＆E staining was used to detect changes in intestinal tissue, the serum levels of LPS and GLP-1 were detected by ELISA. ResultsIn this study, we found that FGF21 significantly improved insulin sensitivity, attenuated intestinal lesions, and decreased serum lipopolysaccharide (LPS) concentrations in T2DM mice. Moreover, FGF21 reshaped the gut microbiota and altered their metabolic pathways in T2DM mice, promoting the production of short-chain fatty acids (SCFAs) and the secretion of glucagon-like peptide 1 (GLP-1). Fecal transplantation experiments further confirmed that feces from FGF21-treated diabetic mice demonstrated similar effects as FGF21 in terms of anti-diabetic activity and regulation of gut microbiota dysbiosis. Additionally, the antibiotic depletion of gut microbiota abolished the beneficial effects of FGF21, including increased GLP-1 secretion and fecal SCFA concentration. Additionally, the FGF21 effects of ameliorating intestinal damage and suppressing plasma LPS secretion were suppressed. All these findings suggest that FGF21 prevents intestinal lesions by modifying the gut microbiota composition. Furthermore, FGF21 affected bile acid synthesis by inhibiting CYP7A1, the key enzyme of bile acid synthesis. ConclussionTherefore, FGF21 enriched beneficial bacteria by preventing bile acid synthesis and stimulating the secretion of the intestinal hormone GLP-1 via the increased production of gut microbiota metabolites, thereby exerting its anti-diabetic effects.

Lipopolysaccharide, arbiter of the gut-liver axis, modulates hepatic cell pathophysiology in alcoholism.

Over the last four decades, clinical research and experimental studies have established that lipopolysaccharide (LPS)-a component of the outer membrane of gram-negative bacteria-is a potent hepatotoxic molecule in humans and animals. Alcohol abuse is commonly associated with LPS endotoxemia. This review highlights LPS molecular structures and modes of release from bacteria, plasma LPS concentrations, induction of microbiota dysbiosis, disruption of gut epithelial barrier, and translocation of LPS into the portal circulation impacting the pathophysiology of hepatic cells via the gut-liver axis. We describe and illustrate the portal vein circulation and its distributaries draining the gastrointestinal tract. We also elaborate on the gut-liver axis coupled with enterohepatic circulation that represents a bidirectional communication between the gut and liver. The review also updates the data on how circulating LPS is cleared in a coordinated effort between Kupffer cells, hepatocytes, and liver sinusoidal endothelial cells. Significantly, the article reviews and updates the modes/mechanisms of action by which LPS mediates the diverse pathophysiology of Kupffer cells, hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells primarily in association with alcohol consumption. Specifically, we review the intricate linkages between ethanol, microbiota dysbiosis, LPS production, gut-liver axis, and pathophysiology of various hepatic cells. The maintenance of the gut barrier structural and functional integrity and microbiome homeostasis is essential in mitigating alcoholic liver disease and improving liver health.

Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

Interactions between the gut microbiome, associated metabolites and the manifestation and progression of heart failure with preserved ejection fraction in ZSF1 rats

BackgroundHeart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here.MethodsHealthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing.ResultsIncreased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (− 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray–Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats.ConclusionsIn the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.Graphical abstract

Construction of fluorescence-sensing molecularly imprinted membranes based on hydrophilic-hydrophobic multifunctional monomers for the detection of LPS molecules

Developing highly selective sensors for lipopolysaccharide (LPS) in plasma is vital for diagnosing sepsis since LPS is a significant cause of this condition. In this study, dansulfonyl derivatives were introduced as functional monomers in molecularly imprinted polymerization creatively, broadening the choice of functional monomers. The designed hydrophilic and hydrophobic functional monomers, tailored for polysaccharides and lipids of LPS, exhibited high selectivity, sensitivity, and biocompatibility with superior stability and reusability. The fluorescent sensor's limit of detection (LOD) was 0.46 µg/L with a linear response of 1–100 µg/L. The material's performance was compared to commercially available LPS detection kits. This study presents a viable method to fabricate molecularly imprinted fluorescent sensors that are highly responsive to LPS and can detect sepsis-inducing agents. Moreover, the designed sensors can potentially replace animal-derived reagents in LPS detection and can be applied to many solution systems.

Fibrinolysis associated proteins and lipopolysaccharide bioactivity in plasma and cerebrospinal fluid in multiple sclerosis

The coagulation cascade and fibrinolysis have links with neuroinflammation and increased activation of the coagulation system has been reported in MS patients. We quantified levels of D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and the bioactivity of bacterial lipopolysaccharide (LPS) in cerebrospinal fluid (CSF) and plasma from newly diagnosed untreated MS patients and controls. These molecules showed multiple correlations with each other as well as with age, HLA-DRB1*15:01, body-mass-index and CSF IgG. Our results confirm previous findings of increased plasma PAI-1 and LPS in MS patients compared to controls indicating changes in platelet function and gut permeability in MS.

Chronic oral LPS administration does not increase inflammation or induce metabolic dysregulation in mice fed a western-style diet.

Lipopolysaccharides (LPS) present in the intestine are suggested to enter the bloodstream after consumption of high-fat diets and cause systemic inflammation and metabolic dysregulation through a process named "metabolic endotoxemia." This study aimed to determine the role of orally administered LPS to mice in the early stage of chronic low-grade inflammation induced by diet. We supplemented the drinking water with E. coli derived LPS to mice fed either high-fat Western-style diet (WSD) or standard chow (SC) for 7 weeks (n = 16-17). Body weight was recorded weekly. Systemic inflammatory status was assessed by in vivo imaging of NF-κB activity at different time points, and glucose dysregulation was assessed by insulin sensitivity test and glucose tolerance test near the end of the study. Systemic LPS exposure was estimated indirectly via quantification of LPS-binding protein (LBP) and antibodies against LPS in plasma, and directly using an LPS-sensitive cell reporter assay. Our results demonstrate that weight development and glucose regulation are not affected by LPS. We observed a transient LPS dependent upregulation of NF-κB activity in the liver region in both diet groups, a response that disappeared within the first week of LPS administration and remained low during the rest of the study. However, WSD fed mice had overall a higher NF-κB activity compared to SC fed mice at all time points independent of LPS administration. Our findings indicate that orally administered LPS has limited to no impact on systemic inflammation and metabolic dysregulation in mice fed a high-fat western diet and we question the capability of intestinally derived LPS to initiate systemic inflammation through a healthy and uncompromised intestine, even when exposed to a high-fat diet.

Reducing dietary lipopolysaccharides to slow progression of cognitive impairment and Alzheimer’s disease

We hypothesize that a dietary reduction of lipopolysaccharide (LPS) could reduce risk and slow progression of cognitive impairment and Alzheimer’s disease by reducing neuroinflammation. LPS is a component of the highly inflammatory cell membrane of Gram-negative bacteria. LPS and inflammatory cytokines are elevated in Alzheimer’s disease, both in plasma and in the central nervous system. Inflammatory cytokines, triggered by LPS in food, can enter the brain via active transport and induce microglial activation and inflammatory damage, including loss of synapses and neurons. Excess LPS and inflammatory cytokines can also induce blood-brain barrier damage and increase amyloid-β production. The highest dietary sources of LPS are processed meat and dairy products, which can rapidly raise levels of plasma LPS within one to two hours. For example, there was a 65-fold increase in plasma LPS after eating a thin-crust cheese pizza. The LPS in these foods is transported via chylomicrons into the bloodstream. Smaller amounts of LPS from colonic microbiota do not account for the sharp postprandial increase of plasma LPS. Once in the bloodstream, LPS can increase inflammatory cytokines 2-fold to 68-fold within two hours. LPS increases cytokines via LPS binding protein and cluster of differentiation-14, triggering toll-like receptor-4, and activating nuclear factor kappa-B. Nuclear factor kappa-B can increase cytokine levels, including interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha. Practical implications: Even low plasma levels of LPS can reduce cognition. Decreasing brain inflammation by reducing dietary LPS can lower risk of cognitive impairment and dementia.

Effects of altering the ratio of C16:0 and cis-9 C18:1 in rumen bypass fat on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls

BackgroundC16:0 and cis-9 C18:1 may have different effects on animal growth and health due to unique metabolism in vivo. This study was investigated to explore the different effects of altering the ratio of C16:0 and cis-9 C18:1 in fat supplements on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls. Thirty finishing Angus bulls (626 ± 69 kg, 21 ± 0.5 months) were divided into 3 treatments according to the randomized block design: (1) control diet without additional fat (CON), (2) CON + 2.5% palmitic acid calcium salt (PA, 90% C16:0), and (3) CON + 2.5% mixed fatty acid calcium salt (MA, 60% C16:0 + 30% cis-9 C18:1). The experiment lasted for 104 d, after which all the bulls were slaughtered and sampled for analysis.ResultsMA tended to reduce 0–52 d dry matter intake compared to PA (DMI, P = 0.052). Compared with CON and MA, PA significantly increased 0–52 d average daily gain (ADG, P = 0.027). PA tended to improve the 0–52 d feed conversion rate compared with CON (FCR, P = 0.088). Both PA and MA had no significant effect on 52–104 days of DMI, ADG and FCR (P > 0.05). PA tended to improve plasma triglycerides compared with MA (P = 0.077), significantly increased plasma cholesterol (P = 0.002) and tended to improve subcutaneous adipose weight (P = 0.066) when compared with CON and MA. Both PA and MA increased visceral adipose weight compared with CON (P = 0.021). Only PA increased the colonization of Rikenellaceae, Ruminococcus and Proteobacteria in the cecum, and MA increased Akkermansia abundance (P < 0.05). Compared with CON, both PA and MA down-regulated the mRNA expression of Claudin-1 in the jejunum (P < 0.001), increased plasma diamine oxidase (DAO, P < 0.001) and lipopolysaccharide (LPS, P = 0.045). Compared with CON and MA, PA down-regulated the ZO-1 in the jejunum (P < 0.001) and increased plasma LPS-binding protein (LBP, P < 0.001). Compared with CON, only PA down-regulated the Occludin in the jejunum (P = 0.013). Compared with CON, PA and MA significantly up-regulated the expression of TLR-4 and NF-κB in the visceral adipose (P < 0.001) and increased plasma IL-6 (P < 0.001). Compared with CON, only PA up-regulated the TNF-α in the visceral adipose (P = 0.01). Compared with CON and MA, PA up-regulated IL-6 in the visceral adipose (P < 0.001), increased plasma TNF-α (P < 0.001), and reduced the IgG content in plasma (P = 0.035). Compared with CON, PA and MA increased C16:0 in subcutaneous fat and longissimus dorsi muscle (P < 0.05), while more C16:0 was also deposited by extension and desaturation into C18:0 and cis-9 C18:1. However, neither PA nor MA affected the content of cis-9 C18:1 in longissimus dorsi muscle compared with CON (P > 0.05).ConclusionsMA containing 30% cis-9 C18:1 reduced the risk of high C16:0 dietary fat induced subcutaneous fat obesity, adipose tissue and systemic low-grade inflammation by accelerating fatty acid oxidative utilization, improving colonization of Akkermansia, reducing intestinal barrier damage, and down-regulating NF-κB activation.

Plant essential oils combined with organic acids restored lipopolysaccharide-induced leaky intestine via gut microbial modulation in weaned piglets

Intestine derived lipopolysaccharide (LPS) is closely related to systemic inflammation and disorders, yet little is known about its roles in the weanling stress of piglets and its potential as a nutritional intervention target. This study aimed to investigate the potential of essential oils (EO) and organic acids (OA) in mitigating weaning stress in piglets by modulating the circulation of intestine derived LPS. Seventy-two weaned piglets at 21 d old with body weight of 8.12 ± 0.168 kg were randomly divided into a control group (CON) and an experimental group, each consisting of six pens with six piglets per pen, and were fed either a basal diet or a basal diet supplemented with 3 kg/t OA + 500 g/t EO (EO + OA). On the 14th day of the feeding trial, 12 weaned piglets were randomly selected from the CON group, and 6 piglets were selected from the experimental group. Based on diet composition and stress treatment, these 18 piglets were divided into the following three groups: 1) CON group. Piglets were fed a basal diet and received an intraperitoneal injection of saline as a control. 2) LPS group. Piglets were fed a basal diet and received an intraperitoneal injection of LPS (100 μg/kg body weight) to induce stress. 3) EO + OA + LPS group. Piglets were fed a basal diet supplemented with EO and OA and received an intraperitoneal injection of LPS (100 μg/kg body weight) to induce stress. The results showed that EO + OA significantly ameliorated the oxidative imbalance and inflammation disorder induced by LPS in piglets' serum and intestine by inhibiting the activation of the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, compared to the LPS group, supplementation with EO + OA restored LPS-induced reductions in Bcl-2 protein expression in the piglets' intestines (P < 0.05) and mitigated morphological damage; it also enhanced both the protein expression and relative gene expression of the tight junction proteins occludin and claudin-1 (P < 0.05), and reduced the plasma diamine oxidase activity (DAO) and LPS content (P < 0.05). Compared to the CON group, supplementation with EO + OA altered the composition of the intestinal microbiota, increasing beneficial bacteria relative abundance (Faecalibacterium) (P < 0.05) and decreasing harmful bacteria relative abundance [Rikenellaceae_RC9_gut_group (P < 0.01), Negativibacillus (P < 0.05)]. Further analysis revealed that plasma LPS content in piglets was negatively correlated with the relative abundance of Faecalibacterium (r = −0.662, P = 0.021), Akkermansia (r = −0.492, P = 0.031), and average daily gain (ADG) (r = −0.912, P = 0.041). Plasma LPS content was also positively correlated with the plasma inflammatory factors interleukin (IL)-1β (r = 0.591, P = 0.021), IL-6 (r = 0.623, P = 0.021), IL-12 (r = 561, P = 0.031) contents, and the relative abundance of Negativibacillus (r = 0.712, P = 0.041). In summary, the addition of EO + OA prevents the leakage of intestine derived LPS into the circulation by improving intestinal integrity and microbiota composition, thereby enhancing antioxidant and anti-inflammatory abilities and growth performance of weaned piglets.

An exploratory study of a multi-species probiotic formulation and markers of health in a real-world oncological cohort in the time of covid

IntroductionThe efficacy of cancer treatments has links to the intestinal microbiome. Mucositis is a dose-limiting intestinal pro-inflammatory side effect of cancer treatments, that increases the risk of diarrhoea, mucositis, and in severe cases, febrile neutropenia.MethodsThe effect of cancer treatments on Quality of Life (QoL) was assessed using the FACT C questionnaire that included patient wellbeing and gut adverse symptoms (e.g. diarrhoea). Participants rated faecal samples via the Bristol Stool Chart. In addition, bacterial DNA was extracted from faecal samples, sequenced, and taxonomically examined. The incidence / severity of neutropenia was assessed with white blood cell and neutrophil counts. Circulating SCFAs and plasma lipopolysaccharide (LPS) endotoxin levels were recorded and correlated to intestinal mucositis.ResultsImprovement in bowel function, with reduction in constipation and or diarrhoea or absence of significant disturbance to bowel function was recorded in 85% of the participants. One participant developed febrile neutropenia and two developed bowel toxicity during the study, that was unrelated to the test formulation. No significant changes in microbiota alpha- and beta-diversity at the phylum and species levels respectively from baseline to end of study treatment was observed. None of the participants had raised plasma-endotoxin levels from baseline to the first and subsequent treatment cycles for their cancers. Probiotics in this cohort were deemed safe and tolerable. Significant improvement in emotional QoL scores (p = 0.015) was reported with increased number of chemotherapy cycles. In a related observational study of exceptional responders to chemotherapy, participants were found to have had a high intake of fruits, vegetables, and fibre possibly indicative of a more balanced intestinal microbiota.ConclusionA multi-strain probiotic formulation was safe and tolerated in this chronically ill cohort that were undergoing oncological treatment. The probiotic formulation alleviated diarrhoea, constipation and maintained stool consistency/frequency during the multiple treatments with chemotherapy and radiotherapy. Intestinal dysbiosis that is characterised by decreased microbial diversity and increased pro-inflammatory species was not observed. Probiotic supplementation may have helped reduce dysbiosis during cancer treatments. These improvements may have been critical with the observation that emotional wellbeing was significantly improved from baseline. Hence albeit that the study had limitations, the probiotic intervention provided adjunctive treatment support to the patients. What is of scientifically plausible interest is that probiotics have a long association historically with human hosts and as such ratify their inclusion offering a significant adjunctive therapeutic potential. Future studies warrant larger sample sizes, control groups and should limit recruitment to a largely homogenous group of patients.

Risk factors and prognostic value of endotoxemia in patients with acute myocardial infarction.

There is increasing evidence regarding the association between endotoxemia and the pathogenesis of atherosclerosis and myocardial infarction (MI). During the acute phase of MI, endotoxemia might increase inflammation and drive adverse cardiovascular (CV) outcomes. We aimed to explore the risk factors and prognostic value of endotoxemia in patients admitted for acute MI. Patients admitted to the coronary care unit of Dijon University Hospital for type 1 acute MI between 2013 and 2015 were included. Endotoxemia, assessed by plasma lipopolysaccharide (LPS) concentration, was measured by mass spectrometry. Major adverse CV events were recorded in the year following hospital admission. Data from 245 consecutive MI patients were analyzed. LPS concentration at admission markedly increased with age and diabetes. High LPS concentration was correlated with metabolic biomarkers (glycemia, triglyceride, and total cholesterol) but not with CV (troponin Ic peak and N-terminal pro-brain natriuretic peptide) or inflammatory biomarkers (C-reactive protein, IL6, IL8, and TNFα). LPS concentration was not associated with in-hospital or 1-year outcomes. In patients admitted for MI, higher levels of endotoxins were related to pre-existing conditions rather than acute clinical severity. Therefore, endotoxins measured on the day of MI could reflect metabolic chronic endotoxemia rather than MI-related acute gut translocation.

Effects of rumen-protected niacin on inflammatory response to repeated intramammary lipopolysaccharide challenges

Nutritional strategies that improve an animal's resilience to various challenges may improve animal health and welfare. One such nutrient is niacin which has reduced inflammation in mice, humans, and swine; however, niacin's anti-inflammatory effects have not been investigated in cattle. Our objective was to determine whether rumen-protected niacin (RPN) alters lactating dairy cows' inflammatory response to intramammary lipopolysaccharide (LPS) challenges, whether RPN resulted in any carry-over effects, and whether repeated LPS challenges result in signs of immune tolerance or innate immune training. Twenty healthy, late-lactation Holstein cows (232 ± 65 d in milk; 39 ± 5.8 kg/d of milk) were enrolled in a randomized complete block experiment which lasted 70 d. Cows received 26 g/d of RPN or no top-dress (CON) for the first 42 d of the experiment. During the final milking of d 27 and 55, cows were challenged in their rear-right mammary gland (RR) with 100 µg of LPS suspended in 5 mL of phosphate buffered saline. Milk yield, milk conductivity, and feed intake were measured daily. Milk composition was measured on d 14, 23, 24, 30, 37, 45, and 52. Blood samples were collected at 0, 8, 12, 24, 48, 72, 96, and 120 h after each LPS challenge, whereas RR quarter milk samples were collected at 0, 8, 16, 24, 48, 72, 96, 120, 144, and 168 h after each LPS challenge. Body temperature was measured continuously during each challenge with an intravaginal thermometer. Linear mixed models with repeated measures were used to analyze the results. Before LPS challenge, RPN did not affect feed intake or milk production, but it reduced SCS (1.24 ± 0.41 vs. 0.05 ± 0.45). After challenge, RPN did not affect feed intake, milk production, milk composition, SCS, body temperature, plasma glucose, or plasma insulin concentrations. Our results suggest RPN reduced peak plasma haptoglobin and lipopolysaccharide binding protein (LBP) during the 1st LPS challenge. Plasma haptoglobin tended to be less after the 2nd challenge for cows previously supplemented RPN while LBP was similar for each treatment group after the 2nd challenge. The 2nd LPS challenge resulted in decreased plasma haptoglobin compared with the 1st LPS challenge, suggestive of tolerance but it also induced a greater peak SCS than the 1st LPS challenge. Our results suggest that repeated LPS challenges promote a systemic tolerance but heightened local response to LPS-induced mastitis. Feeding RPN reduced SCS before challenge and reduced plasma acute phase proteins after challenge suggesting that RPN may reduce systemic inflammation without altering the local inflammatory responses.