Endotoxemia
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Topic Pages
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Toll-like receptors
Endotoxemia reflects circulating LPS activating TLR4–MD2–CD14 on innate immune cells, triggering MyD88/TRIF inflammatory signaling.
News & Publications
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Reduced expression of genes involved in integrity of blood-brain barrier, intestinal barrier in autism: 75% have reduced barrier-forming components www.sciencedaily.com
From the article:
The group analyzed postmortem cerebral cortex and cerebellum tissues from 33 individuals – 8 with ASD, 10 with schizophrenia and 15 healthy controls. Altered expression of genes associated with blood-brain-barrier integrity and function and with inflammation was detected in ASD tissue samples, supporting the hypothesis that an impaired blood-brain barrier associated with neuroinflammation contributes to ASD.
In keeping with the hypothesis that the interplay within the gut-brain axis is a crucial component in the development of neurodevelopmental disorders, the group also analyzed intestinal epithelial tissue from 12 individuals with ASD and 9 without such disorders. That analysis revealed that 75 percent of the individuals affected by ASD had reduced expression of barrier-forming cellular components, compared with controls, and 66 percent showed a higher expression of molecules that increase intestinal permeability.
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Reservatrol strengthens tight-junction proteins in the blood-brain barrier and protects against oxidized LDL academic.oup.com
Abstract
“Cerebrovascular endothelial cells (CEC) comprise the blood-brain barrier (BBB). In a previous study, we showed that oxidized LDL (oxLDL) can induce apoptosis of mouse CEC. Resveratrol possesses chemopreventive potential. This study aimed to evaluate the effects of resveratrol on oxLDL-induced insults to mouse CEC and its possible mechanisms. Exposure of mouse CEC to 200 μmol/L oxLDL for 1 h did not cause cell death but significantly altered the permeability and transendothelial electrical resistance of the cell monolayer. However, resveratrol completely normalized such injury. As for the mechanisms, resveratrol completely protected oxLDL-induced disruption of F-actin and microtubule cytoskeletons as well as occludin and zona occludens-1 (ZO-1) tight junctions. The oxLDL-induced decreases in the mitochondrial membrane potential and intracellular ATP levels were normalized by resveratrol. Exposure of mouse CEC to 200 μmol/L oxLDL for 24 h elevated oxidative stress and simultaneously induced cell apoptosis. However, resveratrol partially protected against oxLDL-induced CEC apoptosis. The oxLDL-induced alterations in levels of Bcl-2, Bax, and cytochrome c were completely normalized by resveratrol. Consequently, resveratrol partially decreased oxLDL-induced activation of caspases-9 and -3. Therefore, in this study, we show that resveratrol can protect against oxLDL-induced damage of the BBB through protecting disruption of the tight junction structure and apoptotic insults to CEC.”
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Resveratrol reinforces the blood-brain barrier and reverses dysfunction due to diabetes www.sciencedaily.com
“The largest nationwide clinical trial to study high-dose resveratrol long-term in people with mild to moderate Alzheimer’s disease found that a biomarker that declines when the disease progresses was stabilized in people who took the purified form of resveratrol. Resveratrol is a naturally occurring compound found in foods such as red grapes, raspberries, dark chocolate and some red wines.”
Abstract “Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-κB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-κB α and IκB kinase β mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.”
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Leaking of the blood-brain barrier disrupts healthy aging and memory www.sciencedaily.com
Abstract:
“The blood–brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain and brain-to-blood permeation of many substances, resulting in nourishment of the CNS, its homeostatic regulation and communication between the CNS and peripheral tissues. The cells forming the BBB communicate with cells of the brain and in the periphery. This highly regulated interface changes with healthy aging. Here, we review those changes, starting with morphology and disruption. Transporter changes include those for amyloid beta peptide, glucose and drugs. Brain fluid dynamics, pericyte health and basement membrane and glycocalyx compositions are all altered with healthy aging. Carrying the ApoE4 allele leads to an acceleration of most of the BBB’s age-related changes. We discuss how alterations in the BBB that occur with healthy aging reflect adaptation to the postreproductive phase of life and may affect vulnerability to age-associated diseases.”
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Increased permeability of the blood brain barrier www.sciencedaily.com
“Endothelial cells of blood vessels of the central nervous system (CNS) constitute blood-CNS barriers. Barrier properties are not intrinsic to these cells; rather they are induced and maintained by CNS microenvironment. Notably, the abluminal surfaces of CNS capillaries are ensheathed by pericytes and astrocytes. However, extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted by CNS pericytes, as a regulator of blood-CNS barrier function via interactions with its integrin receptor, α5, in endothelial cells. Genetic ablation of vitronectin or mutating vitronectin to prevent integrin binding, as well as endothelial-specific deletion of integrin α5, causes barrier leakage in mice. Furthermore, vitronectin-integrin α5 signaling maintains barrier integrity by actively inhibiting transcytosis in endothelial cells. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.”
- Link to full report.00184-2)
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Daily apple consumption decreases multiple markers of obesity-associated inflammation. academic.oup.com
Obesity is characterized by chronic low-grade inflammation, which contributes to the development of cardiovascular disease. While processed foods and beverages high in saturated fats and simple sugars are associated with a higher risk of cardiovascular disease, diets rich in plant-based foods, including fruits, are associated with a lower risk. Findings of a recent report detail the effects of daily apple consumption on inflammation, endotoxemia, and metabolism.
Causes of obesity-associated inflammation include leaky gut, a condition where the intestinal barrier is compromised, leading to increased levels of bacterial endotoxin (toxins that are released when bacteria die) in the bloodstream (called endotoxemia). This increase in endotoxin levels activates white blood cells to secrete pro-inflammatory cytokines such as interleukin (IL)-6 and IL-17. Plant foods such as apples are beneficial for people with obesity because they are rich in bioactive compounds that decrease inflammation and dietary fibers that strengthen the gut barrier.
The researchers recruited 46 participants with overweight and obesity and directed them to avoid foods and beverages rich in polyphenols and/or dietary fibers (e.g., coffee, vegetables, grains, beans, and red/purple/blue fruits) for two weeks. Next, they assigned half of the participants to consume three Gala apples per day for six weeks or to avoid apples. Both groups continued to eat a diet with limited polyphenols and dietary fibers. Participants provided blood samples for the collection of white blood cells and measurement of pro-inflammatory cytokines. After isolating the white blood cells, the researchers stimulated them with endotoxin and measured their response.
Apple consumption decreased plasma C-reactive protein (a pro-inflammatory cytokine) by 17 percent, IL-6 by 12 percent, and endotoxin-binding protein by 20 percent compared with no apple consumption. White blood cells from participants who consumed apples secreted 28 percent less IL-6 and 11 percent less IL-17. While apple consumption increased total antioxidant capacity in blood by 10 percent, it had no effect on cardiovascular disease markers.
These findings suggest that six weeks of daily Gala apple consumption helped mitigate inflammation in those consuming a diet low in polyphenols and fiber, a common feature of the Western diet pattern. Apple consumption may decrease cardiovascular disease risk in those with obesity, even without weight loss.
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Probiotic Bifidobacterium strains and galactooligosaccharides improve intestinal barrier function in obese adults microbiomejournal.biomedcentral.com
Full Title: Probiotic Bifidobacterium strains and galactooligosaccharides improve intestinal barrier function in obese adults but show no synergism when used together as synbiotics
Background: One way to improve both the ecological performance and functionality of probiotic bacteria is by combining them with a prebiotic in the form of a synbiotic. However, the degree to which such synbiotic formulations improve probiotic strain functionality in humans has not been tested systematically. Our goal was to use a randomized, double-blind, placebo-controlled, parallel-arm clinical trial in obese humans to compare the ecological and physiological impact of the prebiotic galactooligosaccharides (GOS) and the probiotic strains Bifidobacterium adolescentis IVS-1 (autochthonous and selected via in vivo selection) and Bifidobacterium lactis BB-12 (commercial probiotic allochthonous to the human gut) when used on their own or as synbiotic combinations. After 3 weeks of consumption, strain-specific quantitative real-time PCR and 16S rRNA gene sequencing were performed on fecal samples to assess changes in the microbiota. Intestinal permeability was determined by measuring sugar recovery in urine by GC after consumption of a sugar mixture. Serum-based endotoxin exposure was also assessed.
Results: IVS-1 reached significantly higher cell numbers in fecal samples than BB-12 (P < 0.01) and, remarkably, its administration induced an increase in total bifidobacteria that was comparable to that of GOS. Although GOS showed a clear bifidogenic effect on the resident gut microbiota, both probiotic strains showed only a non-significant trend of higher fecal cell numbers when administered with GOS. Post-aspirin sucralose:lactulose ratios were reduced in groups IVS-1 (P = 0.050), IVS-1 + GOS (P = 0.022), and GOS (P = 0.010), while sucralose excretion was reduced with BB-12 (P = 0.002) and GOS (P = 0.020), indicating improvements in colonic permeability but no synergistic effects. No changes in markers of endotoxemia were observed.
Conclusion: This study demonstrated that “autochthony” of the probiotic strain has a larger effect on ecological performance than the provision of a prebiotic substrate, likely due to competitive interactions with members of the resident microbiota. Although the synbiotic combinations tested in this study did not demonstrate functional synergism, our findings clearly showed that the pro- and prebiotic components by themselves improved markers of colonic permeability, providing a rational for their use in pathologies with an underlying leakiness of the gut.
Keywords: Synbiotic, Probiotic, Prebiotic, Obesity, Gut barrier function, Autochthonous, Allochthonous, Galactooligosaccharide, Bifidobacteria, Bifidobacterium
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Sulforaphane (found in broccoli sprouts) causes 20% fat loss by changing gut bacteria & increasing mitochondria in fat in mice. www.sciencedaily.comGut Obesity Microbiome Metabolism Inflammation Sulforaphane Fatty Liver NRF2 Endotoxemia Lipopolysaccharide Visceral Fat
Sulforaphane from broccoli sprouts causes 20% visceral fat loss by changing gut bacteria and increasing mitochondria in fat in mice. The mice fed sulforaphane also lowered fatty liver and reduced blood glucose levels. Sulforaphane reduced inflammation by decreasing a species of bacteria in the gut that is responsible for producing endotoxin, which is a major source of inflammation. Also, sulforaphane increased the levels of UCP1, which is responsible for increasing mitochondrial biogenesis (the generation of new mitochondria) in fat (called browning of fat). The browning of fat increases fat metabolism and can lead to fat loss. There have been human studies showing that sulforaphane decreases inflammatory biomarkers and improves blood glucose levels. It will be interesting to see future studies looking at these two new functions of sulforaphane in humans. For more information check out my video on sulforaphane or my podcast with Dr. Jed Fahey, who discovered broccoli sprouts are the best source of sulforaphane. Sulforaphane video: https://youtu.be/zz4YVJ4aRfg Sulforaphane podcast: https://youtu.be/Q0lBVCpq8jc