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The Journal of Experimental Medicine Oct 2021Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of...
Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.
Topics: Animals; Bacterial Infections; Body Temperature Regulation; Endotoxemia; Fibroblast Growth Factors; Heart Rate; Inflammation; Klotho Proteins; Lipopolysaccharides; Liver; Mice, Inbred C57BL; Mice, Mutant Strains; Mice
PubMed: 34406362
DOI: 10.1084/jem.20202151 -
Diabetes & Metabolism Apr 2019To study the effects of a functional food-based dietary intervention on faecal microbiota and biochemical parameters in patients with type 2 diabetes (T2D). (Randomized Controlled Trial)
Randomized Controlled Trial
A dietary intervention with functional foods reduces metabolic endotoxaemia and attenuates biochemical abnormalities by modifying faecal microbiota in people with type 2 diabetes.
AIM
To study the effects of a functional food-based dietary intervention on faecal microbiota and biochemical parameters in patients with type 2 diabetes (T2D).
MATERIALS AND METHODS
This placebo-controlled, randomized, double-blind study included 81 patients with T2D divided into two 3-month treatment groups: one following a reduced-energy diet with a dietary portfolio (DP) comprising high-fibre, polyphenol-rich and vegetable-protein functional foods; the other taking a placebo (P). The primary outcome was the effect of the DP on faecal microbiota. Secondary endpoints were biochemical parameters, lipopolysaccharide, branched-chain amino acids, trimethylamine N-oxide, glycosylated haemoglobin (HbA) and free fatty acids (FFAs).
RESULTS
Patients with T2D exhibited intestinal dysbiosis characterized by an increase in Prevotella copri. Dietary intervention with functional foods significantly modified faecal microbiota compared with P by increasing alpha diversity and modifying the abundance of specific bacteria, independently of antidiabetic drugs. There was a decrease in P. copri and increases in Faecalibacterium prausnitzii and Akkermansia muciniphila, two bacterial species known to have anti-inflammatory effects. The DP group also exhibited significant reductions in areas under the curve for glucose, total and LDL cholesterol, FFAs, HbA (P< 0.05), triglycerides and CRP, and an increase in antioxidant activity (P< 0.01) vs. the P group.
CONCLUSION
Long-term adherence to a high-fibre, polyphenol-enriched and vegetable-protein-based diet provides benefits for the composition of faecal microbiota, and may offer potential therapies for improvement of glycaemic control, dyslipidaemia and inflammation.
Topics: Adult; Biomarkers; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Endotoxemia; Feces; Female; Functional Food; Humans; Male; Microbiota; Middle Aged; Treatment Outcome; Young Adult
PubMed: 30266575
DOI: 10.1016/j.diabet.2018.09.004 -
Redox Biology Feb 2023Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive...
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol use disorder (AUD), including alcohol-related liver disease (ARLD). We hypothesized that Aldh2-knockout (KO) mice are more susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased oxidative stress, gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposing Aldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency in Aldh2-KO mice increases their sensitivity to binge alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia in Aldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury through the gut-liver axis. Treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colon cells. These changes were reversed by Alda-1, an ALDH2 activator. Furthermore, CRISPR/Cas9-mediated knockout of ALDH2 in T84 cells increased alcohol-mediated cell damage and paracellular permeability. All these findings demonstrate the critical role of ALDH2 in alcohol-induced epithelial barrier dysfunction and suggest that ALDH2 deficiency or gene mutation in humans is a risk factor for alcohol-mediated gut and liver injury, and that ALDH2 could be an important therapeutic target against alcohol-associated tissue or organ damage.
Topics: Animals; Humans; Mice; Aldehyde Dehydrogenase, Mitochondrial; Endotoxemia; Ethanol; Liver Diseases, Alcoholic; Mice, Knockout; Intestinal Diseases
PubMed: 36528936
DOI: 10.1016/j.redox.2022.102577 -
International Journal of Molecular... Sep 2021Bacterial endotoxin is a potent inflammatory antigen abundant in the human intestine. Endotoxins circulate in the blood at low concentrations in all healthy individuals.... (Review)
Review
Bacterial endotoxin is a potent inflammatory antigen abundant in the human intestine. Endotoxins circulate in the blood at low concentrations in all healthy individuals. Elevated levels of circulatory endotoxins may cause inflammation with the development of chronic disease, either affecting metabolism, neurological disease, or resistance to viral and bacterial infections. The most important endotoxin is LPS, being a superantigen. In this narrative review, the effect of various food components to postprandially elevate circulating LPS and inflammatory markers is described. There is evidence that the intake of food enriched in fat, in particular saturated fat, may elevate LPS and pro-inflammatory markers. This occurs in both normal-weight and obese subjects. In obese subjects, inflammatory markers are already elevated before meal consumption. The importance of food choice for endotoxemia and inflammatory response is discussed.
Topics: Biomarkers; Dietary Fats; Endotoxemia; Food Contamination; Humans; Inflammation; Lipopolysaccharides; Obesity
PubMed: 34502470
DOI: 10.3390/ijms22179562 -
The Canadian Veterinary Journal = La... May 2018Duodenitis-proximal jejunitis (DPJ) is an inflammatory process of the proximal part of the small intestine and occurs sporadically in horses. It is clinically... (Review)
Review
Duodenitis-proximal jejunitis (DPJ) is an inflammatory process of the proximal part of the small intestine and occurs sporadically in horses. It is clinically characterized by an acute onset of ileus and nasogastric reflux leading to systemic signs of toxemia. This review discusses the definition of the disease, potential etiologic agents, clinical findings, epidemiological features, histopathologic and clinico-pathological findings, and medical management of this condition. spp., mycotoxins, and have all been associated with the disease but there is limited supporting evidence for any agent other than Particular attention, however, was given to etiological investigations and the data available to support the proposed etiological agents. The potential role of as the etiological agent of DPJ, possible pathogenesis, and recent efforts to support this hypothesis are highlighted, but it is recognized that there could be more than one agent that causes the disease.
Topics: Animals; Bacteria; Bacterial Infections; Duodenitis; Horse Diseases; Horses; Jejunal Diseases
PubMed: 29904204
DOI: No ID Found -
Journal of Leukocyte Biology Oct 2016Endotoxemia is in its scientific ascendancy. Never has blood-borne, Gram-negative bacterial endotoxin (LPS) been invoked in the pathogenesis of so many diseases-not only... (Review)
Review
Endotoxemia is in its scientific ascendancy. Never has blood-borne, Gram-negative bacterial endotoxin (LPS) been invoked in the pathogenesis of so many diseases-not only as a trigger for septic shock, once its most cited role, but also as a contributor to atherosclerosis, obesity, chronic fatigue, metabolic syndrome, and many other conditions. Finding elevated plasma endotoxin levels has been essential supporting evidence for each of these links, yet the assays used to detect and quantitate endotoxin have important limitations. This article describes several assays for endotoxin in plasma, reviews what they do and do not measure, and discusses why LPS heterogeneity, LPS trafficking pathways, and host LPS inactivation mechanisms should be considered when interpreting endotoxin assay results.
Topics: Biological Transport; Carboxylic Ester Hydrolases; Endotoxemia; Enzyme-Linked Immunosorbent Assay; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intestinal Absorption; Limulus Test; Lipid A; Lipopolysaccharides; Lymph; Neutralization Tests; O Antigens; Structure-Activity Relationship
PubMed: 27418356
DOI: 10.1189/jlb.3RU0316-151R -
Advances in Experimental Medicine and... 2019Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of... (Review)
Review
Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of polymyxin B in humans is restricted because of its nephrotoxicity and neurotoxicity, and this compound was therefore considered a strong candidate ligand for the extracorporeal selective adsorption of circulating endotoxin in the blood. Toraymyxin® is a direct hemoperfusion column that uses polymyxin B attached to an insoluble carrier to bind endotoxin in the blood. In 1994, the Japanese National Health Insurance system approved the use of Toraymyxin for the treatment of endotoxemia and septic shock.In this chapter, we will review the development, clinical use, and efficacy of Toraymyxin, examine the structure of the Toraymyxin column, and comment on the current position of Toraymyxin in the treatment of severe sepsis and septic shock. We will also highlight some potential new applications of Toraymyxin for pulmonary diseases.
Topics: Anti-Bacterial Agents; Endotoxemia; Endotoxins; Hemoperfusion; Humans; Polymyxin B; Sepsis; Shock, Septic
PubMed: 31364085
DOI: 10.1007/978-3-030-16373-0_19 -
Periodontology 2000 Jun 2022Lipopolysaccharide is a virulence factor of gram-negative bacteria with a crucial importance to the bacterial surface integrity. From the host's perspective,... (Review)
Review
Lipopolysaccharide is a virulence factor of gram-negative bacteria with a crucial importance to the bacterial surface integrity. From the host's perspective, lipopolysaccharide plays a role in both local and systemic inflammation, activates both innate and adaptive immunity, and can trigger inflammation either directly (as a microbe-associated molecular pattern) or indirectly (by inducing the generation of nonmicrobial, danger-associated molecular patterns). Translocation of lipopolysaccharide into the circulation causes endotoxemia, which is typically measured as the biological activity of lipopolysaccharide to induce coagulation of an aqueous extract of blood cells of the assay. Apparently healthy subjects have a low circulating lipopolysaccharide activity, since it is neutralized and cleared rapidly. However, chronic endotoxemia is involved in the pathogenesis of many inflammation-driven conditions, especially cardiometabolic disorders. These include atherosclerotic cardiovascular diseases, obesity, liver diseases, diabetes, and metabolic syndrome, where endotoxemia has been recognized as a risk factor. The main source of endotoxemia is thought to be the gut microbiota. However, the oral dysbiosis in periodontitis, which is typically enriched with gram-negative bacterial species, may also contribute to endotoxemia. As endotoxemia is associated with an increased risk of cardiometabolic disorders, lipopolysaccharide could be considered as a molecular link between periodontal microbiota and cardiometabolic diseases.
Topics: Atherosclerosis; Dysbiosis; Endotoxemia; Humans; Inflammation; Lipopolysaccharides; Periodontitis
PubMed: 35244966
DOI: 10.1111/prd.12433 -
Blood Apr 2020Bacterial infection not only stimulates innate immune responses but also activates coagulation cascades. Overactivation of the coagulation system in bacterial sepsis...
Bacterial infection not only stimulates innate immune responses but also activates coagulation cascades. Overactivation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), a widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC by amplifying the release of high-mobility group box 1 (HMGB1) into the bloodstream. Inhibition of the expression of type 1 IFNs and disruption of their receptor IFN-α/βR or downstream effector (eg, HMGB1) uniformly decreased gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the procoagulant activity of tissue factor by promoting the externalization of phosphatidylserine to the outer cell surface, where phosphatidylserine assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but they also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Endotoxemia; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; HMGB1 Protein; Humans; Immunity, Innate; Interferon-alpha; Interferon-beta; Mice, Inbred C57BL
PubMed: 32016282
DOI: 10.1182/blood.2019002282 -
International Journal of Molecular... Nov 2023In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic... (Review)
Review
In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.
Topics: Humans; Esophageal and Gastric Varices; Hepatorenal Syndrome; Reactive Oxygen Species; Endotoxemia; Gastrointestinal Hemorrhage; Liver Cirrhosis; Hypertension, Portal; Oxidative Stress; Inflammation; Cardiomyopathies; Cardiovascular Abnormalities; Endotoxins
PubMed: 38069125
DOI: 10.3390/ijms242316805