lactoferrin and Endotoxemia

Context • Diet-induced, metabolic endotoxemia is emerging as an important contributory factor to the development of a wide range of chronic diseases, including cardiometabolic, autoimmune, psychiatric, and neurodegenerative illnesses. Emerging human clinical studies have demonstrated that diet and dietary components are potent modifiers of circulating endotoxins and can be used to reduce plasma levels significantly and improve metabolic health. Objective • The aim of the current study was to explore briefly the concept of metabolic endotoxemia and its relationship to disease development, to examine the influence of diet and dietary components on circulating endotoxins, and, finally, discuss the clinical relevance of nutritional interventions for management of metabolic endotoxemia. Design • The researcher performed a literature review of dietary and nutritional interactions with metabolic endotoxemia with a focus on studies relevant to clinical practice. Setting • The study took place at the UK College of Nutrition and Health (London, England). Results • Improving dietary quality, optimizing the intake of phytonutrient-rich foods, improving micronutrient status, consuming fermented foods, manipulating the gut microflora with prebiotics and probiotics, and using specific nutritional supplements, such as glutamine, lactoferrin, resveratrol, and berberine, have been shown to be effective in targeting metabolic endotoxemia. Conclusions • Diet, dietary components, and nutritional supplements, including prebiotics and probiotics, have demonstrated the ability to provide clinically important reductions in circulating endotoxins and improve related sequels, such as inflammation and other negative health markers. The development of personalized nutritional interventions for the management of metabolic endotoxemia is a promising area for future research due to the potential of such interventions to improve multiple aspects of human health and mitigate a wide range of chronic diseases.

Topics: Anti-Infective Agents; Berberine; Diet Therapy; Dysbiosis; Endotoxemia; Fermentation; Glutamine; Humans; Inflammation; Intestinal Mucosa; Lactoferrin; Metabolic Diseases; Permeability; Polyphenols; Prebiotics; Probiotics; Vitamins

Obesity is a strong predictive factor in the development of chronic disease and has now superseded undernutrition as a major public health issue. Chronic inflammation is one mechanism thought to link excess body weight with disease. Increasingly, the gut and its extensive population of commensal microflora are recognized as playing an important role in the development of obesity-related chronic inflammation. Obesity and a high fat diet are associated with altered commensal microbial communities and increased intestinal permeability which contributes to systemic inflammation as a result of the translocation of lipopolysaccharide into the circulation and metabolic endotoxemia. Various milk proteins are showing promise in the prevention and treatment of obesity and chronic low-grade inflammation via reductions in visceral fat, neutralization of bacteria at the mucosa and reduced intestinal permeability. In this review, we focus on evidence supporting the potential antiobesogenic and anti-inflammatory effects of bovine whey-derived lactoferrin and immunoglobulins.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Body Weight; Cattle; Chronic Disease; Disease Models, Animal; Endotoxemia; Functional Food; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Immunoglobulins; Inflammation; Lactoferrin; Lipopolysaccharides; Obesity; Randomized Controlled Trials as Topic; Whey

Lactoferrin, an iron-binding glycoprotein, can be regarded as a cell-secreted mediator that bridges innate and adaptive immune function by regulating target cell response. It is a major pleiotropic mediator that directly assists in the development of T-helper cell polarization. The aim of this minireview is to provide a summary of the most recent work presented at the Lactoferrin Minisymposium at the University of Texas, Health Science Center at Houston, Texas, USA, regarding role of lactoferrin in maintaining immune homeostasis. The data presented here lay emphasis on the significance of lactoferrin in the resolution or progression of the immune responses, thus giving lactoferrin bookend properties in controlling the initial reactions to infectious assault, trauma, and injury. These findings may be critically important in the development of therapeutically relevant protocols.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Cytokines; Endotoxemia; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Inflammation; Intestinal Mucosa; Iron; Lactoferrin; Reactive Oxygen Species

Proinflammatory cytokines released from monocytes/macrophages, in particular tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, and IL-8 seem to play an important role in Inflammatory Bowel Disease (ulcerative colitis and Crohn's disease). Endotoxins or lipopolysaccharides, derived from the outer membrane of Gram-negative bacteria interact with CD14 on surface membrane of macrophages, thus triggering a signal cascade, which leads to the production and release of proinflammatory cytokines, particularly TNF-alpha. Therefore, in IBD, lipopolysaccharides could play a pathogenic role. In this respect, plasma endotoxins have been demonstrated in a not negligible percentage of patients with ulcerative colitis and in their unaffected relatives. The presence of circulating endotoxins could be due, at least in part, to the impaired natural immunity in either patients with ulcerative colitis or in their first degree unaffected relatives. Lactoferrin is an iron-binding glycoprotein, which binds to the lipid A region of lipopolysaccharide with a high affinity and this interaction prevents the binding of lipopolysaccharide to CD14, thus inhibiting the release of proinflammatory cytokines. Therefore, based on the possible pathogenic role exerted by endotoxins in ulcerative colitis, lactoferrin may deserve attention as a possible therapeutical agent in experimental models of Inflammatory Bowel Disease.

Topics: Animals; Antibody Formation; Colitis, Ulcerative; Endotoxemia; Endotoxins; Family; Humans; Immunity, Innate; Lactoferrin; Lipopolysaccharides

Homeostasis is the maintenance of equilibrium in a biological system by means of positive and negative feedback control mechanisms that counteract influences tending toward physiological dissonance. At the molecular level, homeostasis is controlled by the network of the neuro-endocrine-immune system, in which lactoferrin (LF) plays a central role. The purpose of this review is to provide a comprehensive summary of a collaborative study established between the Hirszfeld Institute of Immunology and Experimental Therapy (Wrocław, Poland) and the University of Texas Health Science Center (Houston, USA) regarding LF and its role in homeostasis. In our studies we focused on the immunoregulatory functions of LF, both in vitro and in vivo. We investigated the immune status of individuals subjected to different insults, including experimental endotoxemia in mice and surgery in humans. We also studied a LF-dependent delayed type hypersensitivity (DTH) response to evaluate some of the mechanisms by which LF can effectively substitute an adjuvant in vaccine.

Topics: Adjuvants, Immunologic; Animals; Cytokines; Endotoxemia; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Inflammation; Intestinal Mucosa; Iron; Lactoferrin; Lipopolysaccharides; Reactive Oxygen Species

Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes/ macrophages. In turn, LPS-activated monocytes/ macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12 are the major mediators. Before therapy (To) and at the end of 6-month interferon (IFN)-alpha/Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients. At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg/ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg/ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg/ml). In terms of serum cytokine concentration, at T6 IFN-gamma levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values. The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity. In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration. Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed.

Topics: Autoantibodies; Cytokines; Drug Therapy, Combination; Endotoxemia; Hepatitis C; Humans; Interferon-alpha; Lactoferrin; Lipopolysaccharides; Ribavirin

The article analyzes the results of effect of combined and local cytokine- and ozone therapy on the indices of lipid peroxidation, endogenous intoxication and ferroproteins in 111 patients with diffuse peritonitis. It was shown, that combined sequential local and systemic cytokine and ozone therapy allows correcting the expression of endogenous intoxication and lipid peroxidation in diffuse peritonitis. This method suppresses an inflammation in the abdominal cavity. At the same time, it accelerates the elimination of intestine atony and thereby potentiates the possibilities of traditional methods of treatment.

Topics: Adjuvants, Immunologic; Cytokines; Drainage; Drug Administration Routes; Drug Monitoring; Drug Therapy, Combination; Endotoxemia; Ferritins; Humans; Lactoferrin; Laparotomy; Lipid Peroxidation; Oxidants, Photochemical; Ozone; Peristalsis; Peritoneal Lavage; Peritonitis; Postoperative Complications; Severity of Illness Index; Treatment Outcome

Topics: Alanine; Amino Acid Sequence; Animals; Anti-Bacterial Agents; Cattle; Endotoxemia; Female; Lactoferrin; Lipopolysaccharides; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbial Sensitivity Tests; Peptide Fragments; Salmonella enteritidis; Staphylococcus aureus; Tryptophan

Lactoferrin is a non-heme iron-binding glycoprotein, produced by mucosal epithelial cells and granulocytes in most mammalian species. It is involved in regulation of immune responses, possesses anti-oxidant, anti-carcinogenic, anti-inflammatory properties, and provides protection against various microbial infections. In addition, lactoferrin has been implicated in protection against the development of insult-induced systemic inflammatory response syndrome (SIRS) and its progression into septic conditions in vivo. Here we show a potential mechanism by which lactoferrin lessens oxidative insult at the cellular and tissue levels after lipopolysaccharide (LPS) exposure. Lactoferrin pretreatment of cells decreased LPS-mediated oxidative insults in a dose-dependent manner. Lipopolysaccharide-induced oxidative burst was found to be of mitochondrial origin, and release of reactive oxygen species (ROS) was localized to the respiratory complex III. Importantly, lactoferrin nearly abolished LPS-induced increases in mitochondrial ROS generation and the accumulation of oxidative damage in the DNA. In vivo, pretreatment of experimental animals with lactoferrin significantly (P<0.05) lowered LPS-induced mitochondrial dysfunction as shown by both decreased release of H(2)O(2) and DNA damage in the mitochondria. In contrast, deferoxamine, an iron chelating compound, provided only partial protection in LPS-treated animals. Together, these data suggest that lactoferrin protects against oxidative insult at the mitochondrial level, and indicate a potential utility of lactoferrin in prevention and treatment of SIRS.

Topics: Animals; Deferoxamine; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Immunologic; Electron Transport Complex III; Endotoxemia; Epithelial Cells; Humans; Hydrogen Peroxide; Lactoferrin; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mitochondria; Monocytes; Oxidative Stress; Reactive Oxygen Species; Siderophores; U937 Cells

C3H/HeCr mice are more susceptible to infection compared with other strains. Lactoferrin (LF), a protein involved in innate defense, was shown to protect mice against lethal endotoxemia. In this investigation we attempt to explain the cause of increased susceptibility of C3H/HeCr mice to LPS and lack of protective LF action in these mice. We found that C3H/HeCr mice produced up to 5-fold more serum TNFalpha and 66% higher IFNgamma levels in response to i.v. LPS injection than the control, CBA strain. 24 h pretreatment of C3H/HeCr mice with LF did not cause inhibition of the LPS-induced TNFalpha serum levels, whereas in CBA mice LF significantly decreased TNFalpha level. IL-6 serum levels, in turn, were lowered in C3H/HeCr mice but elevated in CBA mice. That differential regulation of cytokine production by LF in C3H/HeCr mice paralleled a decreased survival after lethal LPS injection - 10% vs. 60% in control, PBS treated mice. In addition, determination of colony forming units (CFU) in livers and spleens after administration of 10(8) Escherichia coli revealed that pretreatment of CBA mice with LF caused a marked reduction of CFU in these organs, whereas in C3H/HeCr mice the changes were insignificant. These results indicate that the altered TNFalpha/IL-6 ratio in C3H/HeCr mice, as compared to control CBA mice, as well as the increased IFNgamma level, may be responsible for the increased susceptibility to endotoxemia in that substrain. We also suggest that an association exists between the LF protective effect against endotoxic sequelae and the insult-induced systemic immune response.

Topics: Animals; Cytokines; Endotoxemia; Escherichia coli; Escherichia coli Infections; Interferon-gamma; Interleukin-6; Lactoferrin; Lipopolysaccharides; Mice; Mice, Inbred C3H; Mice, Inbred CBA; Tumor Necrosis Factor-alpha

Mice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo. Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h post-shock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-alpha (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-alpha and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.

Topics: Animals; Drug Administration Schedule; Drug Evaluation, Preclinical; Endotoxemia; Feedback; Humans; Inflammation Mediators; Injections, Intraperitoneal; Interleukin-10; Interleukin-6; Lactoferrin; Lipopolysaccharides; Mice; Models, Animal; Nitric Oxide; Respiratory Burst; Shock, Septic; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Enterogenic endotoxinemia was induced in 28 Wistar rats by means of intraperitoneal injection of 80 mg/kg carrageenan and intraduodenal administration of 5 x 10(10)/kg Escherichia coli bacteria and 10 mg/kg nebacetin. The control group A received 600 mg/kg albumin in addition via the duodenal probe, and the groups B, C and D received 20, 40 and 80 mg/kg lactoferrin, respectively. The therapeutic effect was investigated by determining the endotoxin activity in the plasma every hour. In addition, the bacterial contamination of peritoneal lavages and mesenteric lymph nodes was checked by incubation for 48 h at 37 degrees C. The period of observation was 5 h. There was a dose-dependent improvement of the endotoxin activity in plasma and the bacterial contamination of the peritoneum cavity and mesenteric lymph nodes after lactoferrin administration. The maximum plasma endotoxin activity could be reduced by 89% with 80 mg/kg lactoferrin.

Topics: Albumins; Animals; Endotoxemia; Endotoxins; Escherichia coli; Lactoferrin; Lymph Nodes; Male; Mesentery; Rats; Rats, Wistar; Statistics, Nonparametric

Lipopolysaccharide (LPS)-induced alterations of gastrointestinal transit were studied in mice using activated charcoal. LPS (10 mg kg-1) induced biphasic alterations of intestinal transit. Increase (acceleration phase) and delay (lag phase) in gastrointestinal transit were observed at 90 and 480 min after LPS injection, respectively. LPS administration induced significant increases in tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and nitrate levels in blood serum with maximal levels observed at 1.5, 4, and 8 h after LPS administration, respectively. The effects of recombinant human lzactoferrin (rhLF) on LPS- induced alteration of gastrointestinal transit, and production of TNF-alpha, IL-1beta and nitrate were also studied. Animals were pretreated with rhLF 24 hours before intraperitoneal administration of LPS. RhLF significantly increased gastrointestinal transit during the lag phase. In addition, rhLF decreased the level of TNF-alpha in endotoxaemic animals. The levels of IL-1beta and nitrate were not significantly changed by rhLF. In conclusion, the effect of LPS on gastrointestinal transit is biphasic and the mechanism controlling the second phase most likely depends on TNF-alpha production, while the first phase most likely does not depend on TNF-alpha. On the other hand, it may be regulated by IL-1beta and nitric oxide production.

Topics: Animals; Cytokines; Endotoxemia; Female; Gastric Emptying; Gastrointestinal Transit; Humans; Interleukin-1; Lactoferrin; Lipopolysaccharides; Mice; Nitric Oxide; Recombinant Proteins; Tumor Necrosis Factor-alpha

The hypothesis that lactoferrin protects mice against lethal effects of bacterial lipopolysaccharide (LPS) is the subject of experimental investigations described in this article. Lipopolysaccharide is a powerful toxin produced by gram negative bacteria that when injected into humans or experimental animals reproduce many of the pathophysiologic and immune responses caused by live bacteria. Lactoferrin administered intraperitoneally 1 hr prior to injection of LPS significantly enhanced the survival of mice, reducing LPS-induced mortality from 83.3% to 16.7%. Changes in locomotor and other behavioral activities resulting from LPS injection were not present in mice treated with lactoferrin. Also, histological examination of intestine revealed remarkable resistance to injury produced by LPS if mice were pretreated with lactoferrin. Severe villus atrophy, edema and epithelial vacuolation were observed in LPS-treated animals but not in lactoferrin-treated counterparts. Electrophysiological parameters were used to assess secretory and absorptive functions in the small intestine. In mice treated with LPS, transmural electrical resistance was reduced and absorption of glucose was increased. Lactoferrin treatment had no significant influence on basal electrophysiological correlates of net ion secretion or glucose absorption nor on changes induced by LPS. Collectively, these results suggest that lactoferrin attenuates the lethal effect of LPS and modulates behavioral and histopathological sequela of endotoxemia.

Topics: Animals; Behavior, Animal; Body Temperature; Electrophysiology; Endotoxemia; Intestinal Mucosa; Jejunum; Lactoferrin; Lipopolysaccharides; Male; Mice; Mice, Inbred Strains; Rectum