Endothelial cells like epithelial cells are tightly linked by intercellular adhesion proteins, called tight junctions, which are key regulators of intestinal barrier permeability and integrity. Various dietary or lifestyle agents, such as alcohol consumption, toxic diet or chronic diseases, modulate intestinal permeability; In addition to the direct effect on the epithelium, these factors modulate the intestinal microbiota, inducing dysbiosis. This is the driving force for increased intestinal permeability, with consequent systemic inflammation related to bacterial translocation (BT) and lipopolysaccharide (LPS) endotoxemia overload.
Unhealthy diets and metabolic disorders, such as obesity and type 2 diabetes mellitus, are associated with intestinal barrier dysfunction and dysbiosis, resulting in increased circulating LPS, a condition called metabolic endotoxemia. The low-grade inflammation caused by MS, in turn, establishes a vicious cycle associated with worsening glucose and lipid metabolism, the development of insulin resistance, and nonalcoholic fatty liver disease (NAFLD). and generates a favorable environment for cancer cell transformation and tumor progression [ 42 ]. The combination of dysbiosis and metabolic changes in microbial metabolites and cellular energy pathways promote a pro-inflammatory environment in intestinal cancer.
Short-chain fatty acids (SCFAs) derived from dietary fermentation of dietary fibers are recognized as protective agents against chronic intestinal inflammation, and experimental studies demonstrated that fiber intake improves the composition of the intestinal microbiota, glucose metabolism and lipids and body weight, all recognized factors involved in tumorigenesis.
Both hyperglycemia and intestinal barrier impairment have a recognized oncogenic potential in the development of colorectal cancer (CRC). ME also increases the formation of reactive oxygen species (ROS) and DNA damage, favoring the process of tumorigenesis. The translocation of LPS into the bloodstream triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both preceded by prolonged inflammatory injury; Furthermore, the risk of recurrence and development of metastasis appears to be associated with endotoxemia.
The American Cancer Society has estimated that there will be approximately 300,590 new cases of breast cancer and 153,020 new cases of colorectal cancer in the United States in 2023. The primary function of macrophages is to protect organisms from bacterial and viral infections by secretion of antimicrobial mediators and proinflammatory cytokines. These cells are very sensitive to lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria that is one of the most common factors to which humans and animals are exposed throughout their lives.
Through this examination, we aim to substantiate the influence of ET on cancer development. By analyzing these findings, we propose a possible correlation between the impairment of the immune system caused by ET and the development of cancer. The effect of endotoxin tolerance on cancer cell growth in vitro. Endotoxin-tolerant macrophages release low levels of TNF-α and IL-6 into the medium. Conditioned medium harvested from these macrophages enhances cancer aggressiveness as measured by cell viability, clonogenic potential, and cell motility.
This recent study confirms the susceptibility of macrophages to endotoxins that changes over time and, finally, a state of tolerance to endotoxins develops. Importantly, it is demonstrated for the first time that endotoxin-tolerant macrophages reprogram themselves and release factors that can affect cancer development and behavior.
The gastrointestinal tract is the most important source of endotoxins. Once endotoxins pass the intestinal barrier, through paracellular or transcellular pathways, they trigger an inflammatory response that consumes energy and nutrients necessary for growth and production. Heat stress, mycotoxins, pathogens, feed changes, weaning) increase intestinal permeability and promote the leakage of endotoxins.
This prospective study included 393 young people and examined the associations of endotoxin biomarkers at baseline with adiposity, body mass index (, visceral adipose tissue, subcutaneous adipose tissue, skinfolds, waist circumference) and cardiometabolic risk ( insulin, glucose, adipokines, lipid profile, blood pressure) at both visits using mixed effects regression and with liver fat fraction (HFF) at follow-up using linear regression.
Higher lipopolysaccharide (LPS) and its binding protein, LPS-binding protein (LBP), predicted higher levels of the studied biomarkers. Metabolic endotoxemia may be a shared mechanism underlying childhood obesity and early-onset cardiometabolic diseases.
This study examines dysregulation of intestinal tight junctions, increased permeability of the intestinal barrier, and apoptosis of epithelial cells during the development of intestinal inflammation. The results showed that glycolysis, Krebs cycle and pyrimidine metabolism were affected by intestinal inflammation. In particular, the activity of complex I of the hepatic mitochondrial respiratory chain was significantly increased. Pathogenic bacteria in the intestine, as well as plasma LPS, significantly increased the dysfunctional metabolism of the liver is related to the dislocation of LPS.
In this meta-analysis. Blood endotoxin levels were higher in patients with simple steatosis versus controls with healthy liver as well as in patients with non-alcoholic steatohepatitis versus patients with non-alcoholic fatty liver/non-alcoholic steatohepatitis. Consistently, higher levels of endotoxin were observed in patients with more advanced histopathological grades of steatosis and liver fibrosis. An increase in blood endotoxin levels was partially attributed to an increase in body mass index in patients with NAFLD compared to controls. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations and, in most cases, were paralleled by an increase in markers of intestinal permeability. Results support blood endotoxin levels as relevant diagnostic biomarkers for NAFLD, both for disease detection and staging during disease progression, and could serve as a surrogate marker for increased intestinal permeability in NAFLD. .
BLOOD ENDOTOXIN LEVELS AS BIOMARKER OF NON-ALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
The inflammatory response to endotoxins is mediated by the release of substances including the cytokines interleukins, prostaglandins, and tumor necrosis factor. Interleukins are pyrogenic, meaning they cause the fever response. Apart from inflammation, these substances also participate in the shock response.
The current study evaluates how endotoxins, insomnia, inflammation, and affective disorders interact to alter pain processing in older adults. The study uses endotoxin as a pain model, as it reliably increases pain sensitivity to thermal and deep pressure stimuli, with limited effects on mechanical pain sensitivity.
In this review, we report on the intestinal microbiota, the intestinal barrier (IBI), which prevents the appearance of lipopolysaccharides (LPS), as a fundamental actor in the protective effects mediated by polyphenols against inflammation of white adipose tissue (WAT). associated with obesity. Obesity is associated with an imbalance of micro- and macronutrients, intestinal dysbiosis and a "leaky" intestinal phenomenon. Polyphenols, such as curcumin, resveratrol, and anthocyanins, may alleviate the systemic effects of obesity, potentially improving the gut microbiota, intestinal barrier (IBI), and zinc homeostasis. The essential micronutrient zinc plays a crucial role in regulating enzymatic processes, including inflammation, maintaining microbial ecology, and intestinal barrier integrity. This occurs through mechanisms that block the movement of the bacterial endotoxin LPS. through the intestinal barrier. Polyphenols reduce WAT and systemic inflammation through interaction with inflammatory NF-κB, the mammalian target of rapamycin (mTOR) signaling, and zinc homeostasis.
Zinc is one of the factors that modulates LPS-induced toll-like receptor 4 (Tlr-4)-dependent inflammation. It is a fundamental micronutrient responsible for the proper functioning of most enzymes in maintaining the integrity of the intestinal barrier.
The normal serum zinc concentration in American adults was about 83 µg/dl. People with obesity have low serum levels of zinc. Zinc homeostasis seems essential for a healthy life. The human gut microbiota contains almost 100 times more genetic material than the human genome. Significant fluctuations in diet can alter microbial composition and function in as little as 24 h. However, significant and long-lasting modifications in the composition of the intestinal microbiota may depend on long-term nutritional behaviors.
There is a significant correlation between obesity and levels of LPS or LPS-binding protein (LBP) in the blood. LPS derived from the intestinal microbiota can travel to adipose tissue incorporating high-density lipoproteins (HDL), low-density lipoproteins (LDL) or chylomicrons (CM). LPS initiates inflammatory reactions in WAT.
Numerous studies have demonstrated the beneficial effects of polyphenols on obesity, inflammation and altered composition of the intestinal microbiota. Polyphenols show prebiotic properties, stimulating the growth of probiotic or health-promoting bacteria, also in the intestinal microbiota. The effects of polyphenols on the alteration of the intestinal microbiota are summarized in Table 2.
Metabolic endotoxemia is a term used to describe a low-grade release of bacterial LPS into the systemic circulation. Subsequent studies confirmed a significant correlation between obesity and levels of circulating LPS and lipopolysaccharide binding protein (LBP), a mediator of immune responses to abundant serum LPS.
Treatment with 1 g curcumin/day for 6 weeks was reported to significantly increase serum zinc levels in human subjects with obesity, indicating the possible influence of curcumin on zinc transporters. Resveratrol and quercetin have similar actions
Most studies observe higher concentrations of LPS or LBP in diabetic subjects than in healthy controls. Subjects with DM1 and DM2 presented higher average fasting LPS of 235.7% and 66.4% compared to non-diabetic subjects. diabetics, respectively. Advanced complications (eg, macroalbuminuria) and disease onset exacerbate endotoxemia. DM1 and DM2 appear to increase metabolic endotoxemia. However, some confounding factors such as diet, age, medication, smoking, and obesity influence both the manifestation of diabetes and endotoxemia.
Increased intestinal permeability may contribute to low-grade inflammation, leading to insulin resistance and DM. A healthy intestinal barrier allows the passage of water, nutrients and bioactive compounds, and prevents the passage of harmful substances such as microbial and dietary antigens. DM favors the translocation of endotoxins (especially lipopolysaccharides (LPS)) across the intestinal barrier, leading to a slight increase in their concentration in the bloodstream.
The degradation of intestinal integrity and increased intestinal permeability favor the translocation of LPS from the intestinal lumen to the bloodstream, causing metabolic endotoxemia. LPS has a short half-life, so LPS-binding protein (LBP) has been used as a marker of metabolic endotoxemia.
In general, we observed that diabetic subjects had higher fasting and postprandial LPS concentrations compared to lean nondiabetic and/or obese subjects. Figure 2 shows the possible mechanisms that explain the increase in plasma LPS in diabetic subjects. Fasting endotoxin concentrations appear to change with nutritional and metabolic status (healthy, obese, diabetic, etc.). Endotoxemia is also associated with low-grade inflammation, metabolic syndrome and a different response to LPS in Type 1 diabetes.
Endothelial cells like epithelial cells are tightly linked by intercellular adhesion proteins, called tight junctions, which are key regulators of intestinal barrier permeability and integrity. Various dietary or lifestyle agents, such as alcohol consumption, toxic diet or chronic diseases, modulate intestinal permeability; In addition to the direct effect on the epithelium, these factors modulate the intestinal microbiota, inducing dysbiosis. This is the driving force for increased intestinal permeability, with consequent systemic inflammation related to bacterial translocation (BT) and lipopolysaccharide (LPS) endotoxemia overload.
Unhealthy diets and metabolic disorders, such as obesity and type 2 diabetes mellitus, are associated with intestinal barrier dysfunction and dysbiosis, resulting in increased circulating LPS, a condition called metabolic endotoxemia. The low-grade inflammation caused by MS, in turn, establishes a vicious cycle associated with worsening glucose and lipid metabolism, the development of insulin resistance, and nonalcoholic fatty liver disease (NAFLD). and generates a favorable environment for cancer cell transformation and tumor progression [ 42 ]. The combination of dysbiosis and metabolic changes in microbial metabolites and cellular energy pathways promote a pro-inflammatory environment in intestinal cancer.
Short-chain fatty acids (SCFAs) derived from dietary fermentation of dietary fibers are recognized as protective agents against chronic intestinal inflammation, and experimental studies demonstrated that fiber intake improves the composition of the intestinal microbiota, glucose metabolism and lipids and body weight, all recognized factors involved in tumorigenesis.
Both hyperglycemia and intestinal barrier impairment have a recognized oncogenic potential in the development of colorectal cancer (CRC). ME also increases the formation of reactive oxygen species (ROS) and DNA damage, favoring the process of tumorigenesis. The translocation of LPS into the bloodstream triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both preceded by prolonged inflammatory injury; Furthermore, the risk of recurrence and development of metastasis appears to be associated with endotoxemia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963870/ (2023).-------
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00131-7/fulltext (2023)
https://www.sciencedirect.com/science/article/pii/S277263202100009X (2022).----
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082020/ (2021).----
https://karger.com/dig/article/102/4/508/100644/Gut-Microbiota-Dysbiosis-Drives-the-Development-of (2020).-----
The American Cancer Society has estimated that there will be approximately 300,590 new cases of breast cancer and 153,020 new cases of colorectal cancer in the United States in 2023. The primary function of macrophages is to protect organisms from bacterial and viral infections by secretion of antimicrobial mediators and proinflammatory cytokines. These cells are very sensitive to lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria that is one of the most common factors to which humans and animals are exposed throughout their lives.
Through this examination, we aim to substantiate the influence of ET on cancer development. By analyzing these findings, we propose a possible correlation between the impairment of the immune system caused by ET and the development of cancer. The effect of endotoxin tolerance on cancer cell growth in vitro. Endotoxin-tolerant macrophages release low levels of TNF-α and IL-6 into the medium. Conditioned medium harvested from these macrophages enhances cancer aggressiveness as measured by cell viability, clonogenic potential, and cell motility.
This recent study confirms the susceptibility of macrophages to endotoxins that changes over time and, finally, a state of tolerance to endotoxins develops. Importantly, it is demonstrated for the first time that endotoxin-tolerant macrophages reprogram themselves and release factors that can affect cancer development and behavior.
https://www.mdpi.com/2072-6694/15/20/5113 (2023)
.
The gastrointestinal tract is the most important source of endotoxins. Once endotoxins pass the intestinal barrier, through paracellular or transcellular pathways, they trigger an inflammatory response that consumes energy and nutrients necessary for growth and production. Heat stress, mycotoxins, pathogens, feed changes, weaning) increase intestinal permeability and promote the leakage of endotoxins.
https://www.nutrex.eu/insights/endotoxins-explained/
This prospective study included 393 young people and examined the associations of endotoxin biomarkers at baseline with adiposity, body mass index (, visceral adipose tissue, subcutaneous adipose tissue, skinfolds, waist circumference) and cardiometabolic risk ( insulin, glucose, adipokines, lipid profile, blood pressure) at both visits using mixed effects regression and with liver fat fraction (HFF) at follow-up using linear regression.
Higher lipopolysaccharide (LPS) and its binding protein, LPS-binding protein (LBP), predicted higher levels of the studied biomarkers. Metabolic endotoxemia may be a shared mechanism underlying childhood obesity and early-onset cardiometabolic diseases.
https://academic.oup.com/jcem/article/107/7/e3018/6547256?login=false (2022)
This study examines dysregulation of intestinal tight junctions, increased permeability of the intestinal barrier, and apoptosis of epithelial cells during the development of intestinal inflammation. The results showed that glycolysis, Krebs cycle and pyrimidine metabolism were affected by intestinal inflammation. In particular, the activity of complex I of the hepatic mitochondrial respiratory chain was significantly increased. Pathogenic bacteria in the intestine, as well as plasma LPS, significantly increased the dysfunctional metabolism of the liver is related to the dislocation of LPS.
https://www.frontiersin.org/articles/10.3389/fimmu.2022.981917/full (2022)
In this meta-analysis. Blood endotoxin levels were higher in patients with simple steatosis versus controls with healthy liver as well as in patients with non-alcoholic steatohepatitis versus patients with non-alcoholic fatty liver/non-alcoholic steatohepatitis. Consistently, higher levels of endotoxin were observed in patients with more advanced histopathological grades of steatosis and liver fibrosis. An increase in blood endotoxin levels was partially attributed to an increase in body mass index in patients with NAFLD compared to controls. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations and, in most cases, were paralleled by an increase in markers of intestinal permeability. Results support blood endotoxin levels as relevant diagnostic biomarkers for NAFLD, both for disease detection and staging during disease progression, and could serve as a surrogate marker for increased intestinal permeability in NAFLD. .
BLOOD ENDOTOXIN LEVELS AS BIOMARKER OF NON-ALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
https://www.cghjournal.org/article/S1542-3565(22)01110-7/fulltext (2022)
The inflammatory response to endotoxins is mediated by the release of substances including the cytokines interleukins, prostaglandins, and tumor necrosis factor. Interleukins are pyrogenic, meaning they cause the fever response. Apart from inflammation, these substances also participate in the shock response.
The current study evaluates how endotoxins, insomnia, inflammation, and affective disorders interact to alter pain processing in older adults. The study uses endotoxin as a pain model, as it reliably increases pain sensitivity to thermal and deep pressure stimuli, with limited effects on mechanical pain sensitivity.
https://www.sciencedirect.com/science/article/pii/S266635462300056X (2023)
In this review, we report on the intestinal microbiota, the intestinal barrier (IBI), which prevents the appearance of lipopolysaccharides (LPS), as a fundamental actor in the protective effects mediated by polyphenols against inflammation of white adipose tissue (WAT). associated with obesity. Obesity is associated with an imbalance of micro- and macronutrients, intestinal dysbiosis and a "leaky" intestinal phenomenon. Polyphenols, such as curcumin, resveratrol, and anthocyanins, may alleviate the systemic effects of obesity, potentially improving the gut microbiota, intestinal barrier (IBI), and zinc homeostasis. The essential micronutrient zinc plays a crucial role in regulating enzymatic processes, including inflammation, maintaining microbial ecology, and intestinal barrier integrity. This occurs through mechanisms that block the movement of the bacterial endotoxin LPS. through the intestinal barrier. Polyphenols reduce WAT and systemic inflammation through interaction with inflammatory NF-κB, the mammalian target of rapamycin (mTOR) signaling, and zinc homeostasis.
Zinc is one of the factors that modulates LPS-induced toll-like receptor 4 (Tlr-4)-dependent inflammation. It is a fundamental micronutrient responsible for the proper functioning of most enzymes in maintaining the integrity of the intestinal barrier.
The normal serum zinc concentration in American adults was about 83 µg/dl. People with obesity have low serum levels of zinc. Zinc homeostasis seems essential for a healthy life. The human gut microbiota contains almost 100 times more genetic material than the human genome. Significant fluctuations in diet can alter microbial composition and function in as little as 24 h. However, significant and long-lasting modifications in the composition of the intestinal microbiota may depend on long-term nutritional behaviors.
There is a significant correlation between obesity and levels of LPS or LPS-binding protein (LBP) in the blood. LPS derived from the intestinal microbiota can travel to adipose tissue incorporating high-density lipoproteins (HDL), low-density lipoproteins (LDL) or chylomicrons (CM). LPS initiates inflammatory reactions in WAT.
Numerous studies have demonstrated the beneficial effects of polyphenols on obesity, inflammation and altered composition of the intestinal microbiota. Polyphenols show prebiotic properties, stimulating the growth of probiotic or health-promoting bacteria, also in the intestinal microbiota. The effects of polyphenols on the alteration of the intestinal microbiota are summarized in Table 2.
Metabolic endotoxemia is a term used to describe a low-grade release of bacterial LPS into the systemic circulation. Subsequent studies confirmed a significant correlation between obesity and levels of circulating LPS and lipopolysaccharide binding protein (LBP), a mediator of immune responses to abundant serum LPS.
Treatment with 1 g curcumin/day for 6 weeks was reported to significantly increase serum zinc levels in human subjects with obesity, indicating the possible influence of curcumin on zinc transporters. Resveratrol and quercetin have similar actions
https://www.sciencedirect.com/science/article/pii/S0955286322003102 (2023)
Most studies observe higher concentrations of LPS or LBP in diabetic subjects than in healthy controls. Subjects with DM1 and DM2 presented higher average fasting LPS of 235.7% and 66.4% compared to non-diabetic subjects. diabetics, respectively. Advanced complications (eg, macroalbuminuria) and disease onset exacerbate endotoxemia. DM1 and DM2 appear to increase metabolic endotoxemia. However, some confounding factors such as diet, age, medication, smoking, and obesity influence both the manifestation of diabetes and endotoxemia.
Increased intestinal permeability may contribute to low-grade inflammation, leading to insulin resistance and DM. A healthy intestinal barrier allows the passage of water, nutrients and bioactive compounds, and prevents the passage of harmful substances such as microbial and dietary antigens. DM favors the translocation of endotoxins (especially lipopolysaccharides (LPS)) across the intestinal barrier, leading to a slight increase in their concentration in the bloodstream.
The degradation of intestinal integrity and increased intestinal permeability favor the translocation of LPS from the intestinal lumen to the bloodstream, causing metabolic endotoxemia. LPS has a short half-life, so LPS-binding protein (LBP) has been used as a marker of metabolic endotoxemia.
In general, we observed that diabetic subjects had higher fasting and postprandial LPS concentrations compared to lean nondiabetic and/or obese subjects. Figure 2 shows the possible mechanisms that explain the increase in plasma LPS in diabetic subjects. Fasting endotoxin concentrations appear to change with nutritional and metabolic status (healthy, obese, diabetic, etc.). Endotoxemia is also associated with low-grade inflammation, metabolic syndrome and a different response to LPS in Type 1 diabetes.
https://www.sciencedirect.com/science/article/abs/pii/S0026049516301871 (2017).------
https://www.researchsquare.com/article/rs-2780541/v1 (2023)
Another great article. Thanx Dr Joe
In an article, it is said that sugar can be consumed, but why this one says sugar can cause endotoxin production?
https://takecontrol.substack.com/p/surprising-reason-why-you-may-need-more-carbs