Search Results (88)

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut–liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome–mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies—ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation—that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a multifactorial condition linked to liver injury, insulin resistance, and disrupted gut–liver interactions. A key aspect of MASLD pathogenesis is the dysfunction of intestinal barriers, including mechanical, immunological, and microbial alterations that amplify liver damage. The disruption of tight junctions and increased intestinal permeability allow microbial products, such as lipopolysaccharides, to enter the bloodstream, triggering liver inflammation via Kupffer cell activation. In MASLD, the gut vascular barrier is also compromised, marked by increased expression of PV-1. Additionally, dysbiosis, driven by high-fat, high-sugar diets, shifts the gut microbiota toward pro-inflammatory species, exacerbating systemic inflammation and intestinal permeability. This imbalance activates Toll-like receptor signaling, which promotes endotoxin-induced liver injury. Gut dysbiosis further impairs lipid metabolism, contributing to hepatic steatosis and MASLD progression. The gut–liver axis plays a critical role, with factors like altered bile acid metabolism and toxic metabolites such as hydrogen sulfide worsening intestinal barrier function and fueling chronic inflammation. This review aims to explore the complex role of the gut–liver axis in MASLD progression, highlighting the mechanisms of intestinal barrier dysfunction, dysbiosis, and microbial contributions to liver injury. It also discusses therapeutic strategies targeting intestinal barriers, including dietary and microbiota-based interventions, while acknowledging the challenges of personalized treatment approaches. Future research should focus on multi-omics technologies and the safety and efficacy of microbiota-targeted therapies in MASLD management. Full article

Background/Objectives: Systemic and tissue inflammation play a crucial role in the pathophysiology of cardiometabolic disorders. Presepsin is a newly discovered marker of acute phase inflammation that is produced by monocytes or macrophages in response to bacterial infection and is a soluble fraction of the lipopolysaccharide (LPS) receptor. LPS is an endotoxin that, through the breakdown of the intestinal barrier, penetrates the systemic circulation and is an important bacterial mediator in the pathogenesis of sepsis and septic shock. Methods: A narrative review of the existing literature. Results: A growing body of evidence demonstrates that intestinal dysbiosis is involved in the pathogenesis of diabetes mellitus (DM) and cardiovascular (CV) disease, leading to increased circulating LPS concentrations in people with cardiometabolic disorders, even in the absence of infection. These data provide the theoretical background for a link between presepsin, DM, and CV pathology. Preliminary studies suggest that presepsin levels are downregulated in patients with well-controlled type 2 DM and correlate with continuous glucose monitoring metrics in infection-free individuals with type 1 DM. However, prospective data on the association between presepsin and the risk of diabetic complications are currently lacking. Presepsin has also been found to be elevated in infection-free individuals with myocardial infarction, heart failure, and myocarditis compared to controls and has been shown to correlate with mortality risk in subjects at high CV risk. Conclusions: The clinical utility of presepsin in the monitoring of patients with cardiometabolic disorders warrants further investigation by future studies. Full article

Obesity affects the adaptability of adipose tissue (AT), impairing its ability to regulate energy and metabolism. Obesity is associated with many metabolic disorders, including dyslipidemia, hypertension, sleep disorders, non-alcoholic liver disease, and some types of cancer. Toll-like receptors (TLRs) are important in obesity and related metabolic disorders. TLRs are pattern-recognizing receptors (PRRs) involved in the innate immune system and recognize pathogen-associated molecular patterns (PAMPs) and endogenous ligands. TLRs, especially TLR2 and TLR4, are activated by fatty acids, endotoxins, and other ligands. TLR2 and TLR4 activation triggers inflammatory responses. Chronic inflammation driven by TLR activation is a hallmark of obesity and metabolic diseases. The inflammatory response triggered by TLR activation alters insulin signaling, contributing to insulin resistance, a key feature of metabolic syndrome and type 2 diabetes. Modulation of TLR activity through lifestyle changes (diet and exercise), obesity surgery, and pharmacological agents is under study as a possible therapeutic approach to controlling obesity and its complications. Full article

In the early postpartum period, dairy cows undergo significant adaptations in Ca and lipid metabolism, immune function, and inflammatory processes. Concurrent exposure to endotoxins from the uterus, gastrointestinal tract, or mammary gland increases the risk of disease and reproductive problems. Metabolic and inflammatory imbalances during this phase can have both immediate and long-term effects on reproductive health. Associations between metabolic disorders and reproductive outcomes are often confounded by immune activation and systemic inflammation. However, optimal markers, thresholds, and durations for identifying maladaptation and predicting adverse health or reproductive outcomes remain unclear. This narrative review examines key physiological changes during the transition period, including hypocalcemia, lipid mobilization, immune activation, systemic inflammation, and uterine disease. We discuss how these events may affect the dominant follicle, corpus luteum, oocyte, and uterus, potentially leading to prolonged anovulation, reduced estrus expression, impaired response to synchronization protocols, lower progesterone concentrations, and compromised fertility. Understanding these mechanisms will support the development of strategies to monitor, prevent, and mitigate the impacts of transition-related maladaptation on reproductive performance. Such advancements can enhance the health and fertility of high-producing dairy cows. Full article

Lipopolysaccharide (LPS) is a potent endotoxin released at high concentrations in acute infections, causing massive host inflammatory response. Accumulating evidence indicates that dysbiosis-associated chronic low levels of circulating LPS can sustain a prolonged sterile low-grade inflammation that increases the risk of several non-communicable diseases. Interventions aimed at increasing the abundance of beneficial/probiotic bacteria, including Akkermansia muciniphila, result in reduced inflammation, favoring metabolic and immune health. Immunosuppression is a common feature in conditions of chronic inflammation, and dendritic cells (DCs) represent key targets given their ability to shift the balance toward immunity or tolerance. In this study, the effects of low concentrations of LPS from pathogenic (Escherichia coli and Salmonella enterica) and probiotic (Akkermansia muciniphila) bacterial species on human DC generation and functions were compared. We report that monocyte precursor priming with Escherichia coli and Salmonella enterica LPS forces the differentiation of PD-L1-expressing DCs, releasing high levels of IL-6 and IL-10, and impairs their capacity to drive full TCR-Vδ2 T cell activation. Conversely, comparable concentrations of Akkermansia muciniphila promoted the generation of DCs with preserved activating potential and immunostimulatory properties. These results shed light on potential mechanisms underlying the impact of low endotoxemia on disease risk and pathogenesis, and increase our understanding of the immunomodulatory effects of Akkermansia muciniphila. Full article

Background and Objectives: The disruption of the intestinal epithelial barrier leads to increased intestinal permeability (IP), allowing endotoxins and pathogens to enter the bloodstream contributing to chronic inflammation. Western diets are associated with increased IP, while diets rich in polyphenols, fiber, and omega-3 fats are linked to decreased IP. The relationship between diet, disease activity, and IP in ulcerative colitis (UC) is poorly understood. We evaluated the effects of serum zonulin and lipopolysaccharide-binding protein (LBP) and their relationship to dietary factors in UC. Methods: A cross-sectional analysis was conducted on 37 UC participants who had baseline measures of dietary intake, disease activity and serum. Serum LBP and zonulin levels were measured by ELISA. Spearman’s rank correlations explored relationships between baseline IP, diet, and disease activity. Results: The median age was 35 years (29–47 years), 54% were male, and 76% were in clinical remission or had mild disease activity (partial Mayo score ≤ 4). LBP was significantly correlated (p < 0.05) with disease activity (partial Mayo score (r = 0.31), and positively correlated with total fat (r = 0.42) and refined grains (r = 0.35), but negatively correlated with fruit consumption (r = −0.50) and diet quality (r = −0.33). Zonulin was negatively correlated with protein (r = −0.39), niacin (r = −0.52) and vitamin B12 (r = −0.45) with a trend for significance (p = 0.06) with body mass index (r = 0.32). Conclusions: Baseline LBP levels were correlated with disease activity markers and dietary factors, suggesting that it could be a useful biomarker for assessing disease activity and diet quality in UC. Further trials are needed to confirm these findings. Full article

Metabolic dysfunction-associated fatty liver disease (MASLD), a persistent liver condition associated with metabolic syndrome, is primarily caused by excessive fructose intake and a typical Western diet. Because there is currently only one approved treatment, lifestyle and dietary interventions are crucial. This study assessed the effects of dietary intervention involving freeze-dried plum (FDP), a natural source of antioxidants containing diverse polyphenols. This study aimed to assess its potential as a protective agent against the gut–liver axis and its therapeutic effects on liver injury and gut permeability issues associated with MASLD. We indicate that 10% FDP intake restored gut barrier proteins and reduced serum endotoxin levels in the MASLD mouse models. Additionally, 10% FDP intake significantly reduced hepatic oxidative stress, lipid metabolism, and fibrosis marker levels. Interestingly, FDP intake significantly reduced the levels of inflammatory cytokine tumor necrosis factor-α and markers of liver damage, such as serum alanine aminotransferase/aspartate aminotransferase and hepatic triglycerides. These results highlight that dietary intervention with FDP that acts as a natural antioxidant may be a significant protective and therapeutic agent against liver and gut damage caused by MASLD. Full article

Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota–gut–brain axis, including in Alzheimer’s disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the neuroinflammatory processes associated with AD, emphasizing novel insights and therapeutic implications. This review reveals that dysbiosis in AD patients’ gut and oral microbiota is linked to heightened peripheral and central inflammatory responses. Specific bacterial taxa, such as Bacteroides and Firmicutes in the gut, as well as Porphyromonas gingivalis in the oral cavity, are notably altered in AD, leading to significant changes in microglial activation and cytokine production. Gut microbiota alterations are associated with increased intestinal permeability, facilitating the translocation of endotoxins like lipopolysaccharides (LPS) into the bloodstream and exacerbating neuroinflammation by activating the brain’s toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and amyloid peptides, can cross the blood-brain barrier and modulate neuroinflammatory responses. While microbial amyloids may contribute to amyloid-beta aggregation in the brain, certain SCFAs like butyrate exhibit anti-inflammatory properties, suggesting a potential therapeutic avenue to mitigate neuroinflammation. This review not only highlights the critical role of microbiota in AD pathology but also offers a ray of hope by suggesting that modulating gut and oral microbiota could represent a novel therapeutic strategy for reducing neuroinflammation and slowing disease progression. Full article

Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body’s natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis. Full article

Preeclampsia is a multifactorial gestational syndrome characterized by increased blood pressure during pregnancy associated with multiorgan involvement. The impact of this disease on maternal and neonatal health is significant, as it can lead to various fetal comorbidities and contribute to the development of maternal comorbidities later in life. Consistent evidence has shown that the microbiota acts as a regulator of the immune system, and it may, therefore, influence the development of preeclampsia by modulating immune factors. This narrative review aims to investigate the role of the immune system in the pathogenesis of preeclampsia and to summarize the most recent literature on the possible link between preeclampsia and alterations in the intestinal microbiota. To this end, we conducted a literature search, aiming to perform a narrative review, on PubMed and Embase from January 1990 to March 2024, focusing on the latest studies that highlight the main differences in microbial composition between patients with and without preeclampsia, as well as the effects of microbial metabolites on the immune system. From the review of 28 studies assessing the intestinal microbiota in preeclamptic women, preeclampsia could be associated with a state of dysbiosis. Moreover, these patients showed higher plasmatic levels of endotoxin, pro-inflammatory cytokines, and T helper 17 cells; however, the findings on specific microbes and metabolites that could cause immune imbalances in preeclampsia are still preliminary. Full article

In healthy conditions, blood was considered a sterile environment until the development of new analytical approaches that allowed for the detection of circulating bacterial ribosomal DNA. Currently, debate exists on the origin of the blood microbiota. According to advanced research using dark field microscopy, fluorescent in situ hybridization, flow cytometry, and electron microscopy, so-called microbiota have been detected in the blood. Conversely, others have reported no evidence of a common blood microbiota. Then, it was hypothesized that blood microbiota may derive from distant sites, e.g., the gut or external contamination of blood samples. Alteration of the blood microbiota’s equilibrium may lead to dysbiosis and, in certain cases, disease. Cardiovascular, respiratory, hepatic, kidney, neoplastic, and immune diseases have been associated with the presence of Gram-positive and Gram-negative bacteria and/or their products in the blood. For instance, lipopolysaccharides (LPSs) and endotoxins may contribute to tissue damage, fueling chronic inflammation. Blood bacteria can interact with immune cells, especially with monocytes that engulf microorganisms and T lymphocytes via spontaneous binding to their membranes. Moreover, LPSs, extracellular vesicles, and outer membrane vesicles interact with red blood cells and immune cells, reaching distant organs. This review aims to describe the composition of blood microbiota in healthy individuals and those with disease conditions. Furthermore, special emphasis is placed on the interaction of blood microbiota with host cells to better understand disease mechanisms. Full article

Background/Objectives: Insulin resistance is crucial in the pathogenesis of Metabolic Syndrome (MetS), type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). The triglyceride–glucose index (TyG index), a validated measure of insulin resistance, also predicts MetS, T2DM, the severity of albuminuria and ASCVD. There are scant data providing mechanistic insights into these sequalae. Accordingly, we investigated the relationship between the TyG index and biomarkers of inflammation, oxidative stress, free fatty acid (FFA) levels and adipokine dysregulation in a cohort comprising both controls and patients with nascent MetS. Methods: Participants (n = 102) included 59 patients with MetS and 43 controls. People with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Results: Receiver Operating Characteristic (ROC) curve analysis revealed that the TyG index was an excellent predictor of MetS with an area under the curve of 0.87, and it correlated with both hepatic and adipose tissue insulin resistance. Both serum RBP-4 levels and non-HDL cholesterol increased significantly over tertiles of the TyG index. Based on the TyG index tertiles and/or correlations, oxidized LDL, nitrotyrosine, C-reactive protein, endotoxin, chemerin, interleukin-6 levels and monocyte toll-like receptor (TLR)-4 and TLR-2 and their cellular signaling were significantly associated with the TyG index. Conclusions: Increased non-HDL-C and, most importantly, a pro-inflammatory and pro-oxidant state could be advanced as potential mechanisms explaining the increased risk for T2DM and ASCVD with an increasing TyG index. Full article

Background: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. Methods: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25–80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann–Whitney test to assess differences between study groups. Pearson’s correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. Results: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. Conclusions: These findings suggest that the pathogenic changes in the gut–liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations. Full article

Endotoxin is a general term for toxic substances in Gram-negative bacteria, whose damaging effects are mainly derived from the lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, and is a strong pyrogen. Obesity is a chronic, low-grade inflammatory condition, and LPS are thought to trigger and exacerbate it. The gut flora is the largest source of LPS in the body, and it is increasingly believed that altered intestinal microorganisms can play an essential role in the pathology of different diseases. Today, the complex axis linking gut flora to inflammatory states and adiposity has not been well elucidated. This review summarises the evidence for an interconnection between LPS, obesity, and gut flora, further expanding our understanding of LPS as a mediator of low-grade inflammatory disease and contributing to lessening the effects of obesity and related metabolic disorders. As well as providing targets associated with LPS, obesity, and gut flora, it is hoped that interventions that combine targets with gut flora address the individual differences in gut flora treatment. Full article