Endotoxin Translocation Research Articles

Study repair function of mucin-2 on the tight junction protein of uterine epithelial cells under bacterial endotoxins

To analysis repair function of mucin-2(MUC2) and glycoprotein particles on the tight junction protein of uterus under bacterial endotoxins. In this experiment, we showed that the thicker mucus layer of the uterus is used to prevent the translocation of endotoxin at 21d postdelivery. When endotoxin acts on the uterus to thin its mucous layer, the cells in the lamina propria of the uterus secrete a large number of glycoprotein particles at 27d postdelivery. Due to a significantly decrease in the expression of glycosyltransferase, the glycoprotein particles are incompletely glycosylation MUC2, which can interact with the cell membrane and are released in large quantities in the form of exocytosis. These glycoprotein particles can significantly repair tight junction proteins in the inter-cellular space and significantly increase the expression of Claudin-1, JAM (Junction adhesion molecule-A), E-cadherin, ZO-1(Zonula occludens-1) and desmosome proteins after endotoxin treatment. The results of the present study show that endotoxins can thin the uterine mucus layer and accelerate the release of incompletely glycosylated MUC2 from lamina propria cells. In inter-cellular spaces, MUC2 can increase its expression levels and distribution area to repair the tight junction structure of cells with larger gaps. Further strengthening of the barrier prevents endotoxin translocation by repairing the tight junction structure of uterine epithelial cells.

Diammonium glycyrrhizinate alleviates iron overload-induced liver injury in mice via regulating the gut-liver axis

BackgroundEvidence indicates a close association between iron overload (IO) and the pathogenesis of chronic liver diseases, highlighting the potential for interventions targeted at IO to impede or decelerate the progression of chronic liver diseases. Diammonium glycyrrhizinate (DG), the medicinal form of glycyrrhizic acid, a principal constituent of licorice, has been clinically employed as a hepatoprotective agent; however, its protective effect against IO-induced liver injury and underlying molecular mechanisms remain elusive. PurposeThe aim of the present study is to investigate the hepatoprotective effect of DG against IO-induced liver injury with a focus on the gut-liver axis. Study design and methodsAnimal models of IO-induced liver injury and DG treatment have been established in vivo. Iron deposition, liver injury, intestinal barrier damage, and liver inflammation were assessed in mice treated with iron dextran or DG. The microbiome composition in feces was analyzed using 16S rRNA full-length sequencing. Bile acids (BAs) profiles in feces were detected by UPLC-Q-TOF-MS technique, and the expression levels of receptors, enzymes or transporters involved in BAs metabolism were also determined. ResultsDG partially reduced the iron deposition and the levels of ferrous ion in the livers of mice with IO, thereby mitigating oxidative damage. DG also improved gut microbiota dysbiosis, repaired intestinal barrier damage, inhibited endotoxin translocation to the liver, and subsequently suppressed TLR4/NF-κB/NLRP3 pathway-mediated liver inflammation caused by IO. Moreover, DG modulated BAs metabolism disorder in IO mice, reducing the accumulation of BAs in the liver. ConclusionDG alleviates IO-induced liver injury in mice by regulating the gut-liver axis. This study provides novel insights into the underlying mechanisms through which DG ameliorates liver injury caused by IO.

Black Rice Extract Reduces Body Weight, Waist Circumference, Body Mass Index and Lipopolysaccharide in Obese Subjects: A Preliminary Study

BACKGROUND: The prevalence of obesity, or an excessive fat accumulation, is keep increasing. In obesity, inflammation can be induced by leaky gut due to the intestinal tight junction barrier dysfunction. Zonula occludens-1 (ZO-1) plays a role in developing intestinal tight junction barrier dysfunction and gut microbiota imbalance, thus promote the translocation of bacterial endotoxin characterized by lipopolysaccharide (LPS) into circulation. Black rice extract (BRE) has been known to have anti-inflammatory property. This study was conducted to investigate the effect of BRE on body weight (BW), waist circumference (WC), body mass index (BMI), ZO-1 and LPS of obese patients.METHODS: Twenty-three male subjects were divided into non-obese group (NOG), obese group (COG) and BRE-obese group (BOG). Subjects in BOG received a daily dose of 5.6 g/day BRE for 4 weeks. BW, WC and BMI, serum ZO-1 and LPS were measured before and after treatment.RESULTS: BRE was prepared successfully and free from microbial contamination. Treatment of BRE for 4 weeks reduce BW (95.40±5.78 vs. 94.59±6.00 kg, p=0.043), WC (109.25±3.55 vs. 107.50±3.46 cm, p=0.000) BMI (32.65±1.86 vs. 32.18±1.80, p=0.000) and LPS (222.27±38.63 vs. 131.63±9.70 ng/mL, p=0.020) of obese subjects. The pre-post ZO-1 levels in all groups were not significantly different (p>0.05).CONCLUSION: Treatment of 5.6 gr BRE daily for four weeks can reduce BW, WC, BMI and serum LPS, but not serum ZO-1 in obese patients. Therefore, BRE may reduce inflammation in obesity.KEYWORDS: black rice, obesity, BW, WC, BMI, LPS, ZO-1

Novelties on Neuroinflammation in Alzheimer's Disease-Focus on Gut and Oral Microbiota Involvement.

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.

The Role of Next-Generation Sequencing (NGS) in the Relationship between the Intestinal Microbiome and Periprosthetic Joint Infections: A Perspective.

Periprosthetic joint infections are still a challenge in orthopedics and traumatology. Nowadays, genomics comes to the aid of diagnosis and treatment, in addition to traditional methods. Recently, a key role of the intestinal microbiota has been postulated, and great efforts are aimed at discovering its interconnection, which shows to be at different levels. Firstly, the gut microbiome influences the immune system through the gut-associated lymphoid tissue (GALT). A balanced microbiome promotes a strong immune response, which is essential to prevent all local and systemic infections, including PJI. Thus, a dysbiosis, i.e., the disruption of this system, leads to an imbalance between the various strains of microorganisms co-existing in the gut microbiome, which can result in a weakened immune system, increasing susceptibility to infections, including PJI. Additionally, the dysbiosis can result in the production of pro-inflammatory mediators that enter the systemic circulation, creating a state of chronic inflammation that can compromise the immune system's ability to fend off infections. Furthermore, the microbiome maintains the integrity of the gut barrier, preventing the translocation of harmful bacteria and endotoxins into the bloodstream; dysbiosis can compromise this protective "wall". In addition, the gut microbiome may harbor antibiotic-resistance genes; during antibiotic treatment for other infections or prophylaxis, these genes may be transferred to pathogenic bacteria, making the treatment of PJI more difficult. In this complex landscape, next-generation sequencing (NGS) technology can play a key role; indeed, it has revolutionized the study of the microbiome, allowing for detailed and comprehensive analysis of microbial communities. It offers insights into the functional potential and metabolic capabilities of the microbiome, studies the collective genome of the microbiome directly from environmental samples sequencing DNA without isolating individual organisms, analyzes the RNA transcripts to understand gene expression and functional activity of the microbiome, analyzes the RNA transcripts to understand gene expression and functional activity of the microbiome, investigates the metabolites produced by the microbiome and studies the entire set of proteins produced by the microbiome. NGS technology, the study of the micromyoma and its implications in the field of orthopedic trauma are innovative topics on which few publications are yet to be found in the international scientific literature. The costs are still high, the focus of research is maximum, and it will certainly change our approach to infections. Our study is an up-to-date review of the hot topic application of NGS in the study and investigation of periprosthetic infections and the microbiome.

Gut microbiota mediates anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice

ABSTRACT Background Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, the potential role of gut microbiota in anxiety induced by the parasite remains unclear. Methods C57BL/6J mice were infected with 10 cysts of T. gondii. Antibiotic depletion of gut microbiota and fecal microbiota transplantation experiments were utilized to investigate the causal relationship between gut microbiota and anxiety. Anxiety-like behaviors were examined by the elevated plus maze test and the open field test; blood, feces, colon and amygdala were collected to evaluate the profiles of serum endotoxin (Lipopolysaccharide, LPS) and serotonin (5-hydroxytryptamine, 5-HT), gut microbiota composition, metabolomics, global transcriptome and neuroinflammation in the amygdala. Furthermore, the effects of Diethyl butylmalonate (DBM, an inhibitor of mitochondrial succinate transporter, which causes the accumulation of endogenous succinate) on the disorders of the gut-brain axis were evaluated. Results Here, we found that T. gondii chronic infection induced anxiety-like behaviors and disturbed the composition of the gut microbiota in mice. In the amygdala, T. gondii infection triggered the microglial activation and neuroinflammation. In the colon, T. gondii infection caused the intestinal dyshomeostasis including elevated colonic inflammation, enhanced bacterial endotoxin translocation to blood and compromised intestinal barrier. In the serum, T. gondii infection increased the LPS levels and decreased the 5-HT levels. Interestingly, antibiotics ablation of gut microbiota alleviated the anxiety-like behaviors induced by T. gondii infection. More importantly, transplantation of the fecal microbiota from T. gondii-infected mice resulted in anxiety and the transcriptomic alteration in the amygdala of the antibiotic-pretreated mice. Notably, the decreased abundance of succinate-producing bacteria and the decreased production of succinate were observed in the feces of the T. gondii-infected mice. Moreover, DBM administration ameliorated the anxiety and gut barrier impairment induced by T. gondii infection. Conclusions The present study uncovers a novel role of gut microbiota in mediating the anxiety-like behaviors induced by chronic T. gondii infection. Moreover, we show that DBM supplementation has a beneficial effect on anxiety. Overall, these findings provide new insights into the treatment of T. gondii-related mental disorders.

Reversal of hepatic accumulation of nordeoxycholic acid underlines the beneficial effects of cholestyramine on alcohol-associated liver disease in mice.

Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.

Mechanistic study of fructus aurantii (Quzhou origin) in regulating ileal reg3g in the treatment for NASH

BackgroundNon-alcoholic steatohepatitis (NASH) is a critical stage in the progression of non-alcoholic fatty liver disease (NAFLD), characterized by obvious inflammation and fibrosis. Because of its high incidence rate and serious consequences, NASH is becoming a global health problem. The influence of endotoxin translocation on NASH is receiving attention. As a traditional Chinese herb that effectively improves hepatic inflammation, Fructus Aurantii (Quzhou origin, FAQ) is widely used in the clinical treatment of NASH. However, the intervention mechanism of FAQ on reg3g and related endotoxin translocation remains unclear. AimTo study the mechanism of the impact by which ileal regenerating family member 3 gamma (reg3g) deficiency and subsequent endotoxin translocation impact the progression of NASH; To elucidate the efficacy and mechanism of FAQ in the treatment of NASH. MethodsClinical serum, ileal tissue, and dynamic NASH model-related analyses collectively confirmed that reg3g is a pivotal gene associated with NASH. Reg3g−/− mice were used to assess the impact of reg3g on liver injury, inflammation, and fibrosis, as well as the underlying mechanism involved. In vitro studies elucidated the regulatory effects of FAQ on reg3g, intestinal barrier function, and intestinal permeability. Subsequently, the efficacy of FAQ was investigated in NASH mouse models. Pathological examinations combined with Western blotting (WB), immunohistochemistry (IHC), and multiplex immunohistochemical (mIHC) analyses were used to evaluate the effects of FAQ on mucosal repair and barrier function. Transepithelial electrical resistance (TEER), fluorescein isothiocyanate-dextran 4 (FD-4) experiments, coupled with enzyme linked immunosorbent assay (ELISA) and chromogenic LAL endotoxin assay were used to confirm intestinal permeability and endotoxin translocation. The results of WB and mIHC reflected the levels of endotoxin recruitment and M1 macrophage polarization in the liver. Parameters such as body weight, transaminases, and cholesterol were utilized to assess the metabolic effects of FAQ. ResultsDecreased expression of reg3g was associated with the progression of NASH. Ileal deficiency in reg3g resulted in damage to the intestinal barrier and permeability, leading to the recruitment of endotoxins via the 'gut-liver' axis to the liver, causing the polarization of M1 macrophages, release of inflammatory factors, excessive inflammation, and activation of hepatic stellate cells (HSCs), leading to fibrosis. FAQ significantly upregulated ileal reg3g expression and the expression of intestinal barrier-related proteins tight junction protein 1 (ZO-1) and occludin (OLCN) in mice (p < 0.05), thereby improving intestinal barrier function and permeability. Reduced intestinal permeability led to decreases in endotoxins entering the bloodstream and accumulating in the liver (p < 0.05). The expression of CD68 suggested reduced polarization of M1 macrophages. Expression levels of actin alpha 2, smooth muscle actin (α-SMA) and extracellular matrix (ECM)-related proteins also decreased, indicating improved liver fibrosis. ConclusionFAQ ameliorates NASH by upregulating the expression of reg3g. The upregulation of reg3g contributes to the repair of the intestinal barrier and permeability, reducing the recruitment of endotoxins and subsequent polarization of M1 macrophages, excessive inflammation, and fibrosis.

Gut barrier dysfunction, endotoxemia and inflammatory response in STEMI patients and effect of primary PCI

BackgroundGut-derived bacterial and endotoxin translocation induce systemic inflammation, which exerts a pivotal pathogenetic role in all phases of atherosclerosis. ObjectivesTo investigate prospectively the gut barrier function, endotoxin translocation and inflammatory response in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary artery intervention (PPCI). MethodsTwenty-seven patients with STEMI that underwent successful PPCI were subjected to peripheral blood sampling at 3-time points; before PPCI (day0), 24 h (day1) and 96 h (day4) after PPCI and were compared with 20 chronic coronary syndrome (CCS) patients and 11 healthy controls. Serum ZO-1, I-FABP and endotoxin concentrations were determined by ELISA. Concentrations of cytokines IL-1β, -6, -8, -10 and TNF-α were determined by flow cytometry. ResultsPatients with STEMI before PPCI (day0) had increased serum ZO-1 and endotoxin, both at significantly higher levels compared to CCS patients. STEMI induced also significant increases of the cytokines IL-6, -8 and -10. After PPCI, a significant improvement of gut barrier integrity (ZO-1) and endotoxemia was observed from the first day. At day4 post PPCI, systemic endotoxin and cytokines IL-6, -8 and -10 levels were reduced to control levels. Serum ZO-1 levels were positively correlated with systemic IL-10 concentrations (r = 0.471). ConclusionSTEMI is associated with gut barrier dysfunction, systemic endotoxemia and inflammatory response, which improve rapidly following successful PPCI.

Salidroside alleviates cholestasis-induced liver fibrosis by inhibiting hepatic stellate cells via activation of the PI3K/AKT/GSK-3β signaling pathway and regulating intestinal flora distribution.

Salidroside (SAL), a phenylpropanoid bioactive compound, has various pharmacological properties, including antioxidant, anti-inflammatory, and hepatoprotective effects. However, the pharmacological effects and mechanisms of action of SAL on cholestatic liver injury are unclear. This study investigated the mechanism and effects of salidroside (SAL) on intestinal flora distribution and hepatic stellate cell (HSC) activation in cholestatic hepatic fibrosis. Bile duct ligation was used to cause cholestasis BALB/c mice. The therapeutic efficacy of SAL in liver fibrosis was assessed via serum/tissue biochemical analyses and liver tissue hematoxylin and eosin and Masson staining. Inflammation and oxidative stress were analyzed using enzyme-linked immunosorbent assay and western blotting. HSC were activated in vitro using lipopolysaccharide, and the effects of SAL on HSC migration and inflammatory factor expression were detected via scratch, transwell, and western blotting assays. The effects of SAL on the PI3K/AKT/GSK-3β pathway in vivo and in vitro were detected using western blotting. 16sRNA sequencing was used to detect the effect of SAL on the diversity of the intestinal flora. Ileal histopathology and western blotting were used to detect the protective effect of SAL on the intestinal mucosal barrier. SAL reduces liver inflammation and oxidative stress and protects against liver fibrosis with cholestasis. It inhibits HSC activation and activates the PI3K/AKT/GSK-3β pathway in vitro and in vivo. Additionally, SAL restores the abundance of intestinal flora, which contributes to the repair of the intestinal mucosal barrier, inhibits endotoxin translocation, and indirectly inhibits HSC activation, reversing the course of cholestatic liver fibrosis. SAL inhibits HSC activation through the PI3K/AKT/GSK-3β pathway and improves intestinal flora distribution, thereby protecting and reversing the progression of hepatic fibrosis.

The relevance of intestinal barrier dysfunction, antimicrobial proteins and bacterial endotoxin in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of end-stage liver disease associated with increased mortality and cardiovascular disease. Obesity and diabetes are the most important risk factors of MASLD. It is well-established that obesity-associated insulin resistance leads to a situation of tissue lipotoxicity characterized by an accumulation of excess fat in non-fat tissues such as the liver, promoting the development of MASLD, and its progression into metabolic dysfunction-associated steatohepatitis. Here, we aimed to review the impact of disrupted intestinal permeability, antimicrobial proteins and bacterial endotoxin in the development and progression of MASLD. Recent studies demonstrated that obesity- and obesogenic diets-associated alterations of intestinal microbiota along with the disruption of intestinal barrier integrity, the alteration in antimicrobial proteins and, in consequence, an enhanced translocation of bacterial endotoxin into bloodstream might contribute to this pathological process through to impacting liver metabolism and inflammation.

Tributyrin Supplementation Rescues Chronic-Binge Ethanol-Induced Oxidative Stress in the Gut-Lung Axis in Mice.

Excessive alcohol consumption increases the severity and worsens outcomes of pulmonary infections, often due to oxidative stress and tissue damage. While the mechanism behind this relationship is multifaceted, recent evidence suggests ethanol-induced changes to the gut microbiome impact the gut-lung axis. To assess this, a chronic-binge ethanol feeding mouse model was used to determine how ethanol altered the gut microbiome, small intestinal epithelial barrier, and immune responses, as well as neutrophil abundance and oxidative stress in the lungs, and how supporting gut health with tributyrin supplementation during chronic-binge ethanol exposure affected these responses. We found that ethanol consumption altered gut bacterial taxa and metabolic processes, distorted small intestinal immune responses, and induced both bacteria and endotoxin translocation into the lymphatic and circulatory systems. These changes were associated with increased neutrophil (Ly6G) presence and markers of oxidative stress, lipocalin-2 and myeloperoxidase, in the lungs. Importantly, tributyrin supplementation during ethanol exposure rescued gut bacterial function (p < 0.05), small intestinal barrier integrity, and immune responses, as well as reducing both Ly6G mRNA (p < 0.05) and lipocalin-2 mRNA (p < 0.01) in the lungs. These data suggest ethanol-associated disruption of gut homeostasis influenced the health of the lungs, and that therapeutics supporting gut health may also support lung health.

A novel approach to the dual sugar test for the assessment of intestinal epithelium permeability in response to exertional heat stress and nutritional intervention

An acute increase in intestinal epithelium permeability is induced by prolonged exertion in the heat, resulting in the translocation of pathogenic bacteria and endotoxins from the lumen into the circulation, causing a systemic inflammatory response and debilitating symptoms(1). Acute exercise-induced gastrointestinal syndrome mimics chronic health conditions with which an impaired intestinal barrier function is associated, including coeliac disease, inflammatory bowel disease, diabetes, Alzheimer’s and liver diseases(2). Intestinal epithelium permeability is typically assessed using a dual sugar absorption test, by administering a drink containing non-metabolisable sugars (e.g. lactulose [L] and L-rhamnose [R]) that can enter the circulation by paracellular translocation when the epithelium is compromised, and are subsequently excreted and measured cumulatively in the urine(3). We aimed to demonstrate that our recently developed ion chromatography protocol(4) can be used to accurately quantify L/R ratio in the plasma of participants exercising in hot ambient conditions and to determine the impact of nutritional intervention on intestinal epithelium permeability. Further, we hypothesised that measuring L/R in plasma collected at intervals during the post-exercise recovery period would reveal more information about intestinal permeability compared to previously published cumulative urine L/R data(3). Endurance-trained participants completed a set of randomised crossover studies, consisting of 2 h running at 60% V˙O2max in temperate, warm and hot ambient conditions (n = 8) and/or in the heat while consuming water, carbohydrate or protein (n = 9). The dual sugar solution was ingested at 90 min of exercise and blood was sampled at 0, 1, 2 and 4 h post-exercise. Plasma sugars were quantified by high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and L/R ratios were compared by two-way repeated measures ANOVA with Tukey’s multiple comparisons. Plasma L/R increased immediately post-exercise in the heat (0.15 ± 0.11) compared with temperate (0.06 ± 0.04, p&lt;0.001) and warm (0.09 ± 0.08, p&lt;0.01) conditions, while consuming glucose before and during exercise alleviated this (0.02 ± 0.02, p&lt;0.001), and this novel information was otherwise missed when measuring urine L/R. Consuming glucose or whey protein hydrolysate during exercise attenuated intestinal permeability from exertional heat stress throughout recovery, with the mean plasma L/R over 4 h reduced from 0.11 ± 0.05 to 0.04 ± 0.03 (p&lt;0.001) and 0.06 ± 0.04 (p&lt;0.01) with glucose and protein, respectively. We recommend using the dual sugar test with quantification of plasma sugars at intervals by HPAEC-PAD to maximise intestinal permeability data collection in exercise gastroenterology research and beyond, as this gives additional acute response information compared to urinary measurements. Our approach can be employed to investigate and develop personalised nutrition strategies that prevent intestinal hyperpermeability during exertional heat stress. This has implications for athlete performance and safety, and can also build upon occupational health and safety practices and inform chronic disease management.

Studies Related to the Involvement of EsA in Improving Intestinal Inflammation in Acute Pancreatitis via the NF-κB Pathway.

Acute pancreatitis (AP) is a clinically frequent acute abdominal condition, which refers to an inflammatory response syndrome of edema, bleeding, and even necrosis caused by abnormal activation of the pancreas's own digestive enzymes. Intestinal damage can occur early in the course of AP and is manifested by impaired intestinal mucosal barrier function, and inflammatory reactions of the intestinal mucosa, among other factors. It can cause translocation of intestinal bacteria and endotoxins, further aggravating the condition of AP. Therefore, actively protecting the intestinal mucosal barrier, controlling the progression of intestinal inflammation, and improving intestinal dynamics in the early stages of AP play an important role in enhancing the prognosis of AP. The viability and apoptosis of RAW264.7 cells treated with Esculentoside A (EsA) and/or lipopolysaccharide were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry, respectively. The expression of apoptosis-related proteins and NF-κB signaling pathway-related proteins were detected by western blot (WB). An enzyme-linked immunosorbent assay was used to measure TNF-α and IL-6 secretion. In vitro experiments demonstrated that EsA not only promoted the apoptosis of inflammatory cells but also reduced the secretion of TNF-α and IL-6 in a dose-dependent manner. Additionally, it inhibited the activation of the NF-κB signaling pathway by decreasing the expression of phosphorylated-p65(p-p65) and elevating the expression of IκBα. Similarly, in vivo experiments using a rat AP model showed that EsA inhibited the expression of p-p65 elevating the expression of IκBα in the intestinal tissues of the rat AP model and promoting the apoptosis of inflammatory cells in the intestinal mucosa in vivo experiments, while improving the pathological outcome of the pancreatic and intestinal tissues. Our results suggest that EsA can reduce intestinal inflammation in the rat AP model and that EsA may be a candidate for treating intestinal inflammation in AP and further arresting AP progression.

Endotoxin Translocation Is Increased in Broiler Chickens Fed a Fusarium Mycotoxin-Contaminated Diet.

Broiler chickens in livestock production face numerous challenges that can impact their health and welfare, including mycotoxin contamination and heat stress. In this study, we aimed to investigate the combined effects of two mycotoxins, deoxynivalenol (DON) and fumonisins (FBs), along with short-term heat stress conditions, on broiler gut health and endotoxin translocation. An experiment was conducted to assess the impacts of mycotoxin exposure on broilers, focusing on intestinal endotoxin activity, gene expression related to gut barrier function and inflammation, and the plasma concentration of the endotoxin marker 3-OH C14:0 either at thermoneutral conditions or short-term heat stress conditions. Independently of heat stress, broilers fed DON-contaminated diets exhibited reduced body weight gain during the starter phase (Day 1-12) compared to the control group, while broilers fed FB-contaminated diets experienced decreased body weight gain throughout the entire trial period (Day 1-24). Furthermore, under thermoneutral conditions, broilers fed DON-contaminated diets showed an increase in 3-OH C14:0 concentration in the plasma. Moreover, under heat stress conditions, the expression of genes related to gut barrier function (Claudin 5, Zonulin 1 and 2) and inflammation (Toll-like receptor 4, Interleukin-1 beta, Interleukin-6) was significantly affected by diets contaminated with mycotoxins, depending on the gut segment. This effect was particularly prominent in broilers fed diets contaminated with FBs. Notably, the plasma concentration of 3-OH C14:0 increased in broilers exposed to both DON- and FB-contaminated diets under heat stress conditions. These findings shed light on the intricate interactions between mycotoxins, heat stress, gut health, and endotoxin translocation in broiler chickens, highlighting the importance of understanding these interactions for the development of effective management strategies in livestock production to enhance broiler health and welfare.

Probiotic Pediococcus pentosaceus Li05 Improves Cholestasis through the FXR-SHP and FXR-FGF15 Pathways

Primary sclerosing cholangitis (PSC), a rare chronic cholestatic liver disease, is characterized by intrahepatic or extrahepatic strictures accompanied by biliary fibrosis. So far, there are no effective therapies to slow down the progression of this disease. Farnesoid X receptors (FXRs) are ligand-activated transcription factors involved in the control of bile acid (BA) synthesis and enterohepatic circulation. Therefore, targeting FXRs holds promise as a potential approach for treating PSC. Pediococcus pentosaceus Li05 is a probiotic that was isolated from healthy volunteers and has previously been shown to have an anti-inflammatory effect in DSS-induced colitis. In this study, we established a 3,5-diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-induced cholestasis mouse model and investigated the effects of Pediococcus pentosaceus Li05 on PSC. Our findings revealed that administration of Li05 significantly attenuated liver damage, hepatic inflammation, and fibrosis, as well as bile duct hyperplasia. Li05 activated the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways to decrease the expression of Cyp7a1. In addition, the Li05-modulated gut microbiota structure especially improved the abundance of 7α-dehydroxylation bacteria like Eubacterium. The intervention of Li05 also improved the intestinal barrier and reduced bacterial endotoxin translocation. Based on these findings, Li05 shows promise for future application as a therapeutic strategy for cholestasis.

Intestinal immunological events of acute and resolved SARS-CoV-2 infection in non-human primates

SARS-CoV-2 infection has been associated with intestinal mucosal barrier damage, leading to microbial and endotoxin translocation, heightened inflammatory responses, and aggravated disease outcomes. This study aimed to investigate the immunological mechanisms associated with impaired intestinal barrier function. We conducted a comprehensive analysis of gut damage and inflammation markers and phenotypic characterization of myeloid and lymphoid populations in the ileum and colon of SARS-CoV-2-exposed macaques during both the acute and resolved infection phases. Our findings revealed a significant accumulation of terminally differentiated and activated CD4+ and CD8+ T cells, along with memory B cells, within the gastrointestinal tract up to 43 days after exposure to SARS-CoV-2. This robust infection-induced immune response was accompanied by a notable depletion of plasmacytoid dendritic cells, myeloid dendritic cells, and macrophages, particularly affecting the colon during the resolved infection phase. Additionally, we identified a population of CX3CR1Low inflammatory macrophages associated with intestinal damage during active viral replication. Elevated levels of immune activation and gut damage markers, and perturbation of macrophage homeostasis, persisted even after the resolution of the infection, suggesting potential long-term clinical sequelae. These findings enhance our understanding of gastrointestinal immune pathology following SARS-CoV-2 infection and provide valuable information for developing and testing medical countermeasures.

INT-767-A Dual Farnesoid-X Receptor (FXR) and Takeda G Protein-Coupled Receptor-5 (TGR5) Agonist Improves Survival in Rats and Attenuates Intestinal Ischemia Reperfusion Injury.

Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park-Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential.

Prunella vulgaris L. attenuates gut dysbiosis and endotoxin leakage against alcoholic liver disease

Ethnopharmacological relevancePrunella vulgaris L. (PVL) is a perennial herb belonging to the Labiate family, first recorded in the “Shen Nong's Classic of the Materia Medica”. PVL can enter the liver and gallbladder channel to show its function in clearing the liver fire, dispersing nodules, dissolving swelling, and improving vision. The traditional use of PVL is to protect liver function and has clinical applications in liver diseases therapy. The modern pharmacological studies have been shown to possess potential hepatoprotection, but its underlying mechanisms against alcoholic liver disease (ALD) in mice remains to be elucidated. Aim of the studyThis study aimed to explore the protective effect and potential mechanism of PVL on alcohol induced liver injury. Materials and methodsWe used Lieber-DeCarli ethanol liquid diet fed Male C57BL/6 mice for four weeks plus a single binge (NIAAA modified model) to establish an ALD model and explored the protective effects of PVL extract against ALD. Western blot, Flow cytometry and RT-qPCR methods were used to detect lipid metabolism disorders and the inflammatory response induced by macrophages in ALD mice, and the gut microbiota composition changes were detected by 16s rRNA to reveal the potential mechanism of PVL against ALD. ResultsIn ALD mice, PVL can ameliorate excessive alcohol intake-induced liver injury and lipid metabolism disorders associated with improvement of gut microbiota dysbiosis and intestinal barrier damage. PVL reduced the translocation of endotoxin, which subsequently inhibits hepatic inflammation mediated by the TLR4/MyD88 signaling pathway. ConclusionThese findings demonstrated the protective potential of PVL against gut dysbiosis and endotoxin leakage in ALD mice, which provides a theoretical basis for PVL against liver diseases.

Gut dysbiosis and the role of probiotics in chronic kidney disease

Chronic inflammatory condition in chronic kidney disease (CKD) patients is associated with increased risk of cardiovascular morbidity and mortality. Gut dysbiosis is assumed as one of leading factors to the chronic inflammatory condition. The relationship between the kidney and the gastrointestinal, knowns as the gut-kidney axis, has a role in production and accumulation of uremic toxins derived from gut microbial fermentation of protein, and translocation of endotoxins and microbial from gut lumen into bloodstream due to alterations of intestinal epithelial barrier in CKD patients. Probiotics supplementation is one of the optional theraphy to restore the gut dysbiosis in CKD patients. Recent studies found that probiotics supplementation in CKD patients decreased uremic toxins and pro-inflammatory cytokines production, and delayed CKD progression. The improvement of this chronic inflammatory condition is expected to decrease cardiovascular disease risk in CKD patients. This review aims to describe the importance of gut-kidney axis in CKD patients, particularly in gut dysbiosis, and the role of probiotics in progression of CKD.