Endotoxin Translocation Research Articles

C/EBP\u03b4 protects from radiation-induced intestinal injury and sepsis by suppression of inflammatory and nitrosative stress

Ionizing radiation (IR)-induced intestinal damage is characterized by a loss of intestinal crypt cells, intestinal barrier disruption and translocation of intestinal microflora resulting in sepsis-mediated lethality. We have shown that mice lacking C/EBPδ display IR-induced intestinal and hematopoietic injury and lethality. The purpose of this study was to investigate whether increased IR-induced inflammatory, oxidative and nitrosative stress promote intestinal injury and sepsis-mediated lethality in Cebpd−/− mice. We found that irradiated Cebpd−/− mice show decreased villous height, crypt depth, crypt to villi ratio and expression of the proliferation marker, proliferating cell nuclear antigen, indicative of intestinal injury. Cebpd−/− mice show increased expression of the pro-inflammatory cytokines (Il-6, Tnf-α) and chemokines (Cxcl1, Mcp-1, Mif-1α) and Nos2 in the intestinal tissues compared to Cebpd+/+ mice after exposure to TBI. Cebpd−/− mice show decreased GSH/GSSG ratio, increased S-nitrosoglutathione and 3-nitrotyrosine in the intestine indicative of basal oxidative and nitrosative stress, which was exacerbated by IR. Irradiated Cebpd-deficient mice showed upregulation of Claudin-2 that correlated with increased intestinal permeability, presence of plasma endotoxin and bacterial translocation to the liver. Overall these results uncover a novel role for C/EBPδ in protection against IR-induced intestinal injury by suppressing inflammation and nitrosative stress and underlying sepsis-induced lethality.

Prevention of Gut Barrier Dysfunction During Acute Massive Blood Loss (Experimental Study)

Purpose of the study: to investigate the influence of hypovolemia correction by infusion of malate-containing preparations and subsequent glutamine-enriched nutritional support on the maintenance of gut barrier and overhydration in animals with acute massive blood loss/ Materials and methods. Blood samples were harvested from the tail and portal veins of rats (n=100) at different time points after the acute blood loss (>30% V/V) . Bacterial blood cultures for growth, lipopolysaccharide and presepsin concentrations, colon structures and animal weight were analyzed in blood and plasma specimens 1 hour, one day and 3 days after the hypovolemia correction. To correct the hypovolemia, in the 1st series of experiments, the Ringer’s solution and standard nutrient mixture were used; in the 2nd series malatecontaining solution and standard nutrient mixture were administered; in the 3rd series a malate-containing solution and glutamine-enriched nutrient mixture were employed.Results. In the portal vein blood of intact animals, endotoxin measurement was equal to 17.8Ѓ}3.9 pg/ml, that of presepsin — 405.6Ѓ}80.1 pg/ml. At all stages, tail and portal blood bacterial cultures were negative demonstrating an absence of bacterial growth and gut barrier intactness for live microorganisms. One hour after hypovolemia correction and blood reinfusion, multifold increase in endotoxin concentration in the blood from both portal and tail veins was accompanied by significant increase of presepsin concentration. 24 hours after the blood loss, in the animals of the 2nd and 3rd series, the levels of endotoxin, presepsin, and edema of the colon mucous membrane and submucosal space has become lower than those in the 1st series. Three days later, the advantages of glutamine-containing nutrition in the 3rd series of the experiment were determined that revealed decreasing the endotoxin and presepsin concentrations in the portal and tail vein blood and diminishing the levels of interstitial edema of colon and animal weight growth.Conclusion. Administration of malate-containing infusion preparations and glutamine-enriched nutrition after an acute massive blood loss contributes to decreasing presepsin production in GIT organs, abrogating endotoxin translocation into the portal vein and systemic circulation, lessening severity of edema of the mucous membrane and submucosal space of the colon, and reducing the previously increased animal body mass.

Microbiota-Immune Interaction in the Pathogenesis of Gut-Derived Infection.

Gut-derived infection is among the most common complications in patients who underwent severe trauma, serious burn, major surgery, hemorrhagic shock or severe acute pancreatitis (SAP). It could cause sepsis and multiple organ dysfunction syndrome (MODS), which are regarded as a leading cause of mortality in these cases. Gut-derived infection is commonly caused by pathological translocation of intestinal bacteria or endotoxins, resulting from the dysfunction of the gut barrier. In the last decades, the studies regarding to the pathogenesis of gut-derived infection mainly focused on the breakdown of intestinal epithelial tight junction and increased permeability. Limited information is available on the roles of intestinal microbial barrier in the development of gut-derived infection. Recently, advances of next-generation DNA sequencing techniques and its utilization has revolutionized the gut microecology, leading to novel views into the composition of the intestinal microbiota and its connections with multiple diseases. Here, we reviewed the recent progress in the research field of intestinal barrier disruption and gut-derived infection, mainly through the perspectives of the dysbiosis of intestinal microbiota and its interaction with intestinal mucosal immune cells. This review presents novel insights into how the gut microbiota collaborates with mucosal immune cells to involve the development of pathological bacterial translocation. The data might have important implication to better understand the mechanism underlying pathological bacterial translocation, contributing us to develop new strategies for prevention and treatment of gut-derived sepsis.

Apolipoprotein A-I mimetics mitigate intestinal inflammation in COX2-dependent inflammatory bowel disease model.

Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2 KO but not WT mice. Cox2 MKO increased pro-inflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2 MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, while administration of an LXA4 analog rescued disease in Cox2 MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2 MKO/CCHF and piroxicam-accelerated Il10-/- models of inflammatory bowel disease (IBD) and reduced elevated levels of pro-inflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2 MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides: i) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (oxPAPC) dependent pro-inflammatory responses in human macrophages and intestinal epithelium; and ii) directly cleared pro-inflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for pro-inflammatory and inflammation resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.

The role of the gut microbiome in chronic liver disease: the clinical evidence revised.

SummaryRecent research has suggested a role for the intestinal microbiota in the pathogenesis and potential treatment of a wide range of liver diseases. The intestinal microbiota and bacterial products may contribute to the development of liver diseases through multiple mechanisms including increased intestinal permeability, chronic systemic inflammation, production of short-chain fatty acids and changes in metabolism. This suggests a potential role for pre-, pro- and synbiotic products in the prevention or treatment of some liver diseases. In addition, there is emerging evidence on the effects of faecal microbial transplant. Herein, we discuss the relationship between the intestinal microbiota and liver diseases, as well as reviewing intestinal microbiota-based treatment options that are currently being investigated.

A Mechanistic Model of Gut–Brain Axis Perturbation and High-Fat Diet Pathways to Gut Microbiome Homeostatic Disruption, Systemic Inflammation, and Type 2 Diabetes

Type 2 diabetes (T2D) is a highly prevalent metabolic disease, affecting nearly 10% of the American population. Although the etiopathogenesis of T2D remains poorly understood, advances in DNA sequencing technologies have allowed for sophisticated interrogation of the human microbiome, providing insight into the role of the gut microbiome in the development and progression of T2D. An emerging body of research reveals that gut-brain axis (GBA) perturbations and a high-fat diet (HFD), along with other modifiable and nonmodifiable risk factors, contribute to gut microbiome homeostatic imbalance. Homeostatic imbalance or disruption increases gut wall permeability and facilitates translocation of endotoxins (lipopolysaccharides) into the circulation with resultant systemic inflammation. Chronic, low-grade systemic inflammation ensues with pro-inflammatory pathways activated, contributing to obesity, insulin resistance (IR), pancreatic β-cell decline, and, thereby, T2D. While GBA perturbations and HFD are implicated in provoking these conditions, prior mechanistic models have tended to examine HFD and GBA pathways exclusively without considering their shared pathways to T2D. Addressing this gap, this article proposes a mechanistic model informed by animal and human studies to advance scientific understanding of (1) modifiable and nonmodifiable risk factors for gut microbiome homeostatic disruption, (2) HFD and GBA pathways contributing to homeostatic disruption, and (3) shared GBA and HFD pro-inflammatory pathways to obesity, IR, β-cell decline, and T2D. The proposed mechanistic model, based on the extant literature, proposes a framework for studying the complex relationships of the gut microbiome to T2D to advance study in this promising area of research.

Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine

The antidiabetic drug metformin has been proposed to affect non-alcoholic fatty liver disease (NAFLD) through its effects on intestinal microbiota and barrier function. However, so far most studies focused on long-term effects and more progressed disease stages. The aim of this study was to assess in two experimental settings, if the onset of NAFLD is associated with changes of intestinal microbiota and barrier function and to determine effects of metformin herein. C57Bl/6J mice were fed a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) for four days or six weeks ±300 mg/kg BW/day metformin (Met). Markers of liver health, intestinal barrier function and microbiota composition were assessed. Metformin treatment markedly attenuated FFC-induced NAFLD in both experiments with markers of inflammation and lipidperoxidation in livers of FFC + Met-fed mice being almost at the level of controls. Metformin treatment attenuated the loss of tight junction proteins in small intestine and the increase of bacterial endotoxin levels in portal plasma. Changes of intestinal microbiota found in FFC-fed mice were also significantly blunted in FFC + Met-fed mice. Taken together, protective effects of metformin on the onset of NAFLD are associated with changes of intestinal microbiota composition and lower translocation of bacterial endotoxins.

SAT-338-Oral arginine supplementation attenuates the progression of steatosis to non-alcoholic steatohepatitis through preventing translocation of bacterial endotoxin

SAT-338-Oral arginine supplementation attenuates the progression of steatosis to non-alcoholic steatohepatitis through preventing translocation of bacterial endotoxin

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain...

Intestinal barrier and intestinal endotoxemia

Intestinal dysfunction can be induced under infection, trauma or stress.The intestinal mucosal barrier injury is a common pathophysiological process in critically ill patients.The bowel is one of the earliest and most severely affected organ under severe infection and tissue hypoxia-ischemia.Intestinal damage leads to a large number of bacterial flora shift, resulting in intestinal infection, intestinal endotoxemia and intestinal sepsis.In recent years, gastrointestinal barrier function has attracted people′s attention, which is closely related to the prognosis of critically ill patients.This article described the normal intestinal barrier function, the effects of trauma and stress on intestinal barrier function, bacterial group migration, and the effects of endotoxin translocation on the body and its prevention and treatment. Key words: Trauma; Stress; Bacterial translocation; Endotoxemia; Intestinal barrier

Green tea extract prevents obesity in male mice by alleviating gut dysbiosis in association with improved intestinal barrier function that limits endotoxin translocation and adipose inflammation

Gut-derived endotoxin translocation provokes obesity by inducing TLR4/NFκB inflammation. We hypothesized that catechin-rich green tea extract (GTE) would protect against obesity-associated TLR4/NFκB inflammation by alleviating gut dysbiosis and limiting endotoxin translocation. Male C57BL/6J mice were fed a low-fat (LF) or high-fat (HF) diet containing 0% or 2% GTE for 8 weeks. At Week 7, fluorescein isothiocyanate (FITC)-dextran was administered by oral gavage before assessing its serum concentrations as a gut permeability marker. HF-feeding increased (P<.05) adipose mass and adipose expression of genes involved in TLR4/NFκB-dependent inflammation and macrophage activation. GTE attenuated HF-induced obesity and pro-inflammatory gene expression. GTE in HF mice decreased serum FITC-dextran, and attenuated portal vein and circulating endotoxin concentrations. GTE in HF mice also prevented HF-induced decreases in the expression of intestinal tight junction proteins (TJPs) and hypoxia inducible factor-1α while preventing increases in TLR4/NFκB-dependent inflammatory genes. Gut microbial diversity was increased, and the Firmicutes:Bacteroidetes ratio was decreased, in HF mice fed GTE compared with HF controls. GTE in LF mice did not attenuate adiposity but decreased endotoxin and favorably altered several gut bacterial populations. Serum FITC-dextran was correlated with portal vein endotoxin (P<.001; rP=0.66) and inversely correlated with colonic mRNA levels of TJPs (P<.05; rP=−0.38 to −0.48). Colonic TJPs mRNA were inversely correlated with portal endotoxin (P<.05; rP=−0.33 to −0.39). These data suggest that GTE protects against diet-induced obesity consistent with a mechanism involving the gut-adipose axis that limits endotoxin translocation and consequent adipose TLR4/NFκB inflammation by improving gut barrier function.

Qingyi decoction attenuates severe acute pancreatitis in rats via inhibition of inflammation and protection of the intestinal barrier.

ObjectiveQingyi decoction (QYD) has beneficial effects in severe acute pancreatitis (SAP). We assessed the therapeutic effect and mechanisms of QYD in SAP.MethodsA rat model of SAP was induced by pancreatic ductal injection of sodium taurocholate. QYD was administered intragastrically immediately postoperatively and once every 12 hours. Serum amylase, endotoxin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and D-lactate levels were measured at 12, 24, and 48 hours. Histological changes in the pancreas and ileum were analyzed. Expression of nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-κB p65), Toll-like receptor 4 (TLR4), and zonula occludens-1 (ZO-1) in the small intestinal mucosa was also assessed.ResultsPancreatic tissue showed extracellular space expansion, inflammatory infiltration, vessels with necrotic walls, and hemorrhage. Ileal tissue showed hemorrhage, inflammatory infiltration, and ileal mucosa destruction. These histological features were dramatically improved by QYD. Increased serum levels of amylase, endotoxin, TNF-α, IL-6, and D-lactic acid were significantly decreased by QYD administration. Increased expression of NF-κB p65 and TLR4 and decreased expression of ZO-1 in the ileal mucosa were also restored to normal levels by QYD treatment.ConclusionQYD alleviates SAP by reducing intestinal barrier dysfunction, inhibiting intestinal bacteria and endotoxin translocation, and preventing NF-κB activation.

Intact anti-LPS IgY is found in the blood after intragastric administration in mice.

Severe burn injury and cirrhosis often cause the translocation of bacterial endotoxins into blood, leading to systemic damage and even death. Our previous studies have shown that anti‐lipopolysaccharide egg yolk antibody (anti‐LPS IgY) can neutralize bacterial endotoxins in vitro and in vivo effectively, thereby reducing endotoxin damage. Whether anti‐LPS IgY can be absorbed into the blood through the intestinal barrier and neutralize endotoxins in circulation remains unclear. In this study, we used in vivo small animal imaging techniques, protein purification, molecular biology, and mass spectrometry to show that intragastrically administered anti‐LPS IgY is detected in the blood of mice as an intact molecule and has the capacity to bind to LPS. Immunohistochemical analysis confirmed that anti‐LPS IgY is associated with the intestinal mucosa of mice. However, the route of absorption of this large protein molecule was not determined. This study suggests that anti‐LPS IgY can be absorbed into the circulation, with the same molecular mass as purified anti‐LPS IgY as a macromolecular protein, suggesting a new strategy for the prevention of damage caused by endotoxins.

Gut derived-endotoxin contributes to inflammation in severe ischemic acute kidney injury

BackgroundRecent researches indicate that the intestinal consequences of renal ischemia reperfusion (IR) would predispose to the translocation of gut-derived endotoxin. Here, we designed experiments to test the hypothesis that the gut-derived endotoxin has a potential role in mediating local inflammatory processes in the acutely injured kidney.MethodsRats were performed sham or renal IR surgery (60 min of bilateral renal ischemia, then 24 h of reperfusion) (n = 5). The intestinal structural and mucosa permeability were evaluated. Serum endotoxin and bacterial load in liver and mesenteric lymph nodes (MLN) were measured. Separate groups were pretreated with oral norfloxacin 20 mg/kg/day or saline for 4 weeks and divided into sham plus saline, sham plus norfloxacin, renal IR plus saline and renal IR plus norfloxacin group. Serum biochemistry and endotoxin were determined. Kidney pathological changes were scored. Protein or mRNA expression of toll-like receptor 4 (TLR4) and proinflammatory mediators were measured in kidney homogenate.ResultsRenal IR led to marked intestinal integrity disruption and increase in intestinal permeability. These are accompanied by low grade of endotoxemia as well as increased bacterial load in liver and MLN. The group pretreated with norfloxacin showed significant attenuation of the increase in serum urea, ALAT, ASAT and endotoxin. The increased renal protein or mRNA of TLR4 and proinflammatory mediators (IL-6 and MCP-1) in the unpretreated animals was significantly attenuated in the norfloxacin-pretreated animals. However, norfloxacin pretreatment did not produce any protective effects on renal tubular integrity.ConclusionsOur results show for the first time that gut-derived endotoxin, resulting from an increased intestinal permeability after severe renal IR, subsequently amplifies intrarenal inflammatory response by activation renal TLR4 signaling. Our study results do not establish that antibiotic administration was effective in improving the overall renal outcome. However, our findings may be the first step to understanding how to tailor therapies to mitigate intrarenal inflammation in select groups of patients.

Probiotics ameliorate renal ischemia-reperfusion injury by modulating the phenotype of macrophages through the IL-10/GSK-3β/PTEN signaling pathway.

After renal ischemic reperfusion injury, a series of pathological changes, such as impaired intestinal barrier function, intestinal flora, and endotoxin translocation, are caused by intestinal ischemia and hypoxia, which then trigger systemic inflammatory responses and affect the condition and prognosis of the patients. In this study, a rat model of ischemia-reperfusion injury was established by examining changes in renal function, intestinal barrier function, inflammatory index, oxidative stress, and macrophage phenotypes to evaluate the effect of probiotic VSL#3 on renal ischemia-reperfusion injury. The results showed that, after VSL#3 intervention, the levels of BUN, Scr, Cys C, PRO, and NGAL were all significantly decreased compared with the I/R group, while the value of Ccr showed a significant increase. In addition, the concentrations of MPO, IL-1β, TNF-α, IL-6, ED-1, and PCNA were all significantly lower than those in the I/R group, while the levels of endotoxin, DOA, and D-lactic acid were significantly decreased. Furthermore, the proteins associated with intestinal barrier functions, such as ZO-1, Occludin, and Claudin-1, were significantly upregulated compared with the I/R group. Overall, the VSL#3 intervention group was able to maintain the required number of beneficial intestinal flora and to inhibit the proliferation of harmful bacteria. At the same time, the VSL#3 intervention could also prevent the decrease in the levels of CAT, GSH-PX, H2O2, and T-SOD, while downregulating the expression of Keap1 and Nrf2. After the intervention with the VSL#3, the expression levels of CD68 and CD86 proteins were significantly decreased, while the expression levels of CD163 and CD206 proteins were significantly higher. Further experiments confirmed that the expression of iNOS protein was significantly decreased after the VSL#3 intervention, and the expression of Arg-1 and Ym1 proteins was significantly increased. The VSL#3 was able to induce high expressions of p-GSK-3β and p-PTEN proteins, while the use of IL-10 antibody impaired the effect of the VSL#3. In summary, this research confirms that probiotics can alleviate renal dysfunction caused by ischemia and reperfusion by protecting the intestinal barrier function and maintaining the functions of intestinal flora. The pathway screening test of this study suggests that IL-10/GSK3β/PTEN may play an important role in the process of the prototypic VSL#3 inducing M2 transformation of macrophages.

Marital distress, depression, and a leaky gut: Translocation of bacterial endotoxin as a pathway to inflammation

BackgroundMarital distress and depression work in tandem to escalate risks for inflammation-related disorders. Translocation of bacterial endotoxin (lipopolysaccharide, LPS) from the gut microbiota to blood circulation stimulates systemic inflammatory responses. MethodsTo investigate increased gut permeability (a “leaky gut”) as one potential mechanistic pathway from marital distress and depression to heightened inflammation, this secondary analysis of a double-blind, randomized crossover study examined serial assessments of two endotoxin biomarkers, LPS-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) during two separate 9.5 h visits. The 43 (N = 86) healthy married couples, ages 24–61 (mean = 38.22), discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors, a hallmark of marital distress. The Structured Diagnostic Interview for DSM-IV assessed participants’ mood disorder history. ResultsParticipants with more hostile marital interactions had higher LBP than those who were less hostile. Additionally, the combination of more hostile marital interactions with a mood disorder history was associated with higher LBP/sCD14 ratios. Higher LBP and LBP/sCD14 were associated with greater CRP production; for example, only 21% of low LBP participants (lowest quartile) had average CRP across the day > 3, compared to 79% of those in the highest quartile. Higher sCD14 was associated with higher IL-6. ConclusionsThese bacterial LPS translocation data illustrate how a distressed marriage and a mood disorder history can promote a proinflammatory milieu through increased gut permeability, thus fueling inflammation-related disorders.

Advances in pathogenesis of intestinal barrier dysfunction in children

Intestinal barrier dysfunction refers to the damage or even atrophy of the intestinal mucosa, disorder of intestinal microbial population and increased intestinal permeability caused by a variety of factors, resulting in the insertion of bacterial and/or endotoxin translocation into other tissues and/or blood circulation, induction and/or aggravation systemic multiple organ dysfunction and inflammatory response.The destruction of the intestinal barrier is associated with many gastrointestinal disorders, but also accompanied by parenteral pathological conditions, such as allergic diseases.Therefore, maintaining a healthy intestinal barrier is critical to children.At present, there are relatively few studies on the intestinal barrier dysfunction in children.This paper reviews the recent progress in the pathogenesis of intestinal barrier in children. Key words: Children; Intestinal barrier dysfunction; Mechanism

Lack of liver steatosis in germ-free mice following hypercaloric diets.

Experimental liver steatosis induced by overfeeding is associated with enhanced gut permeability and endotoxin translocation to the liver. We examined the role of the gut microbiota for steatosis formation by performing the feeding experiments in mice raised under conventional and germ-free (GF) housing. Adult wild-type and GF mice were fed a Western-style diet (WSD) or a control diet (CD), the latter combined with liquid fructose supplementation (F) or not, for 8 weeks. Markers of liver steatosis and gut permeability were measured after intervention. Mice fed a WSD increased body weight compared to those fed a CD (p < 0.01) under conventional, but not under GF conditions. Increased liver weight, liver-to-body-weight ratio and hepatic triglycerides observed in both the WSD and the CD + F groups, when compared with the CD group, were not apparent under GF conditions, whereas elevated plasma triglycerides were visible (p < 0.05). Wild-type mice fed a WSD or a CD + F, respectively, had thinner adherent mucus layer compared to those fed a CD (p < 0.01), whereas GF mice had always a thin mucus layer independently of the diet. GF mice fed a CD showed increased plasma levels of FITC-dextran 4000 (1.9-fold, p < 0.05) and intestinal fatty acid-binding protein-2 (2.4-fold, p < 0.05) compared with wild-type mice. GF housing results in an impaired weight gain and a lack of steatosis following a WSD. Also the fructose-induced steatosis, which is unrelated to body weight changes, is absent in GF mice. Thus, diet-induced experimental liver steatosis depends in multiple ways on intestinal bacteria.

2228 The association of gastrointestinal symptoms and hypertension in persons living with HIV on HAART

OBJECTIVES/SPECIFIC AIMS: The advent of Highly Active Antiretroviral Treatments (HAART) has allowed HIV-positive individuals to live longer in recent years. This has resulted in a higher incidence of mortalities occurring in these individuals due to cardiovascular pathologies, as opposed to deaths due to HIV. Even with long-term HAART, persons living with HIV (PLWHIV) still exhibit inflammation, which is associated with deleterious cardiovascular outcomes. PLWHIV on HAART have a higher prevalence of hypertension, which is associated with an increased risk of cardiovascular events. Moreover, chronic inflammation has been shown to be related to the translocation of microbes and endotoxins across the gastrointestinal tract. Such microbial translocation (MT) is increased in individuals with digestive disorders and their associated symptoms (e.g., diarrhea, abdominal pain, and nausea). This study aims to explore the pathologies common to both MT-induced inflammation and cardiovascular symptoms by examining the associations between gastrointestinal symptoms and hypertension in PLWHIV on HAART. METHODS/STUDY POPULATION: The sample included 351 PLWHIV on HAART. Pre-existing de-identified data were analyzed. Sample demographics included 56.98 % African Americans, 41.31% Caucasians, ages 20–66 years (mean age=43.65years), 21% female, 89% male, HIV viral load, CD4 counts. Self-reported data from the Symptom Co-Morbidity Questionnaire and Socio-demographic questionnaire were analyzed with SPSS v.24. RESULTS/ANTICIPATED RESULTS: In total, 86 PLWHIV (24.50%) stated that they have hypertension; 39 subjects (45.3%) reported having diarrhea, 30 subjects (34.8%) reported nausea, and 12 (13.9%) reported constipation and vomiting. Among ethnicities with hypertension and gastrointestinal symptoms, African Americans compared with Caucasians had a higher percentage of diarrhea (28% vs. 17%), nausea (21% vs. 11%), constipation (11% vs. 2%), and vomiting (8% vs. 5%). Women compared with men reported a higher percentage of nausea (28% vs. 24%) and constipation (8% vs. 6%). Men compared with women reported a higher percentage of diarrhea (38% vs. 7%) and vomiting (8% vs. 5%). DISCUSSION/SIGNIFICANCE OF IMPACT: These data support the need for targeted screening to include both blood pressure and associated gastrointestinal symptoms. Further studies supporting these results may assist practitioners to target treatments that may prevent cardiovascular comorbidities.

MORPHOLOGICAL AND FUNCTIONAL CHANGES OF INTESTINAL MUCOSA AT ACUTE NECROTIZING PANCREATITIS

The purpose - to investigate the morphological and functional changes of the intestinal mucosa during acute necrotic pancreatitis and their effect on the translocation of bacteria and endotoxin. Material and methods. The conditions of the intestinal barrier were studied at 74 patients in clinics and 60 white rats in experiment during acute necrotic pancreatitis. The morphological and histological changes of the mucosal layer of the intestine, its enzyme activity, the microflora and its permeability for the endotoxin were studied. Results and discussion. During the early phase of acute necrotic pancreatitis barrier function of the intestine has been disturbed by increasing the activity of lysosomal enzymes (β-galactosidase double and N-acetyl-β-glucosaminidase triple, p &lt;0.05), which caused the qualitative and quantitative changes of composition of glycoproteins in the epithelial layer of the mucosa shells. Disorders of the intestinal barrier were accompanied by bacterial translocation to the internal organs in 57.4% of patients who were operated early (up to 4 weeks) of the disease and in 90% of the animals after 72 hours of the experiment. High concentrations of endotoxin (over than 0.30EO/ml) delivered from the intestine have activated a specific proinflammatory cascade through the membrane receptor of monocytes/macrophages CD14, which was accompanied by the development of a systemic inflammatory response syndrome and multiple organ failure. Conclusions. During acute necrotizing pancreatitis the structure and protective function of the pre-epithelial mucosal layer are disordered, colonization of intestine by pathogenic and conditionally pathogenic gram-negative microflora is occurred which promoted migration of bacteria and transport of endotoxin into systemic blood circulation.