scholarly journals Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure

2018 ◽  
Vol 132 (6) ◽  
pp. 701-718 ◽  
Author(s):  
Seungbum Kim ◽  
Ruby Goel ◽  
Ashok Kumar ◽  
Yanfei Qi ◽  
Gil Lobaton ◽  
...  
Keyword(s):  
Blood Pressure ◽  
High Blood Pressure ◽  
Gut Microbiome ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Fatty Acid Binding ◽  
Gut Barrier Function ◽  
Junction Protein

Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut–epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R2 = 0.5301, P<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R2 = 0.4608, P<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN.

Abstract 004: Plasma Zonulin, Along With a Unique Gut Microbiome Profile, Are Potential Predictors of Systolic Blood Pressure in Humans

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Seungbum Kim ◽  
Ruby Goel ◽  
Yanfei Qi ◽  
Elaine M Richards ◽  
Mohammed Mohammed ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Gut Microbiome ◽  
Soluble Form ◽  
Metagenomic Sequencing ◽  
Gut Health ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Fatty Acid Binding ◽  
Microbiome Composition ◽  
Circulating Markers

Objectives: We have previously shown that gut pathophysiology and dysbiosis are closely associated with hypertension (HTN) in animal models. However, whether this association also occurs in human HTN is unknown. To address this knowledge gap, we tested two hypotheses. 1. Hypertensive patients (HTN) have gut barrier dysfunction. 2. Prediction of blood pressure will be possible from circulating markers of gut health and gut microbiome composition. Design and Method: Plasma and fecal samples were collected from HTN (n=22, mean SBP 155.8±3.4mmHg) and reference subjects without HTN (REF) (n=18, mean SBP 121.1±1.5mmHg) (see ClinicalTrials.gov, NCT02188381 for protocol). Gut microbiomes were analyzed using shotgun metagenomic sequencing and Qiime. Plasma analytes were measured by ELISA. Results: Plasma intestinal fatty acid binding protein (REF;1.2 ± 0.1 ng/ml, HTN;1.9 ± 0.2 ng/ml, p=0.0097) and lipopolysaccharide (REF; 39.0 ± 9.5 pg/ml, HTN; 98.0 ± 26.2 pg/ml, p=0.0423) were increased in HTN, suggesting increased intestinal inflammation and permeability. Additionally, the soluble form of zonulin (regulator of gut tight junction proteins) was markedly elevated in the plasma of HTN (REF; 28.4 ± 2.0 ng/ml, HTN; 42.6 ± 2.7 ng/ml, P=0.0002) further supporting gut barrier dysfunction. Plasma zonulin was correlated with SBP (R 2 =0.5301, p<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome shotgun metagenomics data and circulating markers of gut health. The first model used plasma zonulin as a single predictor, and the second zonulin plus butyrate producing bacteria (adjusted R 2 values of 0.506 and 0.554 respectively, p<0.001 for both). Our first model was validated by prediction of SBP in a separate validation cohort (n=36) from zonulin plasma levels (R 2 =0.4608, p<0.0001). Conclusions: Markers of increased gut permeability, particularly zonulin, and abundance of butyrate producing bacteria predicted SBP. These results support the hypothesis that gut barrier dysfunction and gut microbiome composition are directly linked with HTN in humans.

IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice

2003 ◽  
Vol 285 (3) ◽  
pp. G621-G629 ◽  
Author(s):  
Runkuan Yang ◽  
Xiaonan Han ◽  
Takashi Uchiyama ◽  
Simon K. Watkins ◽  
Arino Yaguchi ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Barrier Function ◽  
Mrna Levels ◽  
Barrier Dysfunction ◽  
Mesenteric Lymph Nodes ◽  
Gut Barrier ◽  
Mucosal Permeability ◽  
Average Molecular Mass ◽  
Gut Barrier Function ◽  
Junction Protein

We sought to determine the role of IL-6 as a mediator of the alterations in gut barrier function that occur after hemorrhagic shock and resuscitation (HS/R). C57Bl/6 wild-type (WT) and IL-6 knockout (KO) mice on a C57Bl/6 background were subjected to either a sham procedure or HS/R. Organ and tissue samples were obtained 4 h after resuscitation. In WT mice, HS/R significantly increased ileal mucosal permeability to fluorescein isothiocyanate-labeled dextran (average molecular mass, 4 kDa) and bacterial translocation to mesenteric lymph nodes. These alterations in gut barrier function were not observed in IL-6 KO animals. HS/R increased ileal steady-state mRNA levels for IL-6, TNF, and IL-10 in WT but not in IL-6 KO mice. Ileal mucosal expression of the tight junction protein, ZO-1, decreased after HS/R in WT but not IL-6 KO mice. Collectively, these data support the view that expression of IL-6 is essential for the development of gut barrier dysfunction after HS/R.

scholarly journals Gut Barrier Function Is Improved in Infants Colonized by Bifidobacterium Longum Subsp. Infantis EVC001 (FS04-05-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Giorgio Casaburi ◽  
Sercan Karav ◽  
Steve Frese ◽  
Bethany Henrick
Keyword(s):  
Gut Microbiome ◽  
Barrier Function ◽  
Bifidobacterium Longum ◽  
Epithelial Barrier ◽  
Gut Barrier ◽  
Shotgun Metagenomics ◽  
Single Strain ◽  
Colonic Mucin ◽  
Gut Barrier Function ◽  
Gut Epithelium

Abstract Objectives The gut epithelium is single-celled barrier that employs many different mechanisms that together provide the first line of defense to physically separate the gut epithelium from our gut microbiome. Notably, the epithelial barrier is protected by a mucin layer providing a physical barrier limiting pathogen access to the epithelial monolayer. We sought to assess how changes in the gut microbiome resulting from colonization by a single strain of Bifidobacterium longum subsp. infantis EVC001 could alter gut barrier function. Methods Fecal samples from this trial were assessed for: (1) endotoxin (lipopolysaccharide) concentration; (2) functional contributions to the gut microbiome by shotgun metagenome sequencing; and (3) fecal glycan profiles by mass spectrometry to assess gut epithelial barrier integrity via breakdown of colonic mucin glycoproteins. Results Colonization with Bifidobacterium, including B. infantis EVC001, showed a significant four-fold reduction in fecal endoxtoxin levels and reductions in fecal inflammatory markers (P < 0.05). Shotgun metagenomics identified LPS-producing Enterobacteriaceae as the most significant contributor of virulence factors in the infant gut metagenome. These bacteria (primarily E. coli and Klebsiella spp.) were also significantly correlated with both mucolytic bacteria (e.g., Bacteroides) and the signatures of mucin breakdown, as assessed by mass spectrometric quantification of colonic mucin-derived glycans. Five different colonic-mucin specific glycans (3_1_1_0, 2_1_2_0, 2_1_1_1, 2_1_1_0, and 1_1_0_1) were significantly associated with microbiome composition (P < 0.05). Overall mucin glycans were inversely correlated with Bifidobacteriaceae abundance (Spearman's rho −0.66, FDR-corrected P value 0.04). Conclusions Complex interactions between the degradation of gut barrier function (e.g., mucin), the production of pro-inflammatory endotoxins, and the risk of infection by these bacteria coming in close contact with the gut epithelium suggest that B. infantis EVC001 can play a role in reducing these combined risks for neonates. Funding Sources This work was funded by Evolve Biosystems, Inc.

scholarly journals Clinical Analysis of Gut Barrier Dysfunction in Patients with Advanced Colorectal Cancer Undergoing Cytoreductive Surgery and HIPEC

2021 ◽  
Author(s):  
Le lai Ping ◽  
Jiang xu Mian ◽  
Chen Wei
Keyword(s):  
Colorectal Cancer ◽  
Cytoreductive Surgery ◽  
Barrier Function ◽  
Intraperitoneal Injection ◽  
Advanced Colorectal Cancer ◽  
Patient Characteristics ◽  
Barrier Dysfunction ◽  
Large Area ◽  
Gut Barrier ◽  
Gut Barrier Function

Abstract Introduction: Hyperthermic intraperitoneal chemotherapy combinedwith cytoreductive surgery is a preferred treatment option for advanced colorectal cancer patients. However, little is known whether the HIPEC can cause the damage of gut barrier function.Methods: A total of 123 patients underwent surgical resection for advanced CRC. Sixty-five patients were treated HIPEC after cytoreductive surgery whereas 58 patients underwent surgery only. Gut barrier function were evaluated using the expression of serum DAO/D-la/ET on D1/D5/D10 after surgery. Both groups were compared for patient characteristics, perioperative data and gut barrier function. Moreover, rats received intraperitoneal injection of retetrexed to observe possible changes of colonic structure under optical microscope.Results: Both groups were comparable with respect to general patient characteristics and post-operative complications. The HIPEC+CRS group was associated with a higher postoperative serum level of DAO/D-la on D1/D5 (p < 0.05) and ET on D5 after surgery (p < 0.05) than that of the surgery only group. Ten days after surgery showed no statistical difference between the 2 groups (p > 0.05).A large area structure disorder, epithelial necrosis, glandular deformation and a large number of lymphocytes infiltration was found in the lamina propria in animals received intraperitoneal injection of retetrexed.Conclusion: In this study, CRS combined with HIPEC does have but only an irreversible impact on gut barrier for advanced CRC patients.

scholarly journals Role of JAM-A tyrosine phosphorylation in epithelial barrier dysfunction during intestinal inflammation

2019 ◽  
Vol 30 (5) ◽  
pp. 566-578 ◽  
Author(s):  
Shuling Fan ◽  
Caroline M. Weight ◽  
Anny-Claude Luissint ◽  
Roland S. Hilgarth ◽  
Jennifer C. Brazil ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Barrier Function ◽  
Intestinal Inflammation ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Small Gtpase ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Junction Protein

Junctional adhesion molecule-A (JAM-A), an epithelial tight junction protein, plays an important role in regulating intestinal permeability through association with a scaffold signaling complex containing ZO-2, Afadin, and the small GTPase Rap2. Under inflammatory conditions, we report that the cytoplasmic tail of JAM-A is tyrosine phosphorylated (p-Y280) in association with loss of barrier function. While barely detectable Y280 phosphorylation was observed in confluent monolayers of human intestinal epithelial cells under basal conditions, exposure to cytokines TNFα, IFNγ, IL-22, or IL-17A, resulted in compromised barrier function in parallel with increased p-Y280. Phosphorylation was Src kinase dependent, and we identified Yes-1 and PTPN13 as a major kinase and phosphatase for p-JAM-A Y280, respectively. Moreover, cytokines IL-22 or IL-17A induced increased activity of Yes-1. Furthermore, the Src kinase inhibitor PP2 rescued cytokine-induced epithelial barrier defects and inhibited phosphorylation of JAM-A Y280 in vitro. Phosphorylation of JAM-A Y280 and increased permeability correlated with reduced JAM-A association with active Rap2. Finally, we observed increased phosphorylation of Y280 in colonic epithelium of individuals with ulcerative colitis and in mice with experimentally induced colitis. These findings support a novel mechanism by which tyrosine phosphorylation of JAM-A Y280 regulates epithelial barrier function during inflammation.

Total parenteral nutrition adversely affects gut barrier function in neonatal piglets

2003 ◽  
Vol 285 (6) ◽  
pp. G1162-G1170 ◽  
Author(s):  
Ketan Kansagra ◽  
Barbara Stoll ◽  
Cheryl Rognerud ◽  
Harri Niinikoski ◽  
Ching-Nan Ou ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Total Parenteral Nutrition ◽  
Barrier Function ◽  
Myeloperoxidase Activity ◽  
Protein Abundance ◽  
Gut Barrier ◽  
Gut Barrier Function ◽  
Cell Counts ◽  
Peg 4000 ◽  
Junction Protein

Sepsis is the most common morbidity in preterm infants, who often receive total parenteral nutrition (TPN). We hypothesized that gut barrier function is compromised in TPN-fed compared with enterally fed newborn piglets (ENT pigs). Colostrum-deprived newborn pigs were implanted with jugular venous and bladder catheters under general anesthesia. Pigs were either administered TPN ( n = 15) or fed formula (ENT pigs, n = 15). After 6 days, pigs were gavaged a solution of mannitol, lactulose, and polyethylene glycol 4000 (PEG 4000) and urine was collected for 24 h. At 7 days, small bowel samples were assayed for myeloperoxidase activity, morphometry, and tight junction protein abundance. Intestinal contents and peripheral organ sites were cultured for bacteria. Urinary recovery (%dose) of mannitol (53 vs. 68) was lower, whereas that of lactulose (2.93 vs. 0.18) and PEG 4000 (12.78 vs. 0.96) were higher in TPN vs. ENT pigs, respectively ( P < 0.05). Incidence of translocation was similar in TPN and ENT pigs. Myeloperoxidase activity was increased in TPN vs. ENT pigs in the jejunum ( P < 0.001) and was weakly correlated with lactulose ( R2 = 0.32) and PEG 4000 ( R2 = 0.38) recovery. Goblet cell counts did not change, but intraepithelial lymphocyte numbers decreased with TPN. Only claudin-1 protein abundance was increased in the TPN group. We conclude that TPN is associated with impairment of neonatal gut barrier function as measured by permeability but not translocation.

scholarly journals Gut microbiome, endocrine control of gut barrier function and metabolic diseases

2021 ◽  
Vol 250 (1) ◽  
pp. X1
Author(s):  
Marion Régnier ◽  
Matthias Van Hul ◽  
Claude Knauf ◽  
Patrice D Cani
Keyword(s):  
Gut Microbiome ◽  
Barrier Function ◽  
Metabolic Diseases ◽  
Gut Barrier ◽  
Endocrine Control ◽  
Gut Barrier Function

scholarly journals Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Xin Dai ◽  
Bangmao Wang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Barrier Function ◽  
Fatty Liver Disease ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Nonalcoholic Fatty Liver ◽  
Gut Barrier Function

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease.

scholarly journals Methionine Restriction Improves Gut Barrier Function by Reshaping Diurnal Rhythms of Inflammation-Related Microbes in Aged Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Bo Ren ◽  
Luanfeng Wang ◽  
Aiziguli Mulati ◽  
Yan Liu ◽  
Zhigang Liu ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Diurnal Rhythms ◽  
Inflammatory Factors ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Aged Mice ◽  
Gut Barrier Function ◽  
Age Related ◽  
Methionine Restriction

Age-related gut barrier dysfunction and dysbiosis of the gut microbiome play crucial roles in human aging. Dietary methionine restriction (MR) has been reported to extend lifespan and reduce the inflammatory response; however, its protective effects on age-related gut barrier dysfunction remain unclear. Accordingly, we focus on the effects of MR on inflammation and gut function. We found a 3-month methionine-restriction reduced inflammatory factors in the serum of aged mice. Moreover, MR reduced gut permeability in aged mice and increased the levels of the tight junction proteins mRNAs, including those of occludin, claudin-1, and zona occludens-1. MR significantly reduced bacterial endotoxin lipopolysaccharide concentration in aged mice serum. By using 16s rRNA sequencing to analyze microbiome diurnal rhythmicity during 24 h, we found MR moderately recovered the cyclical fluctuations of the gut microbiome which was disrupted in aged mice, leading to time-specific enhancement of the abundance of short-chain fatty acid-producing and lifespan-promoting microbes. Moreover, MR dampened the oscillation of inflammation-related TM7-3 and Staphylococcaceae. In conclusion, the effects of MR on the gut barrier were likely related to alleviation of the oscillations of inflammation-related microbes. MR can enable nutritional intervention against age-related gut barrier dysfunction.

scholarly journals Microbiota, Microbial Metabolites, and Barrier Function in A Patient with Anorexia Nervosa after Fecal Microbiota Transplantation

2019 ◽  
Vol 7 (9) ◽  
pp. 338 ◽  
Author(s):  
Prochazkova ◽  
Roubalova ◽  
Dvorak ◽  
Tlaskalova-Hogenova ◽  
Cermakova ◽  
...  
Keyword(s):  
Anorexia Nervosa ◽  
Gut Microbiome ◽  
Barrier Function ◽  
Fecal Microbiota Transplantation ◽  
Alpha Diversity ◽  
Fecal Microbiota ◽  
Correct Selection ◽  
Microbial Metabolites ◽  
Gut Barrier ◽  
Gut Barrier Function

The change in the gut microbiome and microbial metabolites in a patient suffering from severe and enduring anorexia nervosa (AN) and diagnosed with small intestinal bacterial overgrowth syndrome (SIBO) was investigated. Microbial gut dysbiosis is associated with both AN and SIBO, and therefore gut microbiome changes by serial fecal microbiota transplantation (FMT) is a possible therapeutic modality. This study assessed the effects of FMT on gut barrier function, microbiota composition, and the levels of bacterial metabolic products. The patient treatment with FMT led to the improvement of gut barrier function, which was altered prior to FMT. Very low bacterial alpha diversity, a lack of beneficial bacteria, together with a great abundance of fungal species were observed in the patient stool sample before FMT. After FMT, both bacterial species richness and gut microbiome evenness increased in the patient, while the fungal alpha diversity decreased. The total short-chain fatty acids (SCFAs) levels (molecules presenting an important source of energy for epithelial gut cells) gradually increased after FMT. Contrarily, one of the most abundant intestinal neurotransmitters, serotonin, tended to decrease throughout the observation period. Overall, gut microbial dysbiosis improvement after FMT was considered. However, there were no signs of patient clinical improvement. The need for an in-depth analysis of the donor´s stool and correct selection pre-FMT is evident.

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