scholarly journals Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Leila B. Giron ◽  
Harsh Dweep ◽  
Xiangfan Yin ◽  
Han Wang ◽  
Mohammad Damra ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Intestinal Barrier ◽  
Microbial Translocation ◽  
Gut Permeability ◽  
Gut Barrier ◽  
Potential Force ◽  
Barrier Integrity ◽  
Plasma Metabolome ◽  
Tight Junction Permeability ◽  
Plasma Markers

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.

scholarly journals Severe COVID-19 Is Fueled by Disrupted Gut Barrier Integrity

2020 ◽  
Author(s):  
Leila B. Giron ◽  
Harsh Dweep ◽  
Xiangfan Yin ◽  
Han Wang ◽  
Mohammad Damra ◽  
...  
Keyword(s):  
Systems Biology ◽  
Lung Injury ◽  
Gut Microbiota ◽  
Systemic Inflammation ◽  
Clinical Implications ◽  
Metabolic Function ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
Tight Junction Permeability ◽  
Injury Causes

ABSTRACTA disruption of the crosstalk between gut microbiota and the lung (gut-lung axis) has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. To test the possibility that a disrupted gut contributes to Coronavirus disease 2019 (COVID-19) severity, we used a systems biology approach to analyze plasma from COVID-19 patients with varying disease severity and controls. Severe COVID-19 is associated with a dramatic increase in tight junction permeability and translocation of bacterial and fungal products into blood. This intestinal disruption and microbial translocation correlate strongly with increased systemic inflammation and complement activation, lower gut metabolic function, and higher mortality. Our study highlights a previously unappreciated factor with significant clinical implications, disruption in gut barrier integrity, as a force that contributes to COVID-19 severity.

scholarly journals Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

2020 ◽  
Author(s):  
Elke M. Muntjewerff ◽  
Kechun Tang ◽  
Lisanne Lutter ◽  
Gustaf Christoffersson ◽  
Mara J.T. Nicolasen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Chromogranin A ◽  
Intestinal Barrier ◽  
Enteroendocrine Cells ◽  
Leaky Gut ◽  
Gut Permeability ◽  
Gut Barrier ◽  
Ultrastructural Studies ◽  
New Findings

AbstractBackground and AimsA ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we asked how Chromogranin A (CgA), a major hormone produced by the enteroendocrine cells, and Catestatin (CST), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.Methods and ResultsUltrastructural studies on the colons from Catestatin (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology of tight (TJ) and adherens (AJ) junctions and desmosomes, indicative of junctional stress and (ii) an increased infiltration of immune cells compared to controls. Flow cytometry studies confirmed these cells to be macrophages and CD4+ T cells. Gene expression studies confirmed that multiple TJ-markers were reduced, with concomitant compensatory elevation of AJ and desmosome markers. Consistently, the levels of plasma FITC-dextran were elevated in the CST-KO mice, confirming leakiness’ of the gut. Leaky gut in CST-KO mice correlated with inflammation and a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in a multitude of diseases. Supplementation of CST-KO mice with recombinant CST reversed this leakiness and key phenotypes. Supplementation of CgA-KO mice with either CST alone, or with the pro-inflammatory proteolytic CgA fragment pancreastatin (PST: CgA250-301) showed that gut permeability is regulated by the antagonistic roles of these two peptide hormones: CST reduces and PST increases leakiness.ConclusionWe conclude that the enteroendocrine cell-derived hormone, CgA regulates gut permeability. CST is both necessary and sufficient to reduce the leakiness. CST acts primarily via antagonizing the effects of PST.What you need to knowBackground and ContextThe intestinal barrier is disrupted in many intestinal diseases such as Crohn’s disease. Chromogranin A (CgA) is produced by enteroendocrine cells in the gut. CgA is proteolytically cleaved into bioactive peptides including catestatin (CST) and pancreastatin (PST). The role of CgA in the gut is unknown.New findingsCgA is efficiently processed to CST in the gut and this processing might be decreased during active Crohn’s disease. CST promotes epithelial barrier function and reduces inflammation by counteracting PST.LimitationsThe complete mechanism of intestinal barrier regulation by CST likely involves a complex interplay between the enteroendocrine system, metabolism, the epithelium, the immune system and the gut microbiota.ImpactOur findings indicate that CST is a key modulator of the intestinal barrier and immune functions that correlates with disease severity of Crohn’s disease. CST could be a target for therapeutic interventions in Crohn’s disease.

scholarly journals 2’-fucosyllactose (2’-FL) Supplementation Improves Gut Barrier Function and Lipid Metabolism in HF-fed Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 425-425
Author(s):  
Sunhye Lee ◽  
Michael Goodson ◽  
Wendie Vang ◽  
Karen Kalanetra ◽  
Daniela Barile ◽  
...  
Keyword(s):  
Body Weight ◽  
Lipid Metabolism ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Gut Barrier ◽  
Low Fat ◽  
Barrier Integrity ◽  
Gut Barrier Function

Abstract Objectives 2’-fucosyllactose (2’-FL), the most predominant oligosaccharide found in human milk, acts as a prebiotic with beneficial effects on the host. The aim of this study was to determine the beneficial effect of 2’-FL on intestinal barrier integrity and metabolic functions in low-fat (LF)- and high-fat (HF)-fed mice. Methods Male C57/BL6 mice (n = 32, 8/group; 6 weeks old, JAX, CA) were counter-balanced into four weight-matched groups and fed either a low-fat (LF; 10% kcal fat with 7% kcal sucrose) or HF (45% kcal fat with 17% kcal sucrose) with or without supplementation of 2’-FL in the diet [10% (w/w), 8 weeks; LF/2’-FL or HF/2’-FL; BASF, Germany]. General phenotypes (body weight, energy intake, fat and lean mass), intestinal permeability (ex vivo in Ussing chambers), lipid profiles, and microbial metabolites were assessed. Results 2’-FL significantly attenuated the HF-induced increase in body fat mass with a trend to decrease body weight gain. 2’-FL significantly decreased intestinal permeability in LF-fed mice with a trend for a decrease in HF-fed mice. This was associated with a significant increase in interleukin-22, a cytokine known to have a protective role in intestinal barrier function. Visceral adipocyte size was significantly decreased by 2’-FL in both LF- and HF-fed mice. 2’-FL suppressed HF-induced upregulation of adipogenic transcription factors peroxisome proliferator-activated receptor gamma and sterol regulatory element binding protein-1c in the liver. Lastly, 2’-FL supplementation led to a significant elevation of lactic acid concentration in the cecum of HF-fed mice, which is known to be a product from beneficial microbes. Conclusions 2’-FL supplementation improved gut barrier integrity and lipid metabolism in mice with and without the metabolic challenge of HF feeding. These findings support the use of 2’-FL in the control of gut barrier function and metabolic homeostasis under normal and abnormal physiological conditions. Funding Sources BASF (Germany).

scholarly journals Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation

2020 ◽  
Vol 13 (11) ◽  
pp. dmm043620 ◽  
Author(s):  
Jiang-Hua Liu ◽  
Tao Yue ◽  
Zhong-Wei Luo ◽  
Jia Cao ◽  
Zi-Qi Yan ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Systemic Inflammation ◽  
Bone Healing ◽  
Bone Fracture ◽  
Early Stage ◽  
Gut Permeability ◽  
Bone Fracture Healing ◽  
Gut Barrier ◽  
Vessel Formation ◽  
Akkermansia Muciniphila

ABSTRACTImproving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila, a gut probiotic, ameliorates systemic inflammation by tightening the intestinal barrier. In this study, fractured mice intragastrically administrated with A. muciniphila were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muciniphila at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis, and can be stimulated by PDGF-BB. Moreover, A. muciniphila treatment significantly reduced gut permeability and inflammation at the early stage. Dextran sulfate sodium (DSS) was used to disrupt the gut barrier to determine its role in fracture healing and whether A. muciniphila still can stimulate bone fracture healing. As expected, A. muciniphila evidently improved gut barrier, reduced inflammation and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muciniphila reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB+ preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidence for the involvement of type H vessels in fracture healing and suggests the potential of A. muciniphila as a promising strategy for bone healing.This article has an associated First Person interview with the first author of the paper.

scholarly journals Andrographolide Exerts Antihyperglycemic Effect through Strengthening Intestinal Barrier Function and Increasing Microbial Composition of Akkermansia muciniphila

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Hongming Su ◽  
Jianling Mo ◽  
Jingdan Ni ◽  
Huihui Ke ◽  
Tao Bao ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Glutathione Depletion ◽  
Intestinal Barrier Function ◽  
Microbiota Composition ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
Akkermansia Muciniphila ◽  
Microbial Species ◽  
Junction Protein

Accumulating evidence indicates that type 2 diabetes (T2D) is associated with intestinal barrier dysfunction and dysbiosis, implying the potential targets for T2D therapeutics. Andrographolide was reported to have several beneficial effects on diabetes and its associated complications. However, the protective role of andrographolide, as well as its underlying mechanism against T2D, remains elusive. Herein, we reported that andrographolide enhanced intestinal barrier integrity in LPS-induced Caco-2 cells as indicated by the improvement of cell monolayer barrier permeability and upregulation of tight junction protein expression. In addition, andrographolide alleviated LPS-induced oxidative stress by preventing ROS and superoxide anion radical overproduction and reversing glutathione depletion. In line with the in vitro results, andrographolide reduced metabolic endotoxemia and strengthened gut barrier integrity in db/db diabetic mice. We also found that andrographolide appeared to ameliorate glucose intolerance and insulin resistance and attenuated diabetes-associated redox disturbance and inflammation. Furthermore, our results indicated that andrographolide modified gut microbiota composition as indicated by elevated Bacteroidetes/Firmicutes ratio, enriched microbial species of Akkermansia muciniphila, and increased SCFAs level. Taken together, this study demonstrated that andrographolide exerted a glucose-lowering effect through strengthening intestinal barrier function and increasing the microbial species of A. muciniphila, which illuminates a plausible approach to prevent T2D by regulating gut barrier integrity and shaping intestinal microbiota composition.

Bacterial Translocation from the Gut to the Distant Organs: An Overview

2017 ◽  
Vol 71 (Suppl. 1) ◽  
pp. 11-16 ◽  
Author(s):  
Ravinder Nagpal ◽  
Hariom Yadav
Keyword(s):  
Bacterial Translocation ◽  
Inflammatory Responses ◽  
Close Association ◽  
Intestinal Barrier ◽  
Research Field ◽  
Gut Health ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
Gut Microbes ◽  
Basolateral Side

Background: The intestinal epithelial layer is the chief barricade between the luminal contents and the host. A healthy homeostatic intestinal barrier is pivotal for maintaining gastrointestinal health, which impacts the overall health as it safeguards the gut-blood axis and checks gut microbes including potential pathogens from entering into the circulation. Summary: Under healthy milieus, the intestinal barrier is generally very dynamic and effective, with luminal side being heavily infested with a wide variety of gut microbes while the basolateral side remains virtually sterile. However, certain conditions such as abnormal exposure to toxins, drugs, pathogens etc. or a state of hyper-inflammation due to disease conditions may weaken or destabilize the integrity of gut epithelia. A perturbed gut integrity and permeability (“leaky gut”) may lead to microbial (bacterial) translocation, and the eventual leakage of bacteria or their metabolites into the circulation can make the host susceptible to various types of diseases via inducing chronic or acute inflammatory response. Key Message: Given a close association with gut integrity, bacterial translocation and inflammatory responses have recently emerged as a clinically important research field and have unveiled novel aspects of gut microbial ecology and various gastrointestinal, metabolic, and lifestyle diseases. This review aims to describe the significance of a healthy gut barrier integrity and permeability, as well as the factors and consequences associated with a compromised gut barrier, while discussing briefly the dietary approaches including probiotics and prebiotics that could ameliorate gut health by restoring gut environment and barrier integrity, thereby preventing bacterial translocation.

scholarly journals A glucose-supplemented diet enhances gut barrier integrity in Drosophila

Biology Open ◽  
2021 ◽  
pp. bio.056515
Author(s):  
Anthony Galenza ◽  
Edan Foley
Keyword(s):  
Dietary Intervention ◽  
Caloric Intake ◽  
Intestinal Barrier ◽  
Lifespan Extension ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
Preventative Measures ◽  
Insulin Activity ◽  
Underlying Mechanisms ◽  
Effects Of Aging

Dietary intervention has received considerable attention as an approach to extend lifespan and improve aging. However, questions remain regarding optimal dietary regimes and underlying mechanisms of lifespan extension. Here, we asked how an increase of glucose in a chemically defined diet extends the lifespan of adult Drosophila. We showed that glucose-dependent lifespan extension is not a result of diminished caloric intake, or changes to systemic insulin activity, two commonly studied mechanisms of lifespan extension. Instead, we found that flies raised on glucose-supplemented food increased the expression of cell adhesion genes, delaying age-dependent loss of intestinal barrier integrity. Furthermore, we showed that chemical disruption of the gut barrier negated the lifespan extension associated with glucose-treatment, suggesting that glucose-supplemented food prolongs adult viability by enhancing the intestinal barrier. We believe our data contribute to understanding intestinal homeostasis, and may assist efforts to develop preventative measures that limit effects of aging on health.

scholarly journals Markers of Gut Barrier Function and Microbial Translocation Associate with Lower Gut Microbial Diversity in People with HIV

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1891
Author(s):  
Ronald J. Ellis ◽  
Jennifer E. Iudicello ◽  
Robert K. Heaton ◽  
Stéphane Isnard ◽  
John Lin ◽  
...  
Keyword(s):  
Microbial Diversity ◽  
Gut Microbiome ◽  
Alpha Diversity ◽  
Amplicon Sequencing ◽  
Microbial Translocation ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
16S Rrna Amplicon Sequencing ◽  
Gut Barrier Function ◽  
Relationship Of

People with human immunodeficiency virus (HIV) (PWH) have reduced gut barrier integrity (“leaky gut”) that permits diffusion of microbial antigens (microbial translocation) such as lipopolysaccharide (LPS) into the circulation, stimulating inflammation. A potential source of this disturbance, in addition to gut lymphoid tissue CD4+ T-cell depletion, is the interaction between the gut barrier and gut microbes themselves. We evaluated the relationship of gut barrier integrity, as indexed by plasma occludin levels (higher levels corresponding to greater loss of occludin from the gut barrier), to gut microbial diversity. PWH and people without HIV (PWoH) participants were recruited from community sources and provided stool, and 16S rRNA amplicon sequencing was used to characterize the gut microbiome. Microbial diversity was indexed by Faith’s phylogenetic diversity (PD). Participants were 50 PWH and 52 PWoH individuals, mean ± SD age 45.6 ± 14.5 years, 28 (27.5%) women, 50 (49.0%) non-white race/ethnicity. PWH had higher gut microbial diversity (Faith’s PD 14.2 ± 4.06 versus 11.7 ± 3.27; p = 0.0007), but occludin levels were not different (1.84 ± 0.311 versus 1.85 ± 0.274; p = 0.843). Lower gut microbial diversity was associated with higher plasma occludin levels in PWH (r = −0.251; p = 0.0111), but not in PWoH. A multivariable model demonstrated an interaction (p = 0.0459) such that the correlation between Faith’s PD and plasma occludin held only for PWH (r = −0.434; p = 0.0017), but not for PWoH individuals (r = −0.0227; p = 0.873). The pattern was similar for Shannon alpha diversity. Antiretroviral treatment and viral suppression status were not associated with gut microbial diversity (ps > 0.10). Plasma occludin levels were not significantly related to age, sex or ethnicity, nor to current or nadir CD4 or plasma viral load. Higher occludin levels were associated with higher plasma sCD14 and LPS, both markers of microbial translocation. Together, the findings suggest that damage to the gut epithelial barrier is an important mediator of microbial translocation and inflammation in PWH, and that reduced gut microbiome diversity may have an important role.

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