Metabolomics analysis of gut barrier dysfunction in a trauma-hemorrhagic shock rat model

Abstract Intestinal barrier dysfunction has been implicated in the development of multiorgan dysfunction syndrome caused by the trauma-hemorrhagic shock (THS). However, the mechanisms underlying THS-induced gut barrier injury are still poorly understood. In the present study, we used the metabolomics analysis to test the hypothesis that altered metabolites might be related to the development of THS-induced barrier dysfunction in the large intestine. Under the induction of THS, gut barrier failure was characterized by injury of permeability and mucus layer, which were companied by the decreased expression of zonula occludens-1 in the colon and increased levels of inflammatory factors including tumor necrosis factor-α, interferon-γ, interleukin (IL)-6, and IL-1β in the serum. A total of 16 differential metabolites were identified in colonic tissues from THS-treated rats compared with control rats. These altered metabolites included dihydroxy acetone phosphate, ribose-5-phosphate, fructose, glyceric acid, succinic acid, and adenosine, which are critical intermediates or end products that are involved in pentose phosphate pathway, glycolysis, and tricarboxylic acid cycle as well as mitochondrial adenosine triphosphate biosynthesis. These findings may offer important insight into the metabolic alterations in THS-treated gut injury, which will be helpful for developing effective metabolites-based strategies to prevent THS-induced gut barrier dysfunction.

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Perturbation of gut microbiota plays an important role in micro/nanoplastics-induced gut barrier dysfunction

Nanoscale ◽

10.1039/d1nr00038a ◽

2021 ◽

Author(s):

Jiyan Qiao ◽

Rui Chen ◽

Mengjie Wang ◽

Ru Bai ◽

Xuejing Cui ◽

...

Keyword(s):

Gut Microbiota ◽

Intestinal Barrier ◽

Barrier Dysfunction ◽

Gut Barrier ◽

Bacterial Composition

Exposure to micro/nanoplastics (M/NPLs) deteriorates the intestinal barrier by disturbing the bacterial composition in the gut.

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Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00066.2018 ◽

2018 ◽

Vol 315 (2) ◽

pp. G318-G327 ◽

Cited By ~ 2

Author(s):

Geeta Rao ◽

Hailey Houson ◽

Gregory Nkepang ◽

Hooman Yari ◽

Chengwen Teng ◽

...

Keyword(s):

Inflammatory Response ◽

Hemorrhagic Shock ◽

Unfolded Protein Response ◽

Systemic Inflammatory Response ◽

Proteasome Activity ◽

26S Proteasome ◽

Barrier Dysfunction ◽

Gut Barrier ◽

Unfolded Protein ◽

Protein Response

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock. CLEFMA or EF24 (0.4 mg/kg) were given 1 h after withdrawing 50% of blood from Sprague-Dawley rats; no other resuscitation was provided. After another 5 h of compensation, small gut was collected to process tissue for proteasome activity, immunoblotting, and mRNA levels of genes responsible for unfolded-protein response (XBP1, ATF4, glucose-regulated protein of 78/95 kDa, and growth arrest and DNA damage inducible genes 153/34), polyubiquitin B and C, and immunoproteasome subunits β type-8 and -10 and proteasome activator subunit 1. We found that hemorrhagic shock induced proteasome activity in gut tissue and reduced the amounts of ubiquitinated proteins displayed on antiubiquitin immunoblots. However, simultaneous induction of unfolded-protein response or immunoproteasome genes was not observed. CLEFMA and EF24 treatments abolished the hemorrhagic shock-induced increase in proteasome activity. Further investigations revealed that the induction of proteasome in hemorrhagic shock is associated with disassembly of 26S proteasome; CLEFMA and EF24 prevented this disassembly. Consistent with these data, CLEFMA and EF24 reduced hemorrhagic shock-induced degradation of 20S substrate ornithine decarboxylase in gut tissue. These results suggest that activated proteasome plays an important role in ischemic gut pathophysiology, and it can be a druggable target in shock-induced gut dysfunction. NEW & NOTEWORTHY Ischemic injury to the gut is a trigger for the systemic inflammatory response and multiple organ failure in trauma and hemorrhagic shock. We show for the first time that hemorrhagic shock induces the gut proteasome activity by engendering 26S proteasome disassembly. Diphenyldihaloketones 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone treatment prevented the 26S disassembly. Understanding the role of proteasome in shock-associated gut injury will assist in the development of therapeutic means to address it.

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Role of metabolic changes of mucosal layer in the intestinal barrier dysfunction following trauma/hemorrhagic shock

Pathology - Research and Practice ◽

10.1016/j.prp.2018.08.023 ◽

2018 ◽

Vol 214 (11) ◽

pp. 1879-1884 ◽

Cited By ~ 2

Author(s):

Ran Zhu ◽

Xiao-chun Ma

Keyword(s):

Hemorrhagic Shock ◽

Intestinal Barrier ◽

Metabolic Changes ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction ◽

Mucosal Layer

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Lycium barbarum polysaccharides ameliorate intestinal barrier dysfunction and inflammation through the MLCK-MLC signaling pathway in Caco-2 cells

Food & Function ◽

10.1039/d0fo00030b ◽

2020 ◽

Vol 11 (4) ◽

pp. 3741-3748 ◽

Cited By ~ 1

Author(s):

Wei Li ◽

Mingbo Gao ◽

Ting Han

Keyword(s):

Signaling Pathway ◽

Inflammatory Bowel Diseases ◽

Intestinal Barrier ◽

Vital Role ◽

Inflammatory Factors ◽

Barrier Dysfunction ◽

Lycium Barbarum ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Lycium Barbarum Polysaccharides

Impairment of the intestinal barrier often occurs in inflammatory bowel diseases, and pro-inflammatory factors play a vital role in the pathogenesis of intestinal diseases.

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RINGERʼS ETHYL PYRUVATE SOLUTION (“REPS”) IMPROVES SURVIVAL AND AMELIORATES GUT BARRIER DYSFUNCTION IN A RAT MODEL OF HEMORRHAGIC SHOCK

Shock ◽

10.1097/00024382-200106001-00080 ◽

2001 ◽

Vol 15 (Supplement) ◽

pp. 27

Author(s):

Z. Tawadrous ◽

R. Delude ◽

M. P. Fink

Keyword(s):

Hemorrhagic Shock ◽

Rat Model ◽

Ethyl Pyruvate ◽

Barrier Dysfunction ◽

Gut Barrier

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Blockade of Stellate Ganglion Remediates Hemorrhagic Shock–Induced Intestinal Barrier Dysfunction

Journal of Surgical Research ◽

10.1016/j.jss.2019.06.007 ◽

2019 ◽

Vol 244 ◽

pp. 69-76

Author(s):

Jing Zhang ◽

Xue-Rong Lin ◽

Yu-Ping Zhang ◽

Li-Min Zhang ◽

Hui-Bo Du ◽

...

Keyword(s):

Hemorrhagic Shock ◽

Stellate Ganglion ◽

Intestinal Barrier ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction

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

Frontiers in Nutrition ◽

10.3389/fnut.2021.746592 ◽

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.

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Ghrelin Alleviates Intestinal Dysfunction in Sepsis Through the KLF4/MMP2 Regulatory Axis by Activating SIRT1

Frontiers in Immunology ◽

10.3389/fimmu.2021.646775 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bin Li ◽

Zhimin Dou ◽

Lei Zhang ◽

Lei Zhu ◽

Yongqiang Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Rat Model ◽

Interleukin 1 ◽

Cecal Ligation ◽

Intestinal Barrier ◽

Matrix Metalloproteinase 2 ◽

Inflammatory Factors ◽

Loss Of Function ◽

Barrier Dysfunction

Intestinal barrier dysfunction is an important contributor to morbidity caused by sepsis. This study investigates the molecular mechanism by which Ghrelin affects intestinal dysfunction in rat model of sepsis. A rat model of sepsis was established by cecal ligation and puncture (CLP), revealing that Ghrelin was downregulated when sepsis occurs. Increases in the levels of inflammatory factors tumor necrosis factor α (TNF-α), interleukin-1 (IL-1β), IL-6, gastrin, γ-H2AX and 8-OHdG was also detected in this model system, as was an overall increase in oxidative stress. Introduction of exogenous Ghrelin inhibited these increases in inflammatory response and oxidative stress, leading to a reduction of overall sepsis-induced intestinal dysfunction. Ghrelin was then shown to activate SIRT1 expression in vitro, while SIRT1 was found to co-express with KLF4, which in turn was predicted to bind to matrix metalloproteinase 2 (MMP2) promoter. Finally, gain- and loss-of-function experiment demonstrated that SIRT1 upregulated the expression of KLF4 to downregulate MMP2. Collectively, Ghrelin inhibits the oxidative stress and intestinal dysfunction to attenuate sepsis by activating SIRT1 and regulating a KLF4/MMP2 regulatory axis.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00177.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. G621-G629 ◽

Cited By ~ 109

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.

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