Relationship between expression of triggering receptor-1 on myeloid cells in intestinal tissue and intestinal barrier dysfunction in severe acute pancreatitis

BACKGROUND：Triggering receptor expressed on myeloid cells-1 （TREM-1） in the intestine was upregulated and correlated with disease activity in inflammatory bowel diseases. Membrane- bound TREM-1 protein is increased in the pancreas, liver and kidneys of patients with severe acute pancreatitis （SAP）, suggesting that TREM-1 may act as an important mediator of inflammation and subsequent extra-pancreatic organ injury. This study aimed to investigate the relationship between the expression of TREM-1 in intestinal tissue and intestinal barrier dysfunction in SAP. METHODS： Sixty-four male Wistar rats were randomly divided into a sham operation group （SO group, n=32） and a SAP group （n=32）. A SAP model was established by retrograde injection of 5% sodium deoxycholate into the bile-pancreatic duct. Specimens were taken from blood and intestinal tissue 2, 6, 12, and 48 hours after operation respectively. The levels of D-lactate, diamine oxidase （DAO） and endotoxin in serum were measured using an improved spectro-photometric method. The expression levels of TREM-1, interleukin-1β （IL-1β）, and tumor necrosis factor-α （TNF-α） mRNA in terminal ileum were detected by real-time reverse transcription-polymerase chain reaction （RT-PCR）. Specimens of the distal ileum were taken to determine pathological changes by a validated histology score. The serum levels of D-lactate, DAO and endotoxin were significantly increased in each subgroup of SAP compared with the SO group （P〈0.01, P〈0.05）. The expression levels of TREM-1, IL-1β and TNF-a mRNA in the terminal ileum in each subgroup of SAP were significantly higher than those in the SO group （P〈0.01, P〈0.05）. The expression level of TREM-lmRNA was positively correlated with IL-1βand TNF-α mRNA （r=0.956, P=0.044; r=0.986, P=0.015）, but the correlation was not found between IL-1β mRNA and TNF-a mRNA （P=0.133）. Compared to the SO group, the pathological changes were aggravated significantly in the SAP group. CONCLUSIONS： The expression level of TREM-1 in intestinal tissue of rats with SAP was elevated, leading to the release of inflammatory mediators and intestinal mucosal injury. This finding indicates that TREM-I might play an important role in the development of intestinal barrier dysfunction in rats with SAP.

MicroRNAs:New therapeutic targets for intestinal barrier dysfunction

Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathogenic role in diseases such as inflammatory bowel disease(IBD)and celiac disease,and functional bowel disorders such as irritable bowel syndrome.Therefore,clarification of the inflammatory responses,the defense pathway and the corresponding regulatory system is essential and may lead to the development of new therapies.MicroRNAs(miRNAs)are small(19-22nt)noncoding RNA molecules that regulate genes at the post-transcriptional level by base-pairing to specific messenger RNAs for degradation to repress translation.Recent studies suggested that miRNAs are important in the immune response and mediate a critical role in multiple immune response-related disorders.Based on these discoveries,attention has been focused on understanding the role of miRNAs in regulating intestinal barrier dysfunction,especially in IBD.Here,we provide a review of the most recent state-of-the-art research on miRNAs in intestinal barrier dysfunction.

Honokiol Prevents Intestinal Barrier Dysfunction in Mice with Severe Acute Pancreatitis and Inhibits JAK/STAT1 Pathway and Acetylation of HMGB1

Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and randomly divided into 5 groups using a random number table,including control,SAP,SAP and normal saline(SAP+NS),SAP and ethyl pyruvate(SAP+EP),or SAP+HON groups,6 mice in each group.Samples of pancreas,intestine,and blood were collected 12 h after SAP model induction for examination of pathologic changes,immune function alterations by enzyme linked immunosorbent assay(ELISA),and Western blot.In vitro experiments,macrophages were divided into 5 groups,the control,lipopolysaccharide(LPS),LPS+DMSO(DMSO),LPS+anti-HMGB1 monoclonal antibody(mAb),and LPS+HON groups.The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled.The location and acetylation of HMGB1 were measured by Western blot.Finally,pyridone 6 and silencing signal transducer and activator of the transcription 1(siSTAT1)combined with honokiol were added to determine whether the Janus kinase(JAK)/STAT1 participated in the regulation of honokiol on HMGB1.The protein expression levels of HMGB1,JAK,and STAT1 were detected using Western blot.Results Mice with SAP had inflammatory injury in the pancreas,bleeding of intestinal tissues,and cells with disrupted histology.Mice in the SAP+HON group had significantly fewer pathological changes.Mice with SAP also had significant increases in the serum levels of amylase,lipase,HMGB1,tumor necrosis factor-α,interleukin-6,diamine oxidase,endotoxin-1,and procalcitonin.Mice in the SAP+HON group did not show these abnormalities(P<0.01).Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability,decreased the levels of junctional adhesion molecule C,and elevated intercellular permeability(P<0.01).HON treatment blocked these effects.Studies of macrophages indicated that LPS led to low nuclear levels of HMGB1,however,HON treatment increased the nuclear level of HMGB1(P<0.01).HON treatment also inhibited the expressions of JAK1,JAK2,and STAT1(P<0.01)and increased the acetylation of HMGB1(P<0.05).Conclusion HON prevented intestinal barrier dysfunction in SAP by inhibiting HMGB1 acetylation and JAK/STAT1 pathway.

Intestinal barrier dysfunction in severe burn injury

Severe burn injury is often accompanied by intestinal barrier dysfunction,which is closely associated with post-burn shock,bacterial translocation,systemic inflammatory response syndrome,hypercatabolism,sepsis,multiple organ dysfunction syndrome,and other complications.The intestinal epithelium forms a physical barrier that separates the intestinal lumen from the internal milieu,in which the tight junction plays a principal role.It has been well documented that after severe burn injury,many factors such as stress,ischemia/hypoxia,proinflammatory cytokines,and endotoxins can induce intestinal barrier dysfunction via multiple signaling pathways.Recent advances have provided new insights into the mechanisms and the therapeutic strategies of intestinal epithelial barrier dysfunction associated with severe burn injury.In this review,we will describe the current knowledge of the mechanisms involved in intestinal barrier dysfunction in response to severe burn injury and the emerging therapies for treating intestinal barrier dysfunction following severe burn injury.

P2X7 receptor as the regulator of T-cell function in intestinal barrier disruption

The intestinal mucosa is a highly compartmentalized structure that forms a directbarrier between the host intestine and the environment, and its dysfunction couldresult in a serious disease. As T cells, which are important components of themucosal immune system, interact with gut microbiota and maintain intestinalhomeostasis, they may be involved in the process of intestinal barrier dysfunction.P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effectsof extracellular adenosine triphosphate and is expressed by most innate or adaptiveimmune cells, including T cells. Current evidence has demonstrated thatP2X7R is involved in inflammation and mediates the survival and differentiationof T lymphocytes, indicating its potential role in the regulation of T cell function.In this review, we summarize the available research about the regulatory role andmechanism of P2X7R on the intestinal mucosa-derived T cells in the setting ofintestinal barrier dysfunction.

Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis

Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.

Effect of acupoint application combined with microwave treatment on the intestine barrier functional disturbance of moderately severe acute pancreatitis

Objective: To explore and analyze the effect of acupoint application combined with microwave treatment on the intestinal barrier dysfunction with moderately severe acute pancreatitis. Methods: A convenient sample of 90 moderately severe acute pancreatitis was selected from March 2017 to December 2017 in the comprehensive hospital with third grade in Tianjin. The patients were divided into group A (acupoint application combined with microwave treatment), group B (acupoint application) and group C (routine nursing). Thirty patients were included in each group. This study need to get the informed consent of the patients. Acupoint application combined with microwave treatment was used, basing on routine nursing measures in group A. Acupoint application was used by the same way and the same traditional Chinese medicine ,basing on routine nursing measures in group B. Routine nursing used in group C. C-reactive protein and the score of intestinal function were measured on 3 th day, 7 th day and 10 th day, after intervention. To record the effective ratio of the treatment after 10 days of intervention. Results: There are significant statistical difference among the three group after intervention (P < 0.05). Conclusion: In some way, acupoint application combined with microwave treatment are able to decrease the time about the recovery of intestinal barrier dysfunction in moderately severe acute pancreatitis and to alleviate the suffering of patients.

Ginsenoside Rk2, a dehydroprotopanaxadiol saponin, alleviates alcoholic liver disease via regulating NLRP3 and NLRP6 inflammasome signaling pathways in mice

Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.

Multi-Omics Analysis Provides Insight into the Possible Molecular Mechanism of Hay Fever Based on Gut Microbiota

Due to the worldwide epidemic of allergic disease and a cure nowhere in sight,there is a crucial need to explore its pathophysiological mechanisms.As allergic disease has been associated with gut dysbiosis,we searched for a possible mechanism from the perspective of the molecular interface between host and microbiota with concurrent metabolomics and microbiome composition analysis.Sprague-Dawley rats were injected with Artemisia pollen extract to stimulate a hyper reaction to pollen.This hyper reaction decreased the circulation of valine,isoleucine,aspartate,glutamate,glutamine,indole-propionate(IPA),and myo-inositol,and reduced short-chain fatty acids(SCFAs)in feces.Several beneficial genera belonging to Ruminococcaceae,Lachnospiraceae,and Clostridiales declined in the model group,whereas Helicobacter and Akkermansia were only expressed in the model group.Furthermore,the expression of intestinal claudin-3 and liver fatty acid binding protein was downregulated in the model group and associated with metabolic changes and bacteria.Our results suggest that alterations in amino acids as well as their derivatives(especially valine,and IPA which is the reductive product of tryptophan),SCFAs,and the gut microbiome(specifically Akkermansia and Helicobacter)may disrupt the intestinal barrier function by inhibiting the expression of claudin proteins and affecting the mucus layer,which further results in hay fever.