Research progress on relationship between bile acids and intestinal mucosal mechanical barrier function

BackgroundSystemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized with the secretion of normal autoantibodies, which leads to the involvement of multiple organs. Several observations have showed that the...

Reply to: “Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: The pivotal role of enterocyte tight junctions and future perspectives”

Objective To investigate the effect of somatostatin combined with omeprazole on intestinal mucosal barrier function and oxidative stress in patients with acute pancreatitis. Methods A retrospective analysis was performed on the clinical data from 128 patients with acute pancreatitis who were hospitalized in the Second People’s Hospital of Liaocheng from February 2014 to March 2018. And patients in the study were divided into control group (64 cases, treated with somatostatin) and observation group (64 cases, treated with somatostatin plus omeprazole) by treatment protocols. The intestinal mucosal barrier function, including peripheral blood diamine oxidase (DAO), peripheral blood D-lactic acid, and oxidative stress reaction, such as superoxide dismutase (SOD), Catalase (CTA) and malondialdehyde (MDA) were compared between the two groups. Results DAO and D-lactic acid levels in observation group were lower than those in control group 7 days after treatment, and the difference was statistically significant (P<0.05). SOD and CTA levels in observation group were higher than those in control group, while MDA levels were lower than those in control group 7 days after treatment, with statistically significant differences (P<0.05). Conclusions Somatostatin combined with omeprazole can effectively improve intestinal mucosal barrier function and control oxidative stress in patients with acute pancreatitis. Key words: Acute pancreatitis; Somatostatin; Omeprazole; Intestinal mucosal barrier function; Oxidative stress reaction

Objective To observe the effects of alprostadil injection on intestinal mucosal barrier function in patients with acute pancreatitis(AP). Methods Seventy-eight AP patients admitted in Department of Medicine in Yuhang District Second People′s Hospital of Hangzhou City from May 2016 to March 2017 were divided into 2 groups using random number method, including 38 cases in the control group and 40 cases in the treatment group. Patients in the control group received routine treatment. Patients in the treatment group were given intravenous 10 μg/d alprostadil injection in addition to routine treatment continuously for 14 days. Another 40 healthy volunteers who underwent routine examination in the same period were enrolled as healthy control group. The scores of MCTSI and APACHEⅡ were recorded at admission and 2 days after the treatment. The levels of serum DAO, endotoxin (ET) and IFABP were detected by ELISA. Results There were no significant difference on the scores of MCTSI and APACHEⅡ, the levels of serum DAO, ET, IFABP before treatment between control and treatment group(P>0.05), but were increased significantly than those in the healthy control group(P<0.01). After treatment, the scores of MCTSI and APACHEⅡ, the levels of serum DAO, ET, IFABP were decreased significantly than those before treatment in two groups(P<0.05 or P<0.01), but the scores of MCTSI and APACHEⅡ, the levels of serum DAO, ET and IFABP were decreased significantly than those in the control group(3.78±0.43)vs (5.89±0.13), (5.65±1.77)vs (9.05±1.61), (2.18±0.16)U/ml vs (3.22±0.15)U/ml, (0.15±0.06)EU/ml vs (0.25±0.09)EU/ml, (62.01±12.82)ng/L vs (85.43±16.79)ng/L; all P<0.05). There was a significant positive correlation between serum DAO, ET, IFABP and the scores of MCTSI (P<0.01). There was a significant positive correlation between serum DAO, ET, IFABP and the scores of APACHEⅡ, too (P<0.01). Conclusions Patient with acute pancreatitis have obvious intestinal mucosal barrier injury. Alprostadil injection can improve clinical symptoms and the scores of MCTSI to a certain extent by protecting intestinal mucosal barrier function. Key words: Pancreatitis; Alprostadil; Intestinal mucosal

Hylocereus polyrhizus pomace polysaccharides for the treatment of obesity-induced intestinal mucosal injury.

Effects of trapidil on intestinal mucosal barrier function and bacterial translocation after intestinal ischemia and reperfusion in an experimental rat model

As a natural extract from turmeric, curcumin has extensive pharmacological effects, such as anti-tumor, anti-inflammation, anti-oxidative stress, anti-microbial, immunoregulation and so on. In recent years, an increasing number of basic and clinical researches have shown that curcumin takes therapeutic effects on various diseases, such as gastrointestinal diseases, cardiovascular diseases, autoimmune diseases, neuropsychiatric diseases and so on. Many of the pharmacological effects and mechanisms of curcumin are associated with protective effects of intestinal mucosal barrier. It can protect intestinal mucosal barrier through mutiple pathways, including anti-inflammation, anti-oxidative stress, anti-bacterial, anti-apoptosis, regulating intestinal microecology and intestinal immune response and so on. This paper summarizes the protective effects of curcumin on intestinal barrier function and the mechanism, in order to provide new ideas for diagnosis and treatment of intestinal dysfunction.

Objective To investigate the roles of plasma D-lactate, endotoxin and diamineoxidase (DAO) in assessment of intestinal mucosal barrier function post traumatic brain injury (TBI). Methods We retrospectively studied 70 patients with TBI (TBI group) admitted to Department of Neurosurgery, the 904th Hospital of the Joint Service of Chinese People′s Liberation Army from January 2017 to August 2018, and 45 healthy subjects were enrolled as well (healthy control group) at the physical examination center during the same period. All TBI patients were treated conservatively or surgically. Peripheral blood of patients and healthy subjects were collected to detect levels of plasma D-lactic acid, endotoxin, and DAO. Further use of Spearman correlation analysis was conducted to determine the correlation between preoperative serum D-lactic acid, endotoxin and DAO and Glasgow Coma Scale (GCS) in patients with TBI. Results Compared with the healthy control group, the levels of D-lactic acid (24.7±9.4 mg/L vs. 9.8±4.0 mg/L), endotoxin (9.1±5.8 U/L vs. 4.0±2.2 U/L) and DAO (36.3±22.6 U/L vs. 15.2±3.6 U/L) were significantly increased (t=9.82, 2.84 and 3.49, respectively, all P<0.05). Further correlation analysis showed that serum D-lactic acid, endotoxin and DAO levels were negatively correlated with preoperative GCS scores (r=-0.543, -0.617 and -0.672, respectively, all P<0.01). Conclusion The preliminary results have suggested that the levels of D-lactic acid, bacterial endotoxin and DAO in the serum could be used as important indexes in evaluation of the intestinal mucosal barrier function in patients post TBI. Key words: Traumatic brain injury; Diamineoxidase; D-lactate; Endotoxin; Intestinal mucosa barrier

Reduced Intestinal Motility, Mucosal Barrier Function, and Inflammation in Aged Monkeys.

Clostridium butyricum (CB), a probiotic, is a gram-positive obligate anaerobic bacillus with acid and heat resistant properties. Previous studies have reported that CB has beneficial effects in intestinal diseases and regulates intestinal function. The aim of the present study was to investigate the protective effects and mechanisms of CB on the intestinal barrier function. Mice were randomly divided into three experimental groups (n=15 mice/group), including control, dextran sodium sulfate (DSS) and DSS + CB. In the DSS and DSS + CB groups colitis was induced with 3% DSS dissolved in drinking water for 7 days. DSS + CB group mice were co-treated daily with 200 µl (2x108 CFU) CB solution via gavage. The intestinal mucosal barrier function in mice was assessed by measuring FITC-labeled 4-kDa dextran (molecular weight, 4,000 Da) flux and by analyzing the expression of tight junction (TJ)-related proteins using western blot analysis. In addition, the secretion levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-10 and IL-13, and the concentration of malondialdehyde, glutathione and superoxide dismutase were detected using ELISAs to determine inflammation and oxidative stress, respectively. The activation status of the Akt/mTOR signaling pathway was also investigated using western blot analysis. The results demonstrated that, in mice with DSS-induced colitis treatment, co-treatment with CB attenuated colitis symptoms and intestinal permeability, increased the expression levels of TJ-related proteins, decreased TNF-α, IL-1β and IL-13 secretion levels but increased those of IL-10, and reduced oxidative stress. Additionally, CB elevated the phosphorylation of Akt, mTOR and p70 ribosomal protein S6 kinase. Collectively, the present results indicated that CB protected intestinal barrier function and decreased intestinal mucosal permeability via upregulating the expression levels of TJ-related proteins in a mouse model of DSS-induced colitis. Moreover, the results suggested that the effects of CB could be mediated by the Akt/mTOR signaling pathway.

To observe the effect of electroacupuncture (EA) on the activation of mast cells (MCs) in the colon of rats with diarrhea-predominant irritable bowel syndrome (IBS-D) and to explore the underlying mechanisms of its protective effect on the intestinal mucosal barrier. Of 74 offsprings from 6 pregnant SD rats, 14 offsprings were randomly collected as a normal group, and the remaining 60 offsprings underwent IBS-D model prepared by maternal separation combined with acetic acid enema and chronic restraint stress. Fifty-six successfully modeled rats were randomly divided into a model group, a ketotifen group, an EA group, and an EA+ketotifen (combination) group, 14 rats in each one. In the ketotifen group, the rats received the intragastric administration of ketotifen solution (10 mL/kg). In the EA group, acupuncture was delivered at bilateral "Tianshu" (ST25) and "Shangjuxu" (ST37) with disperse-dense wave, a frequency of 2 Hz/100 Hz and a current of 0.3 mA. In the combination group, the intervention measures of the above two groups were operated in combination. In each group, the intervention was delivered once daily for 7 consecutive days. Separately, before modeling, after modeling and after intervention completion, diarrhea score and the minimum injection volume for the abdominal withdrawal reflex (AWR) in rats were evaluated in each group. After intervention, HE staining was adopted to observe the morphology of colonic mucosa; scanning electron microscopy to examine mucosal ultrastructure; Toluidine blue staining to observe MCs degranulation in the colonic mucosa; ELISA to detect serum levels of calcitonin gene-related peptide (CGRP), diamine oxidase (DAO), D-lactate (D-LA), and lipopolysaccharide (LPS); fluorescence microplate assay to detect the serum concentration of 4 kDa fluorescein isothiocyanate-dextran (FD4); Western blot, real-time quantitative PCR (RT-qPCR), and immunofluorescence to detect the expression of nerve growth factor (NGF), tyrosine kinase receptor A (TrkA), and transient receptor potential vanilloid type 1 (TRPV1) in colon tissue; and Pearson correlation coefficient to analyze the relationship between CGRP level and intestinal barrier function. Compared with the normal group, the model group showed the decrease in AWR minimum injection volume (P<0.01), the increase in diarrhea score and MC degranulation rate (P<0.01), the damage of colonic mucosal structure, obvious inflammatory cell infiltration, and the increase in serum levels of CGRP, DAO, D-LA, LPS, FD4 mean fluorescence intensity (MFI), as well as the protein, mRNA, and positive expression levels of NGF, TrkA, and TRPV1 in colon tissue (P<0.01, P<0.05). Compared with the model group, the ketotifen, EA, and combination groups exhibited the increase in AWR minimum injection volume (P<0.01), the decline in diarrhea score and MC degranulation rate (P<0.01), relatively intact intestinal mucosal structure, reduced inflammatory cell infiltration, and the decrease in serum levels of CGRP, DAO, D-LA, LPS, FD4 MFI, as well as the protein, mRNA, and positive expression levels of NGF, TrkA, and TRPV1 in colon tissue (P<0.01). When compared with the ketotifen group, the EA group demonstrated lower FD4 MFI in serum and reduced protein expression of NGF, TrkA, and TRPV1 in colon (P<0.01), and no statistically significant differences were presented in the other indicators (P>0.05). In comparison with both the ketotifen and EA groups, the combination group showed the improvements in all the aforementioned indicators (P<0.01, P<0.05). Serum level of CGRP was positively correlated with the levels of DAO, D-LA, LPS, and FD4 (P<0.001). Electroacupuncture may ameliorate intestinal mucosal barrier function and alleviate symptoms in IBS-D rats by inhibiting MC activation, modulating the NGF/TrkA pathway, and reducing serum levels of DAO, D-LA, LPS, and FD4.

Inflammatory bowel disease is characterized by dysregulation of the mucosal immune system resulting from impaired intestinal epithelial barrier function. Protein kinase D2 has been implicated in the regulation of immune responses. The present study was to define PKD2 might affect murine colitis. Colitis was induced in wild-type mice (PKD2WT/WT) and PKD2 catalytic activity deficient mice (PKD2SSAA/SSAA) with dextran sulfate sodium. PKD2SSAA-knockin mice displayed catalytic activity deficiency and increased susceptibility to DSS-induced colitis with enhanced weight loss, colonic inflammation compared with PKD2WT/WT mice. Furthermore, crucial inflammatory cytokines mRNA levels in PKD2SSAA-knockin mice were higher than controls accompanied with down-regulation of ZO-1, MUC2 and intestinal barrier dysfunction. However, there were no differences in the proliferation or apoptosis of intestinal epithelial cells in PKD2SSAA-knockin mice compared with wild-type controls. In addition, PKD2 expression was repressed in patients with IBD compared with healthy controls. These studies suggested that activation of PKD2 in the colonic epithelium microenvironment may contribute to protect against DSS-induced colitis through regulation of intestinal mucosal immunity and barrier function.

Objective To observe the clinical effect of continuous intravenous pumping of octreotide in the treatment of intestinal endotoxemia.Methods Eighty patients with intestinal obstruction and non-surgical treatment were divided into group Ⅰ with 34 cases who received conventional-treatment and group Ⅱ with 46 cases who received conventional-treatment combined with octreotide 24 h continuous intravenous pumping.White blood cell count ( WBC ),diamine oxidase (DAO),D-lactic acid (D-LA) and endotoxin were detected before treatment and at 24 h,48 h,4 d after treatment.Results The content of WBC,DAO,D-LA and endotoxin in two groups all reached peak at 48 h after treatment.The difference of the content of WBC,DAO,D-LA and endotoxin between two groups had no statistical significance at 24 h after treatment (P ＞ 0.05).The content of WBC,DAO,D-LA and endotoxin of group Ⅱ at 48 h and 4 d after treatment were lower than those of group Ⅰ.And the difference at 48 h after treatment had statistical significance[(18.40 ±0.10)× 109/L vs.(20.60 ± 2.36) × 109/L,(6.12 ± 1.02) kU/L vs.(8.02 ± 1.54) kU/L,(2.14 ±0.21) mg/L vs.(3.34 ± 0.04) mg/L,(1.65 ±0.16) kEU/L w.(2.23 ±0.36) kEU/L] (P ＜ 0.01).While the difference at 4 d after treatment had no statistical significance(P＞ 0.05 ).Body temperature at 48 h after treatment,gastrointestinal decompression capacity,anus exhaust time of group Ⅱ were (37.60 + 3.01 )℃,(320.00 ± 76.14) ml/d,(54.00 ± 0.94) h respectively,and they all were superior to those of group Ⅰ[(38.50 ± 2.21 ) ℃,(500.00 ± 80.32) ml/d,(68.00 ± 1.02) h] (P ＜0.01).Conclusions Continuous intravenous pumping of octreotide can effectively protect the intestinal mucosal barrier function,improve intestinal permeability,reduce the trmslocation of intestinal flora,inhibit the incidence and development of enterogenous endotoxemia.And it provides new evidence to support the clinioal application of octreotide in patients with intestinal endotoxemia. Key words: Octreotide; Endotoxemia; Intestinal barrier dysfunction

Objective To examine the clinical efficacy and safety of Vitamin D in the treatment of ulcerative colitis in a systematic manner. Methods RCT studies on Vitamin D in the treatment of ulcerative colitis were searched from CNKI, Wanfang Data, PubMed, Cochrane Library, and Web of Science databases. RevMan 5.4 software was used for analysis. Results 10 articles were included, including 1077 patients. Meta-analysis results showed that when clinical efficacy was used as the outcome index, the clinical efficacy of the oral vitamin group was higher than that of the conventional treatment group (OR = 4.07, 95% CI 2.64-6.27), and the difference was statistically significant (Z = 6.38, P < 0.00001). When the Mayo risk score was used as the outcome index, the difference was statistically significant, indicating that oral Vitamin D significantly reduced the Mayo risk score (MD: -0.41, CI = (−0.47, −0.34), Z = 13.09, P < 0.00001). Using the intestinal mucosal barrier as the outcome index, the results showed that (1) the MDA group (MD = −0.75, 95% CI (-0.96~-0.53), P < 0.00001), (2) the DAO group (MD = −1.17, 95% CI (-1.39-0.95), P < 0.00001), and the Vitamin D group could effectively improve intestinal mucosal barrier function after sensitivity analysis (MD = −1.00, 95% CI (-1.08-0.92), P < 0.00001). When inflammatory factors were used as outcome indicators, IL-6, TNF-α, and CRP groups had statistical significance (MD = −4.50, 95% CI (-5.13-3.87), P < 0.00001); MD = −7.27, 95% CI (18.96-5.58), P < 0.00001; and MD = −1.49, 95% CI (-1.76~-1.23), P < 0.00001, respectively). When the incidence of adverse reactions was used as the outcome indicator (OR = 0.73, 95% CI (0.34-1.32), P = 0.23), there was no significant difference between the two groups. Conclusion Vitamin D combined with mesalazine is effective in the treatment of ulcerative colitis, by improving the Mayo score and intestinal barrier function, and reducing inflammatory factors, with no significant safety difference. However, due to the quality of the included researches, more RCT researches needed to provide sufficient evidence to support clinical application. This study is registered with INPLASY 202250044.

This study aims to investigate therapeutic effects and involved molecular mechanisms of Banxia Xiexin Decoction (BXD) in reducing gastrointestinal complications associated with sepsis. Sepsis is a common critical illness that threatens patient survival and costs society a lot. This syndrome is a prominent cause of death in ICUs due to its high mortality rate, which exceeds 30% after 28 days and 35.5% after 90 days. Sepsis remains a major medical challenge despite a 20%-30% drop in fatality rates due to a better understanding of its physiological and pathological features and better therapeutic techniques. There is no pharmacological treatment for sepsis, highlighting the need for more study. We explored the protecting effects of BXD on intestinal functionality in sepsis by investigating its roles in the regulation of mitochondrial autophagy and mitochondrial functioning in small intestinal epithelial cells, primarily via the PINK1/Parkin signaling pathway. We established a cell model of Human Intestinal Epithelial Cell (HIEC) injury induced by lipopolysaccharide (LPS) and a cecal ligation and perforation (CLP) sepsis model in Sprague Dawley (SD) rats. The cell model and animal model of sepsis were divided into control groups and different treatment groups that received different doses of BXD. We utilized HIECs with PINK1 knockdown to assess BXD's protective effects on the sepsis intestinal barrier and its regulatory mechanism both on the PINK1/Parkin signaling pathway, exploring both its facilitative and inhibitory effects. ELISA method was used to measure inflammatory markers IL-6, IL-1β, and intestinal injury-related molecules IFABP and DAO. Pathological assessments were performed with H&E staining, and tight junction proteins ZO-1 and Occludin were detected using immunohistochemical staining. Mitochondrial membrane protein TOM20 was detected through immunofluorescence staining. Mitochondrial membrane potential and autophagy were assessed via flow cytometry. The expression levels of PINK1, Park, LC3, and p62 proteins and mRNA, integral to the PINK1/Parkin autophagy pathway, were evaluated using Western Blot and RT-PCR. Compared to the control group, BXD therapy significantly lowered serum DAO, IFABP, and DA. The BXD therapy group showed a more significant and sustained drop in IL-6 and IL-1β levels than the control group. The BXD therapy reduced intestinal mucosa damage by lowering DAO and IFABP. BXD also restored tight junction proteins ZO-1 and Occludin, improving intestinal mucosal barrier function. In septic rats, BXD therapy lowered serum IL-6 and IL-1β levels, avoiding inflammation and reducing intestinal damage. BXD enhanced TOM20, which protected intestinal epithelial cell mitochondria against decreasing mitochondrial membrane potential. BXD increased the PINK1/Parkin mitochondrial autophagy pathway at the molecular level. Mitochondrial autophagy can repair mitochondria, reduce oxidative stress, maintain mitochondrial homeostasis, and help intestinal epithelial cells survive and function. BXD could improve intestinal mucosal damage and systemic inflammation caused by sepsis. BXD mainly promotes the PINK1/Parkin mitophagy pathway by upregulating PINK1 protein.