Abstract
BACKGROUND
The gut-vascular barrier (GVB) is critical for maintaining intestinal homeostasis, but its involvement in intestinal obstruction (IO) remains unclear.
AIM
To investigate GVB disruption in patients with IO and its association with perioperative infection, organ injury, and clinical prognosis.
METHODS
Intestinal tissues from surgical patients with IO (IO group) and without obstruction (control group) were analyzed for PV1, a biomarker of GVB disruption. In the IO group, PV1 expression correlated with clinical data. Patients were further stratified into PV1-high and PV1-low subgroups, and clinical parameters were compared.
RESULTS
PV1 expression was significantly elevated in the IO group. In the IO group, PV1 levels were positively correlated with perioperative infection markers, liver and kidney injury indices, and adverse prognostic indicators, including prolonged hospitalization, antibiotic use, fever duration, and postoperative complications. Several of these outcomes were significantly worse in the PV1-high subgroup than in the PV1-low subgroup, although severe postoperative complications and mortality did not differ.
CONCLUSION
Our findings demonstrate that IO induces GVB damage, and the extent of impairment is closely associated with infection, organ injury, and adverse clinical outcomes in surgical patients, suggesting a pathogenic role for GVB disruption in IO.
Keywords: Intestinal obstruction, Gut-vascular barrier, PV1, Infection, Organ injury, Clinical prognosis
Core Tip: This study reveals that intestinal obstruction (IO) leads to gut-vascular barrier (GVB) damage, with PV1 expression positively correlating with infection, liver/kidney injury, and adverse outcomes. GVB impairment may contribute to IO pathogenesis, highlighting PV1 as a potential prognostic biomarker.
INTRODUCTION
Intestinal obstruction (IO) is a common surgical emergency, predominantly caused by adhesions, neoplasms, and herniation. It occurs when mechanical factors impair, arrest, or revers the normal passage of intestinal contents factors[1]. IO frequently results in dysmotility, dysbiosis, ischemia, and infection[2]. Gut barrier dysfunction further exacerbates these complications and may progress to multiple organ dysfunction syndrome (MODS)[3-5]. Reported mortality rates for small bowel and colon obstruction in the United States are approximately 10% and 30%, respectively[6]. Consequently, it is necessary to investigate how IO affects intestinal barrier systems.
The intestinal barrier comprises mechanical, chemical, immune, and biological components that maintain intestinal homeostasis[7-10]. In 2015, Spadoni et al[11] identified the gut-vascular barrier (GVB) in mice and humans, a structure similar to the blood-brain barrier. The GVB comprises vascular endothelial cells and intercellular junctional complexes, including adherens and tight junctions, and restricts the passage of macromolecules (> 70 kDa) from the intestinal tract to the bloodstream. When GVB is damaged, bacteria may translocate into the blood circulation, causing systemic infection and remote organ dysfunction. PV1 is a distinctive biomarker of GVB disruption, specifically expressed in the intestinal mucosal layer, and is widely used to assess the extent of barrier disruption[12-15]. Although several studies have focused on the intestinal epithelial barrier in IO, the role of GVB disruption and IO pathogenesis remains unclear.
Therefore, this study aimed to investigate the impact of IO on GVB and analyze the correlation between GVB damage and perioperative infection, liver and kidney function, and clinical prognosis.
MATERIALS AND METHODS
Patients
This controlled study was conducted at The First Affiliated Hospital of Sun Yat-sen University between March 1, 2021, and October 1, 2022. Patients who underwent gastroenteric surgery in the Department of Gastrointestinal Surgery were enrolled. Demographic and clinical data were collected upon admission. The inclusion criteria were as follows: Age 18-75 years, scheduled for intestinal excision surgery, and body mass index (BMI) of 18-28 kg/m2. Patients diagnosed with IO based on clinical and imaging criteria were enrolled in the IO group, whereas patients with tumor without IO served as controls. The exclusion criteria included severe hepatic or renal dysfunction, hematological disease, or a history of radiotherapy or chemotherapy. The Ethics Committee of The First Affiliated Hospital of Sun Yat-sen University approved this study (No.[2021]810). Written informed consent was obtained from all participants.
Tissue sample collection
Tissue samples of the control group were collected from the proximal incisional margin, whereas those of the IO group were collected from regions proximal to the obstruction (Supplementary Figure 1). Each specimen was divided into two portions: One was stored at -80 °C for frozen sections, and the other was examined for reverse transcription-quantitative PCR (RT-qPCR) analysis.
Detection of PV1 expression
Total RNA was extracted from homogenized intestinal tissues using Trizol reagent according to the manufacturer’s instructions. Complementary DNA was synthesized using the HiScript II Q RT SuperMix kit, following the manufacturer’s instructions, and PV1 mRNA expression was quantified using the LightCycler 480 SYBR Green Master Mix (Roche, Mannheim, Germany). The PV1 mRNA expression levels were normalized to that of β-actin. The primer sequences used for amplification were as follows: PV1: 5′-GCCAGGTGGTTGGACTATCTG-3′ and 5′-CTCCATCTCACGTCGCGTA-3′; β-actin: 5′-GTGACGTTGACATCCGTAAAGA-3′ and 5′-GCCGGACTCATCGTACTCC-3′. The relative mRNA expression was calculated using the 2−ΔΔCT method.
For immunofluorescence staining, intestinal tissues from ten patients per group were fixed in 4% paraformaldehyde for 24 hours and embedded in optimal cutting temperature compound for frozen sectioning. Frozen sections were incubated overnight at 4 °C with anti-PV1 antibody (1:100, NB100-77668, Novus Biologicals, CO, United States) and anti-CD34 antibody (1:100, ab81289, Abcam, MA, United States). After incubation with fluorophore-conjugated secondary antibodies at room temperature for 1 hour, nuclei were counterstained with DAPI. Images were acquired using a confocal laser scanning microscope, and fluorescence intensity was analyzed using ImageJ software (NIH, Bethesda, MD, United States). The PV1 nuclear/cytosolic ratio was determined by dividing the mean nuclear PV1 intensity by the mean cytoplasmic PV1 intensity.
Collection of clinical characteristics
Demographic and clinical data, including sex, age, BMI, heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse oxygen saturation (SPO2), medical history, and medication use, were extracted from admission records. Pre- and postoperative laboratory parameters, including procalcitonin (PCT), C-reactive protein (CRP), white blood cell (WBC) count, neutrophil (NEUT) count, lymphocyte (LY) percentage, LY count, neutrophilic granulocyte percentage, alanine transaminase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase, cholinesterase (CHE), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), creatinine (CREA), and blood urea nitrogen, were obtained from the hospital’s biochemical laboratory. These markers are well-established clinical indicators for monitoring infection and assessing liver and kidney function. Prognostic data, including total and postoperative hospitalization, duration of intravenous antibiotic use, duration of postoperative fever (temperature > 37 °C), postoperative complication rate (including skin incision infection, anastomotic fistula, abdominopelvic fluid, local intestinal torsion, pancreatitis, urinary tract infection, pneumonia, bacteremia, infectious shock, and MODS), and mortality rate, were also collected.
Statistical analysis
All statistical analyses were conducted using SPSS version 25.0. Group comparisons of clinical variables and cytokines were conducted using Student’s t-test, χ2 test, or Mann-Whitney U test, as appropriate. Continuous variables are expressed as the median and interquartile range (IQR) or mean ± SD. Associations were analyzed using linear and logistic regression analyses. Binary logistic regression was used to identify the risk factors for postoperative complications and mortality. Statistical significance was set at two-sided P < 0.05.
RESULTS
Demographic and clinical data
A total of 167 patients scheduled for intestinal excision surgery were initially enrolled. After applying the exclusion criteria, 63 patients were excluded (Figure 1). Of the remaining patients, 55 controls and 49 patients with IO were eligible, but 13 and 7 patients, respectively, were excluded due to incomplete information and loss of postoperative follow-up. Finally, 84 patients were included, with 42 in each group. Table 1 shows that there were no statistically significant differences between the groups in age, sex, BMI, DBP, SBP, SPO2, or tissue collection sites. However, the IO group had a significantly higher preoperative heart rate. For infection indicators, patients with IO exhibited increased PCT, CRP, WBC, and NEUT levels, as well as decreased LY levels. For liver and renal functions, ALT, AST, LDH, and TBIL levels were higher in the IO group, whereas CHE level was lower. Additionally, a higher proportion of patients with IO underwent laparotomy due to urgent and complicated medical conditions.
Figure 1.
Flow diagram of recruitment and follow-up research in this study. BMI: Body mass index; IO: Intestinal obstruction.
Table 1.
Demographic and biochemical characteristics between intestinal obstruction and control patients
|
Variables
|
IO group (n = 42)
|
Control group (n = 42)
|
P value
|
| Age (years) | 59.1 (45.5-72.7) | 58.7 (45.8-71.6) | 0.92 |
| Male, n (%) | 22 (52.3) | 19 (45.2) | 0.51 |
| BMI (kg/m2) | 21.4 (18.6-24.2) | 22.3 (19.5-25.1) | 0.14 |
| HR (bpm) | 83.5 (81.8-91.5) | 77.0 (68.0-88.5) | 0.03 |
| SBP (mmHg) | 117.0 (111.0-125.5) | 125.5 (115.5- 133.5) | 0.09 |
| DBP (mmHg) | 76.0 (71.0-82.0) | 74.0 (69.8-80.3) | 0.06 |
| SPO2 (%) | 100 (100-100) | 100 (99-100) | 0.59 |
| ALT (U/L) | 13.5 (9.0-25.0) | 12.0 (9.0-17.3) | 0.01 |
| AST (U/L) | 21.5 (16.8-35.5) | 17.5 (15.0-20.2) | < 0.01 |
| LDH (U/L) | 208.5 (178.5-259.0) | 180.0 (156.0-202.5) | 0.02 |
| ALP (U/L) | 73.0 (55.5-89.0) | 79.0 (67.0-93.0) | 0.31 |
| CHE (U/L) | 5453.5 (3977.3-6092.0) | 6973.0 (6071.3-7705.3) | < 0.01 |
| TBIL (μmol/L) | 12.8 (7.9-17.0) | 9.8 (8.1-13.5) | 0.04 |
| DBIL (μmol/L) | 1.5 (0.0-3.0) | 1.6 (1.2-2.3) | 0.59 |
| IBIL (μmol/L) | 8.7 (5.4-11.7) | 8.0 (6.5-10.9) | 0.61 |
| BUN (mmol/L) | 4.3 (3.0-5.6) | 4.7 (3.5-5.8) | 0.82 |
| CREA (μmol/L) | 62.5 (48.7-90.5) | 67.5 (55.8-88.3) | 0.34 |
| CRP (mg/L) | 20.8 (8.0-58.3) | 3.2 (1.7-5.9) | < 0.01 |
| WBC (109/L) | 7.4 (5.9-9.3) | 6.1 (5.0-6.8) | < 0.01 |
| NEUT% | 0.7 (0.6-0.8) | 0.6 (0.5-0.7) | 0.27 |
| LY% | 0.2 (0.1-0.3) | 0.3 (0.2-0.4) | < 0.01 |
| NEUT (109/L) | 5.2 (3.5-6.8) | 3.6 (2.7-4.5) | < 0.01 |
| LY (109/L) | 1.3 (0.8-1.7) | 1.7 (1.4-2.1) | < 0.01 |
| Laparotomy, n (%) | 16 (38.1) | 3 (7.14) | 0.001 |
| Tissue sample: Colon, n (%) | 24 (57.1) | 28 (66.7) | 0.37 |
BMI: Body mass index; HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; SPO2: Pulse oxygen saturation; ALT: Alanine transaminase; AST: Aspartate aminotransferase; LDH: Lactate dehydrogenase; ALP: Alkaline phosphatase; CHE: Cholinesterase; TBIL: Total bilirubin; DBIL: Direct bilirubin; BUN: Blood urea nitrogen; CREA: Creatinine; CRP: C-reactive protein; WBC: White blood cell; NEUT: Neutrophil; LY: Lymphocyte.
PV1 expression in intestinal mucosa
The PV1 expression levels were measured using RT-qPCR and immunofluorescence. PV1 mRNA and protein expression in intestinal mucosa were significantly higher in the IO group than in the control group (Figures 2 and 3).
Figure 2.
The PV1 mRNA expression in intestinal mucosa was increased in the patients with intestinal obstruction. The expression of PV1 in intestinal mucosa was detected by reverse transcription-quantitative PCR. aP < 0.01. IO: Intestinal obstruction.
Figure 3.
The PV1 protein expression in intestinal mucosa was increased in the patients with intestinal obstruction. A: The expression of the marker of endothelial cell permeability, PV1, was analyzed by immunofluorescence in ileum sections (200 ×). PV1 (green), CD34 (red) and DAPI (blue), scale bars: 200 μm; B: The relative quantification of PV1 in intestinal obstruction and control patients. aP < 0.01. IO: Intestinal obstruction.
Correlation between PV1 expression and clinical indicators
In the IO group, PV1 expression showed significant positive correlations with infection indicators (preoperative PCT, CRP, WBC, and NEUT; postoperative CRP, WBC, and NEUT; Figure 4 and Supplementary Table 1). For liver and kidney function, PV1 expression correlated positively with preoperative ALT, AST, and CREA, along with postoperative ALT, AST, TBIL, DBIL, IBIL, and CREA (Figure 5 and Supplementary Table 1). Moreover, among the prognostic indicators, PV1 expression levels in the IO group exhibited significant positive correlations with the durations of postoperative hospitalization, antibiotic use, and fever (Figure 6 and Supplementary Table 1). Furthermore, univariate and multivariate logistic regression analyses revealed that elevated PV1 expression was associated with an increased risk of postoperative complications in patients with IO (Table 2).
Figure 4.
The PV1 expression was positively correlated with several infection indicators in the patients with intestinal obstruction. The PV1 expression in the patients with intestinal obstruction showed significant positive correlations with preoperative procalcitonin, C-reactive protein (CRP), white blood cell (WBC), neutrophil (NEUT), and postoperative CRP, WBC, NEUT. PCT: Procalcitonin; CRP: C-reactive protein; WBC: White blood cell; NEUT: Neutrophil.
Figure 5.
The PV1 expression was positively correlated with liver and renal functions in the patients with intestinal obstruction. The PV1 expression in the patients with intestinal obstruction showed positive correlations with preoperative alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CREA), and postoperative ALT, AST, total bilirubin, direct bilirubin, indirect bilirubin, and CREA. ALT: Alanine transaminase; AST: Aspartate aminotransferase; CREA: Creatinine; TBIL: Total bilirubin; IBIL: Indirect bilirubin; DBIL: Direct bilirubin.
Figure 6.
The PV1 expression was positively correlated with clinical prognosis in the patients with intestinal obstruction. The PV1 expression in the patients with intestinal obstruction showed significant positive correlations with the durations of postoperative hospitalization, antibiotic use, and fever.
Table 2.
Correlations of PV1 with prognosis among patients with intestinal obstruction
|
Variables
|
OR (univariate)
|
P value
|
OR (multivariate)1
|
P value
|
| Complications | 1.23 | 0.02 | 1.21 | 0.04 |
| Mortality | 0.98 | 0.15 | 0.98 | 0.11 |
Adjusted for age, sex and body mass index.
OR: Odds ratio.
Comparison of PV1-high and PV1-low subgroups
To further assess the association between PV1 expression and infection status, liver and kidney functions, and prognosis under IO condition, the IO group was divided into PV1-high (top 25%, 10 patients) and PV1-low (bottom 25%, 10 patients) subgroups based on PV1 mRNA levels. Compared with the PV1-low subgroup, the PV1-high subgroup showed significantly higher preoperative PCT, CRP, WBC, NEUT, ALT, AST, and CREA levels, as well as postoperative CRP, WBC, ALT, AST, TBIL, and CREA levels. They also exhibited prolonged postoperative hospitalization and antibiotic use (Figure 7 and Supplementary Figure 2). However, severe postoperative complications and mortality rates did not significantly differ between the two groups (Table 3).
Figure 7.
Several infection indicators, liver and renal functions and clinical prognosis were markedly worse in the PV1-high sub-group than that in the PV1-low sub-group. A: Compared to the PV1-low sub-group, the PV1-high sub-group had significantly higher preoperative procalcitonin, C-reactive protein (CRP), white blood cell (WBC), neutrophil, alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CREA) levels; B: Compared to the PV1-low sub-group, the PV1-high sub-group had significantly higher and postoperative CRP, WBC, ALT, AST, total bilirubin, and CREA levels; C: Compared to the PV1-low sub-group, the PV1-high sub-group exhibited extended periods of postoperative hospitalization and antibiotic use. aP < 0.01, bP < 0.05, cP < 0.001. PCT: Procalcitonin; CRP: C-reactive protein; WBC: White blood cell; NEUT: Neutrophil; ALT: Alanine transaminase; AST: Aspartate aminotransferase; CREA: Creatinine; TBIL: Total bilirubin.
Table 3.
Comparison of complications and mortality between PV1-high and PV1-low sub-group among intestinal obstruction patients, n (%)
|
Variables
|
PV1-high sub-group (n = 10)
|
PV1-low sub-group (n = 10)
|
P value
|
| Complications | 4 (40) | 0 (0) | 0.09 |
| Mortality | 2 (20) | 0 (0) | 0.47 |
DISCUSSION
The intestinal tract plays a pivotal role in the progression of critical diseases[3]. The GVB represents the final barrier against bacterial translocation, thereby limiting remote organ injury[16]. GVB disruption has been reported in patients with cirrhosis, nonalcoholic steatohepatitis, alcoholic liver disease, and rheumatoid arthritis[17]. Moreover, our previous studies demonstrated that intestinal sepsis or ischemia-reperfusion injury led to GVB damage in mice[18,19]. The present study is the first to reveal that IO can induce GVB disruption (Figures 2 and 3), and that GVB impairment is closely associated with perioperative infection, organ injury, and adverse clinical outcomes in the surgical IO patients.
The liver receives approximately 80% of its blood supply from the intestine via the portal system[4,20]. Intestinal barrier dysfunction increases permeability, facilitating the entry of bacterial products and inflammatory mediators that promote liver injury[21-24]. The kidney, as the major organ for excreting water-soluble toxins, is also affected: When the intestinal barrier is compromised, dysbiosis and toxin absorption can impair renal function and predispose patients to acute or chronic nephropathy[25,26]. Several studies have highlighted the role of intestinal barrier disruption in hepatic and renal dysfunction. In the present study, liver and kidney function indicators were collected to examine the relationship between GVB damage and remote organ injury in patients with IO. Our correlation analyses revealed positive correlations between intestinal PV1 expression and liver enzymes, bilirubin, and CREA in the patients with IO (Figure 5), and pre- and postoperative liver enzymes and CREA were increased in the PV1-high subgroup (Figure 7A and B). Furthermore, PV1 expression had significant positive correlations with infection markers in the patients with IO (Figure 4). Collectively, these findings suggest that the severity of remote organ injury is positively correlated with GVB disruption, suggesting that GVB damage may be involved in IO deterioration during IO.
Surgical IO patients often present with poor health conditions and worse clinical outcomes. Thus, predicting individualized prognosis of these patients is very important[27]. In this study, we examined whether GVB damage was associated with adverse clinical prognosis in IO. The results demonstrated that elevated PV1 expression correlated with prolonged postoperative hospitalization, antibiotic use, and fever, as well as an increased risk of postoperative complications. Furthermore, four patients in the PV1-high subgroup experienced severe postoperative complications, including enterocutaneous fistula, abdominopelvic effusion, pneumonia, and bacteremia; two of them eventually died. In contrast, no patient in the PV1-low subgroup experienced postoperative complications (Table 3). These findings strongly suggest that GVB damage, as indicated by PV1 expression, may represent a promising biomarker for predicting clinical outcomes in surgical IO patients.
Several limitations exist in our study. First, all patients were recruited from a single hospital, resulting in a relatively small sample size. Therefore, future studies should prioritize larger, multicenter cohorts to strengthen generalizability. Second, due to ethical considerations, patients with intestinal cancer were used as the controls instead of healthy individuals. To minimize bias, however, we carefully screened patients and selected relatively healthy intestinal tissues for analysis. Third, this study was purely clinical, and mechanistic studies are required to elucidate the pathways underlying the contribution of GVB to IO. Finally, PV1 expression was measured only in intestinal tissues, which limits its clinical applicability. Therefore, future research should explore metabolomic or other minimally invasive approaches to identify reliable blood- or urine-based markers for assessing GVB injury and predicting clinical prognosis.
CONCLUSION
In summary, this study demonstrated that IO induces GVB disruption. Moreover, the degree of GVB injury was significantly associated with perioperative infection, liver and kidney injury, and adverse clinical outcomes in patients with IO. This suggests that GVB damage may represent a key pathogenic factor in IO pathogenesis.
Footnotes
Institutional review board statement: This study was approved by the Ethic Committee of The First Affiliated Hospital of Sun Yat-sen University, No.[2021]810.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There is no conflict of interest.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade C
Creativity or Innovation: Grade B
Scientific Significance: Grade C
P-Reviewer: Ramirez JG, PhD, Germany S-Editor: Lin C L-Editor: A P-Editor: Zhao S
Contributor Information
Hu-Fei Zhang, Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
Yi Guo, Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
Xiao-Jun Chen, Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
Yi-Nan Zhang, Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
Hui Peng, Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
Zi-Meng Liu, Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
Xu-Yu Zhang, Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China. zhangxuy@mail.sysu.edu.cn.
Data sharing statement
No additional data are available.
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Data Availability Statement
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