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Probiotic mitigates gut hypoperfusion-associated acute gastrointestinal injury in patients undergoing cardiopulmonary bypass: a randomized controlled trial

BMC Medicine volume 23, Article number: 238 (2025) Cite this article

Abstract

Background

Acute gastrointestinal injury (AGI) after cardiopulmonary bypass (CPB) is associated with poor prognosis. This study aimed to evaluate the effect of preoperative probiotic supplementation on the incidence of AGI in patients undergoing CPB procedure.

Methods

This was a double-blind, randomized controlled trial conducted in a single center. The patients undergoing HVR with CPB between September 2022 and February 2023 were randomly assigned to receive either probiotic (Lac group) or placebo (Placebo group). The probiotic was administered daily for seven days prior to surgery.Univariate and multivariate logistic regression analysis was performed to identify independent risk factors for AGI. A P-value < 0.05 was considered statistically significant. Gut microbiota composition was assessed using 16 s rRNA analysis.

Results

A total of 52 patients were randomly assigned to two groups (26 in the Lac group, 26 in the Placebo group). Patients were followed for at least 30 days after surgery. During the follow-up period, 15 of the 52 patients (28.85%) developed AGI. The incidence of AGI was significantly lower in the Lac group (15.38%) compared to the Placebo group (42.31%), with a difference of 26.93% (P = 0.032). Moreover, patients in the Lac group had a significantly shorter ICU stay (6 [5, 36] vs. 5 [4, 5.5] days, P = 0.041) and a lower incidence of nosocomial infections (11.54% vs. 34.62%, P = 0.048). Multivariate analysis identified a higher Cardiac Surgery Score (CASUS) and CPB duration ≥ 132 min as independent risk factors for AGI, whereas probiotic supplementation was the only protective factor. Furthermore, 16S rRNA sequencing revealed significant differences in gut microbiota composition between the Lac and Placebo groups.

Conclusions

Preoperative probiotic supplementation may be an effective strategy to reduce the incidence of AGI and AGI-related complications in CPB patients. These findings suggest that probiotics could be considered a preventive intervention for AGI in this patient population.

Trial registration

ClinicalTrials.gov: NCT05498948.

Graphical Abstract

Cardiopulmonary bypass (CPB) can cause gut hypoperfusion, microbiota dysbiosis, and acute gastrointestinal injury (AGI), worsening outcomes. Our study shows preoperative probiotic supplementation reduces AGI incidence, enhances gut barrier function, and lowers inflammatory response and myocardial injury, offering a potential strategy to improve prognosis in CPB patients.

Peer Review reports

Background

Recent studies have shown a strong link between gut microbiota and cardiovascular health [1]. Cardiopulmonary bypass (CPB) is commonly used in cardiac surgery but can cause gut hypoperfusion and systemic inflammatory response syndrome [1, 2]. Deng et al. [2] noted that gut microbiota influences inflammation and immune regulation through metabolites and immune cell activation. Given inflammation's role in cardiovascular diseases, modifying gut microbiota could affect the risk of such conditions [1, 3]. CPB may also disrupt the intestinal barrier, allowing bacteria and metabolites to enter the bloodstream, exacerbating inflammation [4, 5].

Previous studies, including ours, have found that acute gastrointestinal injury (AGI) is linked to poor outcomes after CPB, highlighting the need for AGI prevention [6]. Significant changes in gut microbiota before and after CPB have been observed, consistent with other research [7, 8]. Preliminary findings suggest that probiotic supplementation may improve prognosis by modulating gut microbiota [9]. Probiotics may reduce oxidative stress, intestinal damage, and inflammation, potentially benefiting various organs [8, 10, 11]. While probiotics show potential in gut microbiota modulation, their effects and mechanisms require further study. The efficacy of probiotic interventions can vary based on strain, dosage, and individual patient factors, necessitating further investigation. Probiotics, particularly certain Lactobacillus strains, have been widely studied for their beneficial effects on gut health. Strains such as Lactobacillus rhamnosus and Enterococcus faecium have been shown to improve gut barrier function by enhancing tight junction integrity and reducing inflammation [12,13,14,15]. Based on the above-mentioned benefits of probiotics, this study aimed to evaluate whether preoperative probiotic supplementation could mitigate AGI incidence and improve recovery outcomes after CPB surgery.

Methods

Study design and participants

This was a double-blinded, single-center, randomized controlled trial performed in the cardiovascular surgery department of the First Hospital of Lanzhou University, Lanzhou, China. Between September 2022 and February 2023, patients with heart valve diseases who underwent heart valve replacement (HVR) with CPB were recruited. This study has complied with the Consolidated Standards of Reporting Trials (CONSORT) guideline.

The inclusion criteria: patients with moderate to severe congestive heart failure (New York Heart Association (NYHA) classification III-IV), those with heart valve disease undergoing HVR with CPB, and individuals aged 18 to 70 years. Exclusion criteria included severe left ventricular dysfunction (left ventricular ejection fraction (LVEF) ≤ 30%), infective endocarditis, recent major gastrointestinal surgery (within 5 years), inflammatory bowel disease, or chronic gastrointestinal disorders (such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, or peptic ulcer), gastrointestinal neoplasms, polyps, or significant liver disease. Other exclusions were pregnancy; cognitive impairment preventing informed consent; recent use of antibiotics, probiotics, or antidiarrheal medications (within the past month); enrollment in other clinical trials; and patients with insufficient data for analysis.

Administration protocol

Patients were randomly assigned to receive either probiotics (Lac group) or placebo (Placebo group) in a 1:1 ratio. Randomization was performed by an independent statistician using a computer-generated random number with a block size of ten. Both groups were blinded to treatment allocation. Participants in the Lac group received a probiotic supplement (Meitong®, Jiangsu, China), containing three different strains (Lactobacillus rhamnosus CMCC (B) P0028 (Strain I), Lactobacillus rhamnosus CMCC (B) P0029 (Strain II), and Enterococcus faecium CMCC (B) P0030). These probiotic strains have enhanced gut barrier function and reduced intestinal permeability [12,13,14]. Based on previous studies, the intervention consisted of a daily oral dose of 6 × 10⁹ CFU for seven consecutive days before surgery [16, 17]. The Placebo group received an identical placebo containing only maltose. Both treatments were indistinguishable in appearance, taste, and smell.

All patients received standard prophylactic antibiotics (Cefazolin) before and after surgery, with additional antibiotics chosen based on bacterial culture for hospital-acquired infections. Twelve patients developed pulmonary infections, and antibiotic regimens included third-generation Cephalosporins, Carbapenems, or combinations (Additional file 1, Table S1).

Baseline data collection

Patients’ basic characteristics included age, gender, body mass index (BMI), NYHA classification, and history of hypertension, diabetes, coronary artery disease, chronic obstructive pulmonary disease, arrhythmia, white blood cells, platelet, hemoglobin (Hb), fibrinogen, N-Terminal pro-brain natriuretic peptide (NT-pro BNP), high sensitive troponin I (hs-TnI), LVEF, types of surgery, etc.. Intraoperative information included transfusion of red blood cells, duration of CPB, and duration of aortic cross-clamping. Cardiac Surgery Score (CASUS) within 24 h after surgery. After the research doctors record the basic information of all subjects, the follow-up researchers will verify and confirm that there were no defaults before filling out the subject registration form.

Outcomes

The primary outcome was the occurrence of AGI. The European Society of Intensive Care Medicine (ECICM, 2012) proposed an AGI grade to define, grade, and guide the treatment of AGI (Additional file 1, Table S2) [6]. Daily assessment using the AGI grading system was performed according to standard care in the first seven follow-up days; a maximum AGI grade ≥ 2 was diagnosed as AGI. The detection of AGI scores was performed by researchers blinded to the group allocation. The secondary outcomes included postoperative complications, nosocomial infection, multiple organ dysfunction syndrome (MODS), ventilator assistance time, intensive care unit (ICU) stay time, and 30 postoperative days (POD) mortality.

Nosocomial infection was defined as a new infection after 48 h postoperation; MODS was defined by a daily total Sequential Organ Failure Assessment score of more than 5; CASUS is a prognostic scoring system developed for cardiac surgery patients (Additional file 1, Table S3) [18], ventilator assistance time, ICU stay time, and 30 POD mortality were registered.

Clinical information

Additional monitored parameters included inflammatory markers: interleukin 6 (IL- 6), procalcitonin (PCT), C-reactive protein (CRP), and white blood cells at 24 h and 72 h; Myocardial injury markers: NT-pro BNP, hs Tn I at 24 h and 72 h; Hepatic function indicators: aspartate transaminase, alanine aminotransferase, total bilirubin, and γ-glutamyl transferase at 72 h; Gastrointestinal function indicators: bowel sounds return time, intra-abdominal pressure (IAP), number of bowel sounds, first defecation time, Bristol Stool Form Scale score, and proportion of coccus feces were assessed daily as part of standard care within POD 7.

Blood sample collection

Blood samples were collected at 24 h and 72 h postoperation for analyses of intestinal fatty acid binding protein 2 (I-FABP 2). The levels of I-FABP 2 in plasma is a confirmed positive marker for predicting and diagnosing AGI. I-FABP 2 in the plasma samples was measured using a human I-FABP 2 enzyme-linked immunosorbent assay (ELISA) Kit (Elabscience®, Wuhan, China) at multiple time points (24- and 72-h post-operation) to determine concentration differences.

Fecal sample collection

Fecal samples were collected from participants following standardized protocols, ensuring proper handling and preservation to maintain microbial integrity. Fecal samples were collected daily, detection after unblinding at two-time points for Lac group and Placebo group (The first sample was before the patients took the probiotic/placebo; The second sample was from the first postoperative sample). Patients placed the fecal samples directly into two tubes (approximately 2.0 g/tube). The samples were placed in a freezer at − 80 °C within 30 min of excretion for analysis of the fecal microbiota. All samples are processed uniformly after the experiment is completed.

Gut microbiota analysis

DNA was extracted from the sample using Cetyltrimethylammonium Bromide (CTAB) and assessed for purity and concentration by agarose gel electrophoresis. The 16S rRNA genes were amplified using primers (515F and 806R) with a barcode. PCR was performed with 15 μL of Phusion® High-Fidelity PCR Master Mix (New England Biolabs), 2 μM of forward and reverse primers, and approximately 10 ng of template DNA. Thermal cycling included an initial denaturation at 98 °C for 1 min, followed by 30 cycles of 98 °C for 10 s, 50 °C–60 °C for 30 s, and 72 °C for 30 s, with a final elongation at 72 °C for 5 min. Illumina MiSeq sequencers generated barcoded amplicon libraries targeting the V3-V4 16S rRNA region using Nextera XT index kits (Illumina). Library preparation was performed using the TruSeq® DNA PCR-Free Sample Preparation Kit, and the constructed library was quantified by Qubit and Q-PCR. Sequencing was done on a NovaSeq6000 after the library passed quality control.

Sample size

Based on an expected AGI incidence of 15% in the Lac group and 42% in the Placebo group, with an alpha of 0.05 and a beta of 0.20, the sample size calculation performed using G*Power software determined that 28 patients per group were required to ensure statistical significance. To account for a 10% dropout rate, a total of 56 patients (28 per group) were initially targeted for recruitment. However, due to unforeseen logistical constraints (patient availability), the final cohort consisted of 26 patients per group, for a total of 52 patients. Although slightly underpowered, the sample size was deemed sufficient to detect clinically relevant trends and associations, supported by robust statistical analyses.

Statistical analysis

Data were analyzed using SPSS v.27.0, R language (4.0.3), and Prism 9.0. Continuous variables were presented as mean (SD) or median (range) and compared using a t-test, Mann–Whitney U test, or Wilcoxon test. Categorical data were presented as numbers (percentages) and compared using chi-square or Fisher’s exact test. Binary logistic regression assessed the relationship between clinical risk factors and AGI, with results shown as odds ratios (OR) and 95% confidence intervals (CI). Variables with P < 0.10 in univariable analysis were included in multivariable logistic regression. Alpha diversity indices (e.g., Chao1, abundance-based coverage estimator [ACE]) were used to compare community diversity, while beta-diversity was analyzed with principal coordinate analysis (PCoA) using the phyloseq package in R. Linear discriminant analysis (LDA) effect size (LEfSe) was performed using LEfSe software. A P-value < 0.05 was considered statistically significant.

Results

Patient characteristics

Between September 2022 and February 2023, 133 consecutive patients with heart valve diseases scheduled for HVR with CPB were assessed for eligibility. After screening, 72 patients were excluded. Thirty-two patients did not meet the inclusion criteria, and 40 patients met at least one of the exclusion criteria. The remaining 61 patients were randomly assigned to the Lac group and Placebo group. 9 patients were lost to follow-up (due to follow-up refusal by patients or family members). Finally, a total of 52 patients were included in the per-protocol population (Lac group [n = 26], Placebo group [n = 26]), all of whom completed at least 30 POD of follow-up (Fig. 1). The baseline characteristics, including age, gender, BMI, NYHA, and history of hypertension, diabetes, coronary artery disease, chronic obstructive pulmonary disease, arrhythmia, white blood cells, platelet, Hb, fibrinogen, NT-pro BNP, LVEF, types of surgery, CASUS, Duration of CPB, aortic occlusion time, intraoperative RBC transfusion, and hospital costs of the enrolled patients are shown in Table 1. The significant baseline difference between the two groups was seen in preoperative Hb and hospital costs. However, both groups were within the normal range, therefore, we did not consider this difference clinically relevant.

Fig. 1
figure 1

Study flow chart. IE, infective endocarditis; GI, gastrointestinal

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Table 1 Patient characteristics
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Clinical outcomes

Compared to the Placebo group, the Lac group showed significant differences in several outcomes. 15 of the 52 patients (28.85%) developed AGI. The incidence of AGI was significantly lower in the Lac group (15.38%) compared to the Placebo group (42.31%), with a difference of 26.93% (P = 0.032). The Lac group also had a shorter ICU stay time (5 [4, 5.5] vs. 6 [5, 19], P = 0.041) and lower incidence of nosocomial infections (11.54% vs. 34.62%, P = 0.048). While the Lac group showed trends toward lower incidence of MODS and shorter ventilator assistance time, these differences were not statistically significant. The 30-day mortality rate was 1.92%, with no deaths in the Lac group (Table 2).

Table 2 Primary and secondary outcome
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Effect of probiotics on gastrointestinal function, intestinal barrier function, systemic inflammatory and myocardial injury markers

Compared to the Placebo group, the Lac group showed a significant reduction in IAP and time to first defecation, with P-values of 0.042 and 0.006, respectively. However, no significant differences were found between the groups in bowel sound return time, number of bowel sounds, Bristol Stool Form Scale score, or fecal coccus proportion (P > 0.05) (Table 3).

Table 3 Clinical information
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At 24 h, the I-FABP 2 was significantly lower in the Lac group compared to the Placebo group (0.29 vs. 1.64, P = 0.01), and this trend continued at 72 h (0.18 vs. 0.87, P = 0.012), indicating improved gastrointestinal injury in the Lac group (Table 3).

There were no differences in white blood cells between the groups at 24 and 72 h (P > 0.05), but CRP was significantly lower in the Lac group at both time points (P < 0.05). IL- 6 (at 24 h point) and PCT (at 72 h point) were also significantly lower in the Lac group, indicating greater improvement in inflammation (P < 0.05) (Table 3).

Myocardial injury markers showed significant differences between two groups, with lower levels of hs-Tn I, NT-pro BNP, and higher LVEF in the Lac group at 24 and 72 h (P < 0.05), indicating better myocardial recovery (Table 3).

Risk factor analysis

Univariate analyses showed that intra-operative red blood cells transfusion, the duration of CPB ≥ 132 min, and CASUS were associated with significantly increased incidence of AGI (P < 0.05). Probiotic supplementation was a preventive factor for the occurrence of AGI (P = 0.038). Multivariate analyses showed that CASUS (OR 2.248; 95% CI, 1.205–4.194, P = 0.011), and the duration of CPB ≥ 132 min (OR 18.288; 95% CI, 1.31–255.352, P = 0.031) were independent risk factors for the occurrence of AGI. Probiotic supplementation was the only preventive factor for the occurrence of AGI (OR 0.079; 95% CI, 0.007–0.861, P = 0.037) (Table 4).

Table 4 Univariate and multivariate for post-operative occurrence of AGI
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For patients with AGI, age greater than 47; the aortic occlusion time longer than 89 min; the duration of CPB longer than 132 min; the CASUS higher than 4.5 were high–risk factors (Table 5).

Table 5 The predicted value parameters of risk factors of AGI
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Differences in the gut microbiota pre- and post-CPB procedure

The Venn diagram highlighted a reduction in unique microbial features after CPB, with 4,168 unique amplicon sequence variants (ASVs) identified preoperatively compared to 2,318 postoperatively, and only 663 ASVs shared between groups (Fig. 2A). Pre- and post-operative gut microbiota as demonstrated by the ACE and Chao 1, alpha diversity significantly changed post-operation compared to pre-operation (Fig. 2B and C). The potential community-level differences between groups were analyzed using beta-diversity analysis. Both the unweighted and weighted PCoA analysis showed differences between pre- and post-operation (R2 = 0.055, P < 0.001; R2 = 0.06, P = 0.014; respectively) (Fig. 2D and E). The LEfSe showed preoperative samples were enriched in taxa such as Prevotellaceae, Faecalibacterium prausnitzii, and Lachnospiraceae, while postoperative samples were dominated by taxa such as Enterococcus, Enterobacteriaceae, and Methanobacteriales (Fig. 2F). The Cladogram (Fig. 2G) confirmed the enrichment of health-associated taxa preoperatively and potentially pathogenic taxa postoperatively.

Fig. 2
figure 2

CPB affect abundance of the gut microbiota. A The Venn diagram of operational taxonomic units (OTUs) sample distribution. B, C Alpha-diversity of pre- or post-operative gut microbiota (Chao1 and ACE index, Wilcoxon test). D, E Beta-diversity analysis by PCoA analysis of unweighted and weighted between Pre- and post-operation. F, G Linear discriminant analysis (LDA) effect size (LEfSe) of different species between groups. F The bar plots represent the significantly differential taxa between pre- or post-operative, based on effect size (LDA score [log 10] 2). G The cladogram showed the differences in enriched taxa between pre- or post-operative

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Differences in the gut microbiota between the Lac group and the Placebo group post-CPB procedure

The Venn diagram analysis identified 2,458 unique ASVs in the Lac group, 2,058 unique ASVs in the Placebo group, and 580 shared ASVs between the two groups, highlighting notable differences in microbial composition (Fig. 3A). We detected no significant differences between the Lac and Placebo group in alpha-diversity indexes (P > 0.05) (Fig. 3B and C). The unweighted and weighted PCoA analysis significantly differed between Lac and Placebo groups (R2 = 0.046, P = 0.008; R2 = 0.038, P = 0.2; respectively) (Fig. 3D and E). The LEfSe demonstrated that the probiotic intervention selectively enriched specific taxa, including Methanobacterium and Oscillospiraceae, while the Placebo group was enriched in Gammaproteobacteria and other taxa commonly associated with microbial dysbiosis (Fig. 3F). The cladogram (Fig. 3G) supported these findings, illustrating distinct taxonomic differences between two groups.

Fig. 3
figure 3

Differences in the gut microbiota between the Lac group and the Placebo group post-CPB procedure. A The Venn diagram of operational taxonomic units (OTUs) sample distribution. B, C Alpha-diversity of Lac and Placebo groups gut microbiota (Chao1 and ACE index, Wilcoxon test). D, E Beta-diversity analysis by PCoA analysis of unweighted and weighted between Lac and Placebo groups. F, G Linear discriminant analysis (LDA) effect size (LEfSe) of different species between groups. F The bar plots represent the significantly differential taxa between Lac and Placebo groups, based on effect size (LDA score [log 10] 2). Displayed species with significant differences in abundance among different groups, the length of the bar graph represents the impact of different species (i.e. LDA Score). G The cladogram showed the differences in enriched taxa between Lac and Placebo groups

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Discussion

This study demonstrates, for the first time, that preoperative probiotic supplementation may reduce the incidence of AGI after CPB by modulating gut microbiota and improving clinical outcomes. AGI is a serious complication of cardiac surgery with CPB, contributing to high postoperative mortality [20,21,22]. However, the optimal strategy for preventing AGI remains unclear, as most previous studies have been retrospective, with limited prospective research on preventive interventions [20,21,22]. The potential for probiotics to improve gastrointestinal inflammation is well-supported by existing research [23]. However, the extent of their clinical benefits and underlying mechanisms remain under investigation, as different strains and dosages may produce varying effects. Previous studies have demonstrated that probiotics can be beneficial in post-CPB patients. For instance, [10, 24] reported that preoperative probiotic supplementation reduced postoperative inflammatory responses and improved gut integrity in cardiac surgery patients. Another study [8] found that Lactobacillus murinus administration protected against intestinal ischemia/reperfusion injury in CPB models by modulating macrophage activity. These findings support the potential role of Lactobacillus rhamnosus and Enterococcus faecium in mitigating CPB-induced AGI.

In this study, we investigated whether preoperative probiotic supplementation could mitigate AGI and improve clinical outcomes in CPB patients. Our findings revealed that preoperative probiotic supplementation significantly reduced AGI incidence (Lac: 15.4% vs. Placebo: 42.3%) and was identified as the only protective factor in both univariate and multivariate analyses. We also identified CASUS and CPB duration ≥ 132 min as independent risk factors for AGI, highlighting the critical role of these factors in predicting AGI occurrence [25,26,27]. Probiotic supplementation, on the other hand, emerged as the only protective factor, emphasizing its potential in reducing the risk of AGI in high-risk patients. These findings underscore the importance of early identification of high-risk patients based on these factors and suggest that probiotic supplementation could serve as a valuable adjunctive strategy to mitigate AGI risk. Further research is needed to elucidate the mechanisms by which prolonged CPB duration and higher CASUS scores contribute to AGI and to better understand the protective effects of probiotic intervention in this context.

Probiotic supplementation was associated with a shorter ICU stay and a lower incidence of nosocomial infections, suggesting a faster postoperative recovery. This benefit may be attributed to reduced systemic inflammation, as evidenced by lower CRP, IL- 6, and PCT levels, as well as potential cardioprotective effects reflected by decreased hs-TnI and NT-pro BNP. Probiotics exert their protective effects on gut permeability and barrier function through multiple mechanisms. First, they regulate the expression of tight junction proteins (e.g., occludin, claudin- 1, and ZO- 1), thereby reinforcing intestinal epithelial integrity and reducing permeability [28, 29]. Second, probiotics modulate immune responses by promoting anti-inflammatory cytokines (e.g., IL- 10) and reducing pro-inflammatory cytokines (e.g., IL- 6, TNF-α), which helps control systemic inflammation [30,31,32,33]. Third, probiotics produce short-chain fatty acids such as butyrate, which serve as an energy source for intestinal epithelial cells and further enhance mucosal barrier function [34]. Since systemic inflammation is closely linked to myocardial injury, we also examined markers of cardiac damage. The decrease in hs-TnI and NT-pro BNP points to potential cardioprotective effects, possibly by reducing inflammation and oxidative stress [19, 35]. These studies suggest that probiotics may help improve prognosis and accelerate postoperative recovery by reducing gastrointestinal damage, enhancing gut permeability, alleviating systemic inflammation, and mitigating myocardial injury, ultimately protecting heart function in patients [19, 23, 35]. However, further research is needed to explore additional biomarkers and clinical outcomes for a more comprehensive understanding.

Given the importance of gut barrier in systemic inflammation, we observed significantly lower I-FABP 2 levels in the Lac group, suggesting reduced intestinal injury. Additionally, improved gastrointestinal function, reflected by shorter first defecation time and lower IAP, further supports the protective role of probiotics. Deng et al. [7] reported that patients who underwent CPB complicated with AGI had an increase in IFABP. Sun et al. [31] showed that pre-administration of probiotics could improve intestinal barrier function to some extent after CPB in rats. These results are consistent with the known ability of probiotics to enhance mucosal barrier integrity, promote gut motility, and reduce bacterial translocation [28, 36].

There is a strong relationship between gut barrier function and microbial composition, we further analyzed changes in gut microbiota after CPB. Like previous studies, we observed significant gut microbiota dysbiosis in CPB patients, reinforcing its role in AGI pathogenesis [2,3,4]. CPB-induced dysbiosis was evident in postoperative microbiota profiles, characterized by a decline in health-associated taxa such as Prevotellaceae, Faecalibacterium prausnitzii, and Lachnospiraceae, and an increase in potentially pathogenic taxa, including Enterococcus, Enterobacteriaceae, and Methanobacteriale. These shifts in microbial composition have been linked to increased intestinal permeability, systemic inflammation, and AGI development [37,38,39]. Such dysbiosis can lead to increased intestinal permeability, systemic inflammation, and AGI, highlighting the importance of maintaining gut microbiota balance during and after CPB [2,3,4,5].

The effects of probiotics on gut health and inflammation are strain-dependent. Lactobacillus rhamnosus has been shown to enhance intestinal barrier function by increasing tight junction protein expression. Enterococcus faecium, on the other hand, has been reported to compete with pathogenic bacteria and modulate host immune responses [12,13,14,15]. LEfSe analysis revealed distinct microbial differences between the Lac and placebo groups. The Lac group showed an increase in beneficial taxa like Oscillospiraceae and Methanobacterium, which are associated with anti-inflammatory pathways and improved tight junction integrity, supporting gut barrier function [40, 41]. In contrast, the placebo group exhibited an increase in Gammaproteobacteria, a tax on linked to gut dysbiosis, elevated intestinal permeability, and systemic inflammation, all of which contribute to AGI pathogenesis [42, 43]. These strain-specific effects suggest that the combination used in this study may have synergistic benefits in protecting against CPB-induced AGI.

Interestingly, while alpha-diversity did not differ significantly between the Lac and Placebo groups, beta-diversity analysis showed clear differences in microbial composition. This suggests that probiotics may not increase species richness but can shift the microbiota toward a healthier balance. These findings support the idea that probiotics improve postoperative outcomes by maintaining gut microbiota stability and increasing beneficial bacteria. Previous studies have shown that probiotic supplementation can lead to the colonization of new strains in the gut [44, 45]. Even when probiotics do not colonize, they can still influence other bacteria and their metabolites, helping to maintain a healthy gut community [30, 46].

Despite these promising findings, our study has several limitations. First, the single-center design and small sample size may limit generalizability. Second, dietary habits, including fermented food consumption, were not considered, which may confound results. Third, excluding patients who had used antibiotics within a month before surgery may introduce selection bias. Fourth, while a 7-day preoperative probiotic regimen was based on prior evidence, the potential benefits of longer supplementation remain unclear. Fifth, functional metagenomic analyses were not conducted, limiting insights into microbial metabolic and immunological pathways. Sixth, the 30-day follow-up period may not capture long-term effects on recovery and survival. Future multicenter studies with larger cohorts and extended follow-up are needed to validate our findings.

Conclusions

In conclusion, our results indicate that preoperative probiotic supplementation may help mitigate CPB-related AGI by modulating gut microbiota composition and reducing systemic inflammation. Probiotic supplementation may protect against AGI by preserving gut barrier function and modulating inflammation, highlighting its potential as an adjunctive therapy in CPB patients.

Data availability

The raw data for this study, including the deidentified results of statistical analyses, study protocol, statistical analysis plan, and data dictionary, are available upon reasonable request from the first or corresponding author. The data set for this study has been uploaded to Mendeley Data and can be accessed using the following DOI: doi: https://doiorg.publicaciones.saludcastillayleon.es/10.17632/j3hfvn28yy.2  (2025). Additionally, the 16S rRNA sequencing data has been uploaded to the NCBI SRA database and can be accessed via the following link: https://www.ncbi.nlm.nih.gov/sra/PRJNA1188732 (2025).

Abbreviations

ACE:

Abundance-based coverage estimator

AGI:

Acute gastrointestinal injury

ASV:

Amplicon sequence variant

BMI:

Body mass index

CASUS:

Cardiac Surgery Score

CI:

Confidence intervals

CONSORT:

Consolidated Standards of Reporting Trials

CPB:

Cardiopulmonary bypass

CRP:

C-reactive protein

CTAB:

Cetyltrimethylammonium Bromide

ECICM:

European Society of Intensive Care Medicine

ELISA:

Enzyme-linked immunosorbent assay

Hb:

Hemoglobin

HVR:

Heart Valve Replacement

hs-TnI:

High-sensitive troponin I

IAP:

Intra-abdominal pressure

I-FABP 2:

Intestinal fatty acid binding protein 2

ICU:

Intensive care unit

IL- 6:

Interleukin 6

LEfSe:

Linear discriminant analysis effect size

LVEF:

Left ventricular ejection fraction

MODS:

Multiple organ dysfunction syndrome

NT-pro BNP:

N-Terminal pro-brain natriuretic peptide

NYHA:

New York Heart Association

OR:

Odds ratios

PCoA:

Principal coordinate analysis

PCT:

Procalcitonin

POD:

Postoperative day

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Acknowledgements

We thank all participating patients and their families. We appreciate the support from the Natural Science Foundation of Gansu Province (23 JRRA1600), the National Natural Science Foundation of China (82260729), and Foundation of the First Hospital of Lanzhou University (ldyyyn- 2022 - 27).

Funding

This work was supported by Natural Science Foundation of Gansu Province (23 JRRA1600), National Natural Science Foundation of China (82260729), Foundation of the First Hospital of Lanzhou University (ldyyyn- 2022–27).

Author information

Author notes

  1. Xiaofang Yang and Ruisheng Liu contributed equally to this work.

Authors and Affiliations

  1. The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China

    Xiaofang Yang, Ruisheng Liu & Wenbo Meng

  2. Department of Cardiovascular Surgery, The First Hospital of Lanzhou University, Lanzhou, , Gansu, China

    Xiaofang Yang, Ruisheng Liu, Zhijing An, Yuanmin Li & Bing Song

  3. Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China

    Yanyan Lin & Wenbo Meng

  4. Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, Gansu, China

    Wenbo Meng

  5. Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, Gansu, China

    Boxia Li

  6. Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China

    Jinqiu Yuan

  7. Trauma Intensive Care, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Christian Waydhas

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Contributions

X.Y. Conceptualization; methodology; validation; formal analysis; writing-original draft; resources; data curation; visualization; software; investigation; funding acquisition. R.L. Validation; writing-review and editing. Z.A. Methodology; validation; data curation; writing-original draft. B.L. Validation; statistical analysis; funding acquisition; Y.Y.L. Methodology. Y.M.L. Validation. B.S. Resources; validation. J.Y. Validation; supervision. W.M. Conceptualization; writing-original draft; writing-review & editing; supervision; project administration. C.W. Writing-original draft; writing-review & editing. All authors read and approved of the final manuscript.

Corresponding authors

Correspondence to Jinqiu Yuan or Wenbo Meng.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the First Hospital of Lanzhou University (LDYYLL- 2021–422), and written consent was obtained from the patients or their guardians prior to enrollment. The copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Supplementary Information

12916_2025_4082_MOESM1_ESM.pdf

Additional file 1: Table S1. Antibiotic administration. Table S2. AGI grading system. Table S3. Additive Cardiac Surgery Score

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Yang, X., Liu, R., An, Z. et al. Probiotic mitigates gut hypoperfusion-associated acute gastrointestinal injury in patients undergoing cardiopulmonary bypass: a randomized controlled trial. BMC Med 23, 238 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-025-04082-2

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BMC Medicine

ISSN: 1741-7015

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