Analgesia & Resuscitation : Current ResearchISSN: 2324-903X

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Research Article, Analg Resusc Curr Res Vol: 7 Issue: 2

Bifidobacterium longum BB536 and Changes in Septicemia Markers Associated with Antibiotic Use in Critically Ill Patients

Takao Arai1*, Shiro Mishima2, Shoichi Ohta2, Tetsuo Yukioka2 and Tetsuya Matsumoto3

1Department of Emergency Medicine and Critical Care, Tokyo Medical University Hachioji Medical Center, 1163 Tatemachi, Hachioji, Tokyo, Japan

2Department of Emergency and Critical Care Medicine, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, Japan

3Department of Microbiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, Japan

*Corresponding Author : Takao Arai
Department of Emergency Medicine and Critical Care, Tokyo Medical University Hachioji Medical Center, 1163 Tatemachi, Hachioji, Tokyo, Japan
Tel: +81-42-665-5611
E-mail: [email protected]

Received: April 05, 2018 Accepted: April 23, 2018 Published: April 30, 2018

Citation: Arai T, Mishima S, Ohta S, Yukioka T, Matsumoto T (2018) Bifidobacterium longum BB536 and Changes in Septicemia Markers Associated with Antibiotic Use in Critically Ill Patients. Analg Resusc: Curr Res 7:2. doi:10.4172/2324-903X.1000161

Abstract

Objective: Probiotics exert beneficial effects on gastrointestinal microflora, but these effects may be counteracted by antibiotics, particularly when used in critically ill patients. The aim of this study was to examine the effects of probiotics in association with antibiotics on septicemia markers.

Methods: In total, 64 critically ill patients were randomized to receive conventional therapy alone (control group) or with a transluminal preparation containing Bifidobacterium longum BB536 (probiotic group). Patients were retrospectively divided into two subgroups depending on whether they received antibiotic therapy during the study period. Outcome measures included fecal bifidobacteria numbers and serum concentrations of procalcitonin and interleukin 6.


Results: After probiotic/control intervention, in the non-antibiotic subgroup, mean fecal bifidobacteria number was significantly
higher in the probiotic group compared with the control group (8.30 ± 0.84 vs. 6.80 ± 0.90 102 colony-forming units/g, respectively, P<0.01). Mean serum procalcitonin (0.44 ± 0.78 vs. 1.19 ± 1.16 ng/mL, P<0.05) and interleukin 6 (116 ± 131 vs. 230 ± 162 ng/mL, P<0.01) levels were significantly lower in the probiotic group. The outcome measures of patients who received antibiotics were not significantly different between the probiotic and control groups.


Conclusion: Our findings suggest that B. longum BB536 suppresses upregulation of procalcitonin and interleukin 6, preventing infectious
complications, but the effect was counteracted by antibiotics. This may partly explain why probiotics are not always effective in critically ill patients. Nevertheless, our findings suggest that routine prophylactic use of B. longum BB536 would be beneficial for critically ill patients with non-infectious diseases not receiving
treatment with antibiotics.

Keywords: Critical care; Probiotics; Antibiotics; Procalcitonin; Interleukin 6; Non-infectious diseases

Introduction

Complications resulting from sepsis and multisystem organ failure are commonly seen in patients with critical illness, and often have a high mortality rate. The gut has recently been described as the “undrained abscess” or “motor” of multisystem organ failure [1] and is the site of a process referred to as Bacterial translocation (BT) [2]. In addition, stress can decrease the number of luminal microflora, increase the number of pathogenic microorganisms, and suppress gastrointestinal barrier function in patients with critical illness, further promoting BT [3].

While some studies effectively used probiotics as adjunct therapies to enhance the gut barrier [4], probiotic treatments had limited prophylactic effects in other studies [5-7], and thus the efficacy of probiotics for preventing infections in severely ill patients is inconclusive [8]. The administration of antimicrobial agents often results in disruption of the normal ecological balance of intestinal microflora [9]. Moreover, broad-spectrum antimicrobial agents may negate the positive effects of probiotics.

Interleukin-6 (IL-6), a 21-KDa glycoprotein conventional proinflammatory marker, and procalcitonin (PCT), a 116-amino acid propeptide of calcitonin, are specific markers of septicemia in critically ill patients [10-12]. Systemic inflammatory response syndrome is characterized by sequential release of cytokines, with subsequent cytokine cascade. IL-6 is secreted by numerous cell including lymphocytes, monocytes, and fibroblasts, and exerts various systemic and local effects including B and T lymphocyte activation and induction of the hepatic acute phase response with production acute phase proteins, respectively. Previous reports have shown that IL-6 is a potent marker of cytokine cascade activation, enabling the prediction of subsequent organ dysfunction and mortality [6].

PCT levels in patients with severe bacterial or fungal infections and sepsis have been found to be markedly elevated [11]. Also, PCT induction is associated with monocyte activation and adherence, a feature of sepsis and other pathological conditions including traumatic tissue injury. Among several proinflammatory markers, PCT is the most sensitive and specific predictor of systemic inflammation [13-16].

In this study, we examined the prophylactic effect of B. longum BB536 for preventing infection in patients with critical illness. This organism was selected because it fulfills all the criteria of a probiotic [17]. This non-pathogenic commercially available organism successfully transits the gut, survives, and eventually colonizes the human gastrointestinal tract following oral administered. Probiotic organisms, including bifidobacteria, adhere to the gut mucosa via a distinctive mannose-specific adhesion molecule [18], contending with pathogens for adherence sites in the intestines [19]. Largely through this ability, probiotics modify local mucosal and systemic immune systems in the host [4].

To test our hypothesis that the effects of probiotic microorganisms are counteracted by antimicrobial agents, we measured the numbers of fecal bifidobacteria and serum PCT and IL-6 concentrations and compared the results between patients who received or did not receive antibiotic therapy. To our knowledge, this is the first clinical investigation in which PCT concentrations have been measured to examine the effects of B. longum BB536.

Materials and Methods

This study was conducted by the Emergency and Critical Care Department of Tokyo Medical University Hachioji Medical Center, a tertiary emergency center that provides acute intensive care for patients with serious illness or trauma.

Subjects

Subjects were 72 critically ill patients who were treated randomly by conventional therapy alone (control group, n = 36) or with probiotics (probiotic group, n = 36) at the Intensive Care Unit (ICU) of Tokyo Medical University Hachioji Medical Center between April 2006 and March 2007.

Regardless of disease type, patients who were being managed with respirators and nasogastric tubes on their first hospital day were also included in this study. Disease severity at the time of study entry was graded using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Patients who were treated with steroids or immunosuppressive drugs (0 in the control group, 2 in the probiotic group) or those who died during the study period (2 in the control group, 4 in the probiotic group) were excluded, making the final number of patients 34 in the control group and 30 in the probiotics group (Figure 1 for a flow chart of patient inclusion and exclusion, Table 1 for characteristics of the included patients, and Table 2 for those of the excluded patients).

    Probiotic group Control group   P value
Age (y)   63.1 ± 13.2 67.4 ± 11.0   n.s.
Sex (male/female)   13/17 19/15   n.s.
APACHE II score   28.5 ± 7.82 29.4 ± 7.73   n.s.
Illness Type       Total  
  Sepsis 5 3 8 n.s.
  Trauma 4 6 10 n.s.
  Pancreatitis 1 1 2 n.s.
  Burns 2 1 3 n.s.
  CVD 6 7 13 n.s.
  Post CPR 6 8 14 n.s.
  Aortic dissection 1 1 2 n.s.
  Toxic disease 2 2 4 n.s.
  Liver failure 1 1 2 n.s.
  Metabolic syndrome 1 1 2 n.s.
  Epilepsy 0 2 2 n.s.
  Heart failure 1 1 2 n.s.
Total   30 34 64 n.s.

Table 1: Pre-intervention characteristics of patients included in the study.

  Reason for exclusion Age Sex Diagnosis Group Antibiotic/Non-antibiotic Date of death (hospital day)
1 Steroid use 69 F Acute exacerbation of chronic obstructive pulmonary disease Probiotic antibiotic -
2 Steroid use 64 M Interstitial pneumonia Probiotic Non-antibiotic -
3 Death 72 M Necrotizing fasciitis Control Antibiotic Day 5
4 Death 79 F Multiple trauma Control Antibiotic Day 4
5 Death 88 F Brain hemorrhage Probiotic Non-antibiotic Day 3
6 Death 81 M Subarachnoid hemorrhage Probiotic Non-antibiotic Day 9
7 Death 75 M Multiple trauma Probiotic Non-antibiotic Day 5
8 Death 81 M Meningitis Probiotic Antibiotic Day 4

Table 2: Characteristics of excluded patients.

Figure 1: Subjects were 72 critically ill patients who were treated randomly by conventional therapy alone (control group, n = 36) or with probiotics (probiotic group, n = 36). Patients who were treated with steroids or immunosuppressive drugs (0 in the control group, 2 in the probiotic group) or those who died during the study period (2 in the control group, 4 in the probiotic group) were excluded, making the final number of patients 34 in the control group and 30 in the probiotics group.

Typical therapy and probiotic intervention

To allocate patients for either conventional therapy alone or with a B. longum BB536 preparation, patients were alternately assigned to the control and probiotic groups as they consented to participate in the study. Conventional treatment, antibiotic therapy, inotropic agents, and adjuvant nutritional support (enteral or parenteral) were provided as needed. The source of probiotics was a commercial B. longum BB536 stick product (Morinaga Milk Industry Co., Ltd., Tokyo, Japan) containing 5.0 × 1010 colony-forming units (CFU) of B. longum BB536 and dextrin as a carrier. In the probiotic group, a preparation containing one stick of BB536 dissolved in 10 ml water was administered 3 times a day via a nasogastric tube, beginning on post-admission day 1 or 2 after stabilizing emergency medical conditions. The administration of B. longum BB536 was continued for 7 days on average (up to 9 days only in those who had no bowel movement on day 7), and feces were collected from patients for colonization assay.

Antibiotic therapy

To analyze the effects of antibiotic therapy on the effects of B. longum BB536, patients were retrospectively divided into two subgroups according to whether they had received antibiotic therapy or not during the study period. The decision to administer antibiotics was made by faculty physicians. Antibiotic therapy was defined as any antibiotic started on the day of admission and continued for at least 3 days. Among the 64 patients, half (n = 32) received antibiotic therapy. All patients with sepsis (n = 8), acute pancreatitis (n = 2), burns (n = 3), and most trauma patients (8/10) received antibiotic therapy. Conversely, most patients with cerebrovascular disorders and coma after cardiopulmonary resuscitation did not receive antibiotic therapy. The antimicrobial agents included ampicillin/sulbactam (n = 13), imipenem (n = 3), meropenem (n = 2), biapenem (n = 3), vancomycin (n = 5), cefazolin (n = 1), ceftazidime (n = 1), cefmetazole (n = 3), ceftriaxone (n = 3), tazobactam sodium/piperacillin sodium (n = 2), clindamycin (n = 9), and ciprofloxacin (n = 1).

Antimicrobial susceptibility testing

We performed antimicrobial susceptibility testing to determine the susceptibility of B. longum BB536 to various antimicrobial agents. Minimum inhibitory concentrations (MICs) were determined according to standard broth microdilution and agar dilution methods by the Clinical and Laboratory Standards Institute (CLSI; formerly the National Committee for Clinical Laboratory Standards). The MICs of sulbactam/ampicillin and imipenem/cilastatin were determined using Brucella broth (Oxoid USA Inc., Columbia, MD) supplemented with hemin (5 μg/mL), vitamin K1 (1 μg/mL), and lysed horse blood (5%). The MICs of ceftriaxone and vancomycin were determined using Brucella agar supplemented with 5 μg hemin, 1 μg vitamin K1 per mL, and 5% (v/v) lysed sheep blood. Plates were incubated anaerobically at 35°C for 48 h. MICs were also determined in accordance with the CLSI recommended quality control strains of Bacteroides fragilis ATCC25285, Bacteroides thetaiotaomicron ATCC29741, and Eubacterium lentum ATCC43055.

Colonization assay

To assess intestinal colonization, fecal sampling was performed before and after the administration of B. longum BB536. Feces were collected in test tubes and maintained under anaerobic CO2 saturation conditions. Test tubes were cooled in an icebox before culture. Fecal samples were homogenized in 9 mL of anaerobic diluent (containing 0.78% K2HPO4, 0.47% KH2PO4, 1.18% NaCl, 1.20% (NH4)2SO4, 0.12% CaCl2, 0.25% MgSO4・H2O, 0.1% resazurin, 0.5 g L-cysteine・HCl・H2O, 25% L-ascorbic acid, 8% Na2CO3, and 0.5 g agar in purified water), and further 10-fold dilutions were made up to 10-8 in anaerobic diluents. For each dilution we plated a total of 0.05 mL on BL agar (Sysmex BioMérieux, Kobe, Japan), Center for Disease Control (CDC) anaerobe blood agar (Becton Dickinson, Sparks, MD), and bromothymol-blue saccharose agar (Eiken Chemicals, Tokyo, Japan). The agar plates were incubated anaerobically for 3 to 5 days. Colonies that showed typical shapes for Bifidobacteria by Gram staining were counted and expressed as the log of CFU per gram of feces. The laboratory staff had no direct contact with patients and was blinded to the randomization process.

Levels of procalcitonin and interleukin 6

To quantify septic complications, the serum concentrations of IL-6 and PCT were measured before and after probiotic/control intervention, at the same time as fecal sampling. Serum IL-6 concentrations were measured using a commercially available enzyme-linked immunosorbent assay (Quantikine, R&D Systems Inc., Minneapolis, MN). Serum PCT concentrations were measured using a commercially available chemiluminescence immunoassay (CLEIA; SphereLight Brahms PCT, Wako Pure Chemical Industries, Ltd., Osaka, Japan).

Statistical analysis

Intergroup analyses were performed using the Mann– Whitney U-test. Analysis of variance (ANOVA) was used to examine interactions between the groups. Statistical analyses were performed using the general linear models of the SPSS v.17 statistical package (SPSS Inc., Chicago, IL), with statistical significance set at P<0.05.

Ethics and consent

This study was approved by the Ethics Committee of Tokyo Medical University Hachioji Medical Center. Written informed consent was obtained from a suitable patient advocate on enrollment, and patients were asked for their consent at a later time.

Results

Patient characteristics before intervention in the probiotic and control groups are shown in (Table 1). The demographic data, APACHE II scores (severity of illness), and number of cases with each disease type did not differ significantly between the groups.

(Table 3) shows characteristics and measurement values of patients when they were divided into two subgroups based on whether they had received antibiotic therapy or not during the study period. While disease types varied, there were no significant differences in age, sex, APACHE II score (acute physiology score of ICU patients), or the number of fecal bifidobacteria among the patients before probiotic/control intervention. However, the pre-intervention levels of PCT and IL-6 were significantly higher in the antibiotic subgroup than in the non-antibiotic subgroup (P<0.01 and P = 0.01, respectively, Mann–Whitney U-tests).

  Units Subgroup P value
Antibiotic Non-antibiotic
Age (y)   64.7 ± 12.6 66.1 ± 11.9 n.s.
Sex (Male/Female)   15/17 17/15 n.s.
APACHE II score   27.6 ± 6.56 30.38 ± 8.63 n.s.
Bif 102 CFU/g 6.76 ± 2.32 7.74 ± 1.54 n.s.
PCT ng/mL 7.10 ± 7.15 0.84 ± 1.09 P < 0.01
IL-6 ng/mL 399 ± 276 238 ± 277 P = 0.01
    8 0  
  Trauma 8 2  
  Pancreatitis 2 0  
  Burns 3 0  
  CVD 4 9  
  Post-CPR 4 10  
  Aortic dissection 2 0  
  Toxic disease 1 3  
  Liver failure 0 2  
  Metabolic syndrome 0 2  
  Epilepsy 0 2  
  Heart failure 0 2  
Total   32 32  

Table 3: Patient characteristics before intervention in the antibiotic and non-antibiotic subgroups.

Among all patients, no significant intergroup differences were noted in fecal bifidobacteria levels or PCT and IL-6 concentrations before or after probiotic/control intervention (Table 4). Among patients who did not receive antibiotics, pre-intervention fecal bifidobacteria levels and PCT and IL-6 concentrations did not differ significantly between the probiotic and control groups (Table 5). However, after probiotic/control intervention, the mean number of bifidobacteria was significantly higher in the probiotic group than in the control group (8.30 ± 0.84 vs. 6.80 ± 0.90 102 CFU/g, respectively, P<0.01, Mann–Whitney U-test) (Figure 2). In addition, the serum concentrations of PCT (0.44 ± 0.78 vs. 1.19 ± 1.16 ng/mL, P<0.05, Mann–Whitney U-test) (Figure 3) and IL-6 (98.0 ± 131 vs. 201 ± 162 ng/mL, P<0.01, Mann–Whitney U-test) (Figure 4) were significantly lower in the probiotic group than in the control group. Serial changes in these outcome measures showed a significant interaction between the probiotic group and the control group (P<0.05, ANOVA).

  Units Intervention Probiotic group Control group P value
Mean ± SD Mean ± SD  
Bif 102 CFU/g Before 6.94 2.38 6.8 2.53 n.s.
After 5.68 2.14 5.37 2.21 n.s.
PCT ng/mL Before 7.18 8.77 7.95 6.45 n.s.
After 3.46 3.68 2.97 2.78 n.s.
IL-6 ng/mL Before 410 301 449 292 n.s.
After 298 228 275 149 n.s.

Table 4: Fecal bifidobacteria levels and PCT and IL-6 concentrations before and after intervention for all patients.

  Units Intervention Probiotic group Control group P value
Mean ± SD Mean ± SD  
Bif 102 CFU/g Before 7.84 1.53 7.69 0.98 n.s.
After 8.3 0.84 6.8 0.9 P < 0.01
PCT ng/mL Before 0.6 0.83 0.78 0.88 n.s.
After 0.44 0.78 1.19 1.16 P < 0.05
IL-6 ng/mL Before 234 219 176 183 n.s.
After 98 131 201 162 P < 0.01

Table 5: Fecal bifidobacteria levels and PCT and IL-6 concentrations before and after intervention in patients who did not receive antibiotics.

Figure 2: A. Number of fecal bifidobacteria in patients without antibiotics. Standard error bars with 95% confidence intervals (CI) are shown. The diagonal lines show a significant interaction between the probiotic group and the control group (P<0.05, analysis of variance [ANOVA]). After probiotic/control intervention, the number of bifidobacteria (102 colony-forming units [CFU]/g) was significantly higher in the probiotic group than in the control group (8.30 ± 0.84 CFU/g vs. 6.80 ± 0.90 102 CFU/g, P<0.01, Mann–Whitney U-test). B. Number of fecal bifidobacteria in patients with antibiotics. Standard error bars with 95% CI are shown. The diagonal lines show no significant interaction between the probiotic group and the control group (P>0.5, ANOVA). After probiotic/ control intervention, the number of bifidobacteria (102 CFU/g) was not significantly higher in the probiotic group than in the control group (5.61 ± 2.09 CFU/g vs. 5.29 ± 2.35 102 CFU/g, P = 0.6, Mann–Whitney U-test).

Figure 3: A. Serum concentrations of procalcitonin in patients without antibiotics. Standard error bars with a 95% CI are shown. The diagonal lines show a significant interaction between the probiotic group and the control group (P < 0.05, ANOVA). After probiotic/control intervention, the serum concentrations of procalcitonin (ng/mL) in the probiotic and control groups were 0.44 ± 0.78 ng/mL vs. 1.19 ± 1.16 ng/mL, respectively (P<0.05, Mann–Whitney U-test). B. Serum concentrations of procalcitonin in patients without antibiotics. Standard error bars with a 95% CI are shown. The diagonal lines show no significant interaction between the probiotic group and the control group (P>0.5, ANOVA). After probiotic/control intervention, the serum concentrations of procalcitonin (ng/mL) in the probiotic and control groups were 2.97 ± 2.81 ng/mL vs. 2.13 ± 2.38 ng/mL, respectively (P = 0.9, Mann–Whitney U-test).

Figure 4: A. Serum concentrations of interleukin-6 in patients without antibiotics. Standard error bars with 95% CI are shown. The diagonal lines show a significant interaction between the probiotic group and control group (P<0.05, ANOVA). After probiotic/control intervention, the serum concentrations of interleukin-6 (ng/mL) of the probiotic and control groups were 98.0 ± 131 ng/mL and 201 ± 162 ng/mL, respectively (P<0.01, Mann–Whitney U-test). B. Serum concentrations of interleukin-6 in patients without antibiotics. Standard error bars with 95% CI are shown. The diagonal lines show no significant interaction between the probiotic group and control group ( >0.5, ANOVA). After probiotic/control intervention, the serum concentrations of interleukin-6 (ng/ mL) of the probiotic and control groups were 258 ± 212 ng/mL and 233 ± 109 ng/mL, respectively (P = 0.9, Mann–Whitney U-test).

Lastly, we compared pre- and post-intervention measurement values among patients who received antibiotics and observed no significant differences between the probiotic and control groups (Table 6). MIC results (μg/mL) showed that B. longum BB536 was susceptible to ampicillin/sulbactam (0.5 μg/mL), imipenem (0.25 μg/ mL), ceftriaxone (4 μg/mL), and vancomycin (0.5 μg/mL).

  Units Intervention Probiotic group Control group P value
Mean ± SD Mean ± SD  
Bif 102 CFU/g Before 6.93 2.25 6.75 2.51 n.s.
After 5.61 2.09 5.29 2.35 n.s.
PCT ng/mL Before 5.31 8.51 6.54 6.12 n.s.
After 2.97 2.81 2.13 2.38 n.s.
IL-6 ng/mL Before 351 201 389 278 n.s.
After 258 212 233 109 n.s.

Table 6: Fecal bifidobacteria levels, and PCT and IL-6 concentrations before and after intervention in patients who received antibiotics.

Discussion

Bifidobacteria, lactobacilli, and several other probiotic organisms have been reported to secrete several antimicrobial substances, including bacteriocins that exert a direct inhibitory effect on the growth of pathogens [20,21]. Probiotics are believed to exert their positive effects on the host by these mechanisms. The aim of the present study was to evaluate the effects of Bifidobacterium longum BB536 on quantifiable indices of gut barrier function in patients with critically illness. The isolation of enteric organisms from normally sterile extra-intestinal tissues is considered the gold standard index of gut barrier function [22] and harvesting mesenteric lymph nodes is an established mode of evaluating of BT, but this was not feasible in the present study because only a few patients underwent surgery during the study period. Obtaining samples of thoracic duct lymph nodes directly has been performed in patients with critically illness, but the procedure is extremely invasive and inappropriate for a study of this size [23]. Among the possible measurements, including the assessment of intestinal microbiota, gut permeability, or immunoglobulin M anti-endotoxin core antibody (endogenous) [7], we opted to assess intestinal microflora in accordance with our objective to determine the interaction between B. longum BB536 and antibiotics, both of which measurably change intestinal microflora. Therefore, we considered that measuring the number of fecal bifidobacteria would be the most appropriate way to assess these changes.

Following enrollment, many patients in this study had elevated serum PCT and IL-6 concentrations, indicative of a marked inflammatory response or systemic infection, both of which are commonly observed in clinical settings [24]. After probiotic/control intervention, the concentrations of these markers among patients who did not receive antibiotics were significantly lower in the probiotic group compared with the control group. Although we did not examine any clinical outcomes such as ICU days or mortality rate in this study, the serological results provided some lines of evidence that B. longum BB536 suppresses septic complications in critically ill patients by improving/maintaining the health of microflora. However, when used concurrently with antibiotics, B. longum BB536 had no effects on the number of fecal bifidobacteria or the concentrations of serum septic markers, suggesting that antibiotics used commonly in our ICU suppressed the beneficial effect of B. longum BB536. In this study, most antimicrobial agents were administered as an empiric therapy, and broad-spectrum agents such as ampicillin/sulbactam and imipenem were used often against unknown pathogenic organisms. Therefore, the use of broad-spectrum agents may have suppressed the multiplication of B. longum BB536 in the intestinal microflora. This may partially explain why no previous studies have shown the beneficial effects of probiotics in critically ill patients. Nevertheless, the present findings suggest that probiotics are beneficial in specific groups of critically ill patients, especially patients with non-infectious disease, and thus have no need for antibiotic intervention. In such patients, probiotics could potentially reduce the risk of infectious complications (ventilator- and catheter-associated pneumonia), which are risks that most critically ill patients inevitably face.

There are several limitations to this study. First, the sample size was small (64 patients in total; 15-17 in each subgroup), suggesting low statistical power. Therefore, further study with a larger number of patients is needed in the future. Secondly, during initial treatment, attending physicians decided subjectively whether patients should receive antibiotics. Therefore, the allocation of patients into the antibiotic and non-antibiotic groups involves sampling bias. Furthermore, we did not investigate whether or how the gut microbiome was affected by ischemia-reperfusion injury [25], feeding route [26], or use of morphine [27] or proton pump inhibitors [28] in these patients Lastly, clinical outcomes such as overall survival or the length of ICU stay were not measured. However, our findings present a rationale for a future large-scale multicenter study with strict inclusion criteria and various outcome measures (those mentioned above such as feeding routes).

Conclusion

In conclusion, this prospective randomized study suggests that B. longum BB536 prevents septic complications by improving and maintaining the health of microflora and that the routine prophylactic use of B. longum BB536 is appropriate in critically ill patients with non-infectious disease.

References

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