Probiotic-based therapy as a new useful strategy for the treatment of patients with traumatic brain injury | BMC Infectious Diseases | Full Text

BMC Infectious Diseases volume 24, Article number: 1240 (2024) Cite this article

Metrics details

In the new era, microbial-based medicine is one of the best strategies that try to modify the normal flora with the aim of treating some disorders. This systematic review and meta-analysis was performed to evaluate the use of probiotics in the treatment of the clinical outcomes in cases with traumatic brain injury..

In this regard, the search strategy was done using databases such as PubMed, Embase, Scopus, CENTRAL, and Google Scholar, from 2006 until April 2024. All studies about the efficacy of probiotic supplementation on the clinical outcomes in traumatic brain injury patients were retrieved. During the assessment process of the eligible studies, we evaluated clinical characteristics such as the Glasgow Coma Scale score, the Sequential Organ Failure Assessment score, the Acute Physiology and Chronic Health Evaluation II score, referral rate and hospitalization period in the intensive care unit, mortality rate, as well as opportunistic infections in both groups of case and control..

In this study, the authors analyzed data from 6 articles including 391 cases with traumatic brain injury. Our results showed that the probiotic therapy increases the Glasgow Coma Scale score in patients with the average age of more than 50 years. However, there was no a significant difference in the Sequential Organ Failure Assessment and the Acute Physiology and Chronic Health Evaluation scores between the group that had received probiotics and the control group. Although probiotic-based treatment did not significantly affect the intensive care unit admission (or length of stay), but, the risk of infection, and also mortality was significantly lower in the probiotic group (OR: 0.53; 95% CI: 0.3 to 0.8, as well as OR: 0.41; 95% CI: 0.2 to 0.7, respectively)..

Overall, due to the modification of microbial flora, probiotic supplements can balance microflora disturbances, which in turn leads to improvement the clinical outcomes in patients with brain injury. Therefore, probiotic-based therapy can be considered as a promising strategy for the treatment of the central nervous system disorders. However, given the limited evidence, more clinical trial studies need to strengthen our results..

Peer Review reports

Traumatic brain injuries (TBIs or TBI) are considered among the most common causes of death in the young population, especially in developing countries [1, 2]. In addition, recent reports indicate a significant increase in the global burden of TBIs, as it is expected by 2030, TBI will be considered as one of the main causes of disability and death [3]. Cerebral inflammatory responses occur in human following the occurrence of TBI, e.g. increase in interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) [4]. Immune dysregulation increases the chance of infection, which in turn leads to the poor clinical outcomes, particularly morbidity and mortality [5]. There are numerous evidence about the adverse outcomes of the central nervous system (CNS) due to TBI-induced immune system responses; for example, free radicals produced by the immune system in response to TBIs [6]. Based on the recent clinical trial studies, antioxidant micronutrients-based therapies can be led to the improvement of clinical sings in patients with systemic inflammatory response syndrome (SIRS) [7]. Moreover, studies show that in patients with mild TBI, proinflammatory cytokines such as IL-6 and THF-α, as well as C-reactive protein (CRP) concentrations significantly increase the risk of posttraumatic stress disorder (PTSD) [8]. Probiotics are a heterogeneous group of microorganisms that provide health benefits for their host [9]. In addition, the microflora living in the gastrointestinal tract affects the activities of the gut-brain axis (GBA) through interaction and regulation of immune system responses, body homeostasis, and the production of its own metabolites [10]. According to recent meta-analyses, it has been proven that the probiotic supplements play an influential role in reducing the mortality of ventilator-associated pneumonia patients admitted to the intensive care unit (ICU) by regulating immune system responses and reducing infectious diseases [11]. In a comprehensive review, it was shown that the probiotic supplementation maintains the health of human through several mechanisms such as stimulation of IgA and mucus production, inhibition of nuclear factor kappa B (NF-kB) signaling, production of antioxidant metabolites, and production of antimicrobial peptides [12]. In addition, this therapeutic strategy can inhibit the expression of proinflammatory cytokines, especially NF-kB, IL-6, IL-10, CRP, and TNF-α [13]. Based on the available evidence, inflammation caused by immune system disorders can lead to the prolonged hospitalization of patients in the ICU [14]. In this regard, in recent meta-analyses it was shown that the consumption of probiotics such as Lactobacillus, Bifidobacterium, and Streptococcus leads to a decrease in CRP levels, and consequently trauma healing [15]. As a result and according to the mentioned contents, probiotics can be effective in regulating immune system responses, and also in reducing stress caused by inflammatory responses following trauma [16, 17]. However, the actual role of probiotic-based therapy in reducing TBIs still remains a question. Therefore, the aim of this study was to evaluate the probiotic supplementation strategy in reducing the clinical outcomes of severe brain injuries using randomized control trials (RCTs).

In a comprehensive study, we tried to evaluate the effect of probiotic therapy on the final clinical outcomes of TBI patients. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. For the first step, using the global databases such as ISI Web of Science, PubMed, Embase, Scopus, CENTRAL, and Google Scholar, all relevant studies were retrieved from 2006 until April 2024. It was noted that the first author used from all databases, while the second author used the same databases except Embase and CENTRAL. Therefore, there was inconsistency in the retrieved results between the two researchers. These studies were selected based on MeSH terms regardless of publication date and article language restrictions. The keywords were: “Probiotics”; “Traumatic brain injury”; “TBI”; “Randomized control trials”; “RCT”; “Intensive care unit or ICU”. Also, to avoid missing articles, the reference list of eligible studies was manually evaluated.

In the present study, inclusion criteria were as follows: (1) patients with TBI; (2) randomized clinical trials on TBI; (3) studies based on both case (probiotic consumer) and control (placebo consumer) groups; (4) studies on human subjects. On the other hand, studies such as observational studies, duplicate studies, in vivo and in vitro studies, non-original articles (e.g. letters, editorials, case reports, and review articles), and original articles with unclear methods were excluded from our study.

In this step, the methodological quality assessment of the eligible studies was evaluated by two independent authors [18]. The risk of bias was classified into three groups: low risk, unclear, and high risk. Then the following information was extracted and listed in Table 1: first author, publication year, country, intervention details, total size/mean age in both groups (case and control), the Glasgow Coma Scale (GCS) score, the Sequential Organ Failure Assessment (SOFA) score, the Acute Physiology and Chronic Health Evaluation (APACHE) II score, ICU length of stay, 28-mortality rate, infections, and SIRS [19,20,21,22,23,24]. Conflicts were decided by discussion by all authors.

All statistical analyses were done by Comprehensive Meta-Analysis (CMA) software version 2.2 (Biostat, Englewood, NJ). To evaluate the effect of probiotic therapy on TBI patients, we used indexes such as event rate, odds ratio (OR), and mean differences corresponding 95% confidence intervals (CI). Summary of estimates was selected based on heterogeneity. To estimate the heterogeneity between studies, authors used of Cochran’s Q test and I2 statistic. Considering the presence of possible heterogeneity, we used tools such as subgroup analysis and sensitivity analysis. Publication bias was declared by items such as Egger’s regression test, Begg’s p value test and asymmetry of funnel plots. In all statistical analyses, p value < 0.05 was considered as a significant level.

In the initial search of the databases, 783 studies were obtained, and after removing duplicates, 409 studies remained. We excluded 403 irrelevant articles in three steps as follows: Screening step: excluded records e.g. irrelevant articles, review and case reports (n = 51); Eligibility step: excluded records e.g. unavailable full text, non-human samples, in vitro studies (n = 276); Included step: excluded records e.g. unclear methods, repetitive samples, insufficient data, TBI patients without probiotic therapy (n = 76). Ultimately, based on applied exclusion criteria, 6 articles with full text that had described the clinical benefits of probiotic-based therapies on severe TBIs were selected for this study (Fig. 1). All included studies had been conducted in countries such as Greece, Slovenia, China, and Egypt during 2006–2020. The risk of bias assessment of the eligible RCTs are illustrated in Table 2. Prescribed probiotics in TBI patients included Pediococcus, Lactobacillus, Bifidobacterium, Enterococcus, and Leuconostoc. In the present study, we evaluated the data of 391 patients; the average age in the case and control groups was 42.89 ± 1 and 43.68 ± 8 years, respectively.

Flow-diagram of study selection process

Five studies evaluated the effect of the probiotic supplementation on GCS score changes in TBI patients. According to our results, there was no significant difference in GCS scores between case and control groups (mean difference: -3.89; 95% CI: -17.5 to 9.78; p value: 0.5; I2: 99.3; p value: 0.01). Nonetheless, in patients with an average age of more than 50 years, the probiotic supplementation significantly increased the GCS score (mean difference: 0.16; 95% CI: 0.15 to 0.16; p value: 0.01; I2: 0.00; p value: 0.9). SOFA score is also a system to estimate the patient-related outcomes by evaluating the failure of organs including liver, lungs, heart, kidneys, and nerves, where higher scores indicate a higher probability of death. Our analysis showed that although probiotic therapy reduces the score of SOFA, but its value was not significant (mean difference: -31.18; 95% CI: -145.8 to 83.46; p value: 0.5; I2: 99.39; p value: 0.01). Among all studies, only two studies assessed the SOFA score, and therefore we could not perform subgroup analysis. In addition, APACHE II (that examines 12 physiological variables) is intended as a performance system to demonstrate the quality of ICU care; higher APACHE II scores indicate a higher probability of death. Our findings revealed that the probiotic supplementation reduces APACHE II, but it was not meaningful (mean difference: -0.1; 95% CI: -0.9 to 0.5; p value: 0.6; I2: 99.99; p value: 0.01). Nevertheless, regarding to the low sample size, further subgroup analysis as well as sensitivity analysis could not decrease the heterogeneity between studies. But due to clinical, methodological, and statistical heterogeneity, there was inconsistency between similar studies.

Our findings showed that the probiotic supplementation does not have a significant effect on the ICU admission (OR: 1.31; 95% CI: 0.65–2.59; p value: 0.45; I2: 27.79; p value: 0.23). As well as our findings indicated that the probiotic supplementation reduces the duration of hospitalization of patients in ICU, although the values were not significant (mean difference: -5.18; 95% CI: -13.85 to 3.48; p value: 0.2; I2: 99.99; p value: 0.01). Unfortunately, only three studies had assessed the duration of stay in ICU, and therefore we could not perform further subgroup analysis or sensitivity analysis.

The data of six eligible studies showed that the probiotic supplementation significantly reduces the risk of 28-day mortality in TBI patients (OR: 0.53; 95%CI: 0.31 to 0.9; p-value: 0.01; I2: 3.43; p-value: 0.39; Egger’s p-value: 0.6; Begg’s p-value: 0.35). Interestingly, the rate of heterogeneity in this index is very low. In addition, probiotic-based therapy reduces the risk of infection in TBI patients (OR: 0.4; 95% CI: 0.21 to 0.76; p value: 0.02; I2: 19.8; p value: 0.29; Egger’s p value: 0.01; Begg’s p value: 0.04). Finally, regarding the role of the probiotic supplementation in reducing immune system complications such as SIRS in TBI patients, our finding showed that probiotics have no protective effect against this syndrome (OR: 0.68; 95% CI: 0.3 to 1.57; p value: 0.37; I2: 0.00; p value: 0.5; Egger’s p value: 0.1; Begg’s p value: 0.5). As a result, the probiotic supplementation can reduce the risk of infection and mortality in TBI patients (Figs. 2 and 3). Due to the stability of pooled estimates, the level of heterogeneity in the estimation of these indexes was insignificant, and the sensitivity analysis also confirmed this relationship.

The forest plot of the impact of the probiotic supplementation on the infection rate of patients with TBI

The forest plot of the impact of the probiotic supplementation on the mortality rate of patients with TBI

The results of Egger’s p value test and Begg’s p value test indicated the presence of bias in some studies. Also, the asymmetry of funnel plot confirmed a slight bias, but the analysis of the trim-fill method showed that there was no discrepancy between the original pooled estimates and the adjusted pooled estimates, which in turn indicated the stability of the results (Fig. 4).

The funnel plot of the publication bias of studies reporting the impact of the probiotic supplementation on the clinical outcomes of patients with TBI

In the present meta-analysis, data from six RCTs were evaluated. We analyzed the effect of the probiotic supplementation on the clinical outcomes of patients with severe TBIs. These items included GCS score, SOFA score, APACHE II score, infection complication, SIRS, ICU admission rate, ICU length of stay, and mortality rate. A pooled analysis showed that this new treatment strategy leads to an increase in the GCS scale in patients over fifty years old. Moreover, our results indicated that probiotic administration significantly reduced the risk of mortality in patients with severe TBIs and infectious diseases. However, there was no significant change in some indexes such as ICU admission rate, ICU length of stay, SOFA score, APACHE II score, and also proinflammatory responses in the probiotic supplementation group compared to placebo group. Overall, our hypothesis regarding the efficacy of probiotic treatment for patients with severe TBI was not fully substantiated. It is evident that stress-related responses such as hormonal, metabolic, and cytokine changes will occur after TBI [25, 26]. Trauma causes hypoxia and ischemia in the gastrointestinal tract through the splanchnic vasoconstriction, which ultimately affects the GBA [27]. Gut microbiota controls immune system activities using direct and indirect mechanisms; therefore, due to disturbance of immune balance following TBIs and consequently perturbation of gut microbiota, the GBA becomes disordered [28]. GBA modulates the function of dendritic cells and T cells located in the intestine through some mediators such as norepinephrine (norepinephrine) and neuropeptide messengers [29]. In this regard, studies have shown that the gut microbiomes and their metabolites e.g. short chain fatty acids (SCFAs) are associated with the differentiation of T cells such as Th1, Th2, Th17, and Treg [30, 31]. According to recent studies, CRP serum levels increase in the first hours after a TBI event [32]. Based on a study conducted by Lin et al., it was shown that the consumption of probiotic L. reuteri could suppress proinflammatory cytokines such as IL-6, TNF-α, and CRP [33]. Short-chain fatty acids (SCFAs) production is the main mechanism of reducing inflammation and oxidative stress by probiotics [34]. In their study on TBI patients, Tan et al. found a significant decrease in CRP levels in patients who took probiotics such as B. longum ATCC 15,697, L. bulgaricus ATCC 11,842, and Streptococcus thermophiles ATCC 19,987 [22]. In contrast, Brenner et al. showed in their study that probiotic consumption could not reduce inflammatory indicators such as IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-α, as well as IFN-γ in TBI patients [35]. Although we investigated the effect of the probiotic supplementation on changes in the expression of inflammatory cytokines, our results showed that this therapeutic strategy did not reduce inflammatory responses e.g. SIRS in patients with severe TBI (OR: 0.68; 95% CI: 0.3 to 1.57; p value: 0.37; I2: 0.00; p value: 0.5). In this regard, Noshadi et al. showed as our findings that treatment with probiotics in TBI patients cannot significantly reduce CRP levels [27]. In addition, in a meta-analysis, Mazidi et al. showed that the consumption of probiotics could not reduce inflammatory cytokines such as TNF-α and IL-10 in patients with disorders such as inflammatory bowel syndrome (IBS), obesity, and TBI [13]. Severe TBI and ultimately an imbalance in immune responses can predispose patients to the poor clinical outcomes such as nosocomial infections as well as ICU length of stay [36]. In our study we also demonstrated that this strategy significantly reduced the risk of nosocomial infections (OR: 0.4; 95% CI: 0.21 to 0.76; p value: 0.02; I2: 19.8) and consequently mortality rate (OR: 0.53; 95% CI: 0.31 to 0.9; p value: 0.01; I2: 3.43) in TBI patients. In a study conducted by Gu et al., they showed that probiotic consumption could reduce the length of ICU stay in patients with TBI [37]. Nevertheless, our results were controversial, so that the probiotic supplementation had no effect on reducing the number of referrals of patients with TBIs to ICU. Based on our results, although this type of treatment reduced the ICU length of stay, this value was not significant. Similar to our findings, Noshadi et al. did not find a significant relationship between probiotic consumption and reduced length of stay in the ICU [27]. In summary, we investigated the therapeutic effect of the probiotic supplementation in reducing the poor clinical outcomes in patients with severe TBIs.

Our findings showed that the use of probiotics reduces the complications of nosocomial infections and thus mortality, but it has no effect on the length of stay in the ICU and inflammatory responses. However, there were certain limitations in our study including (1) the sample size was small and included studies were usually single-center; (2) it would be better to consider a time point to evaluate and compare indexes between patients; (3) due to multiple strains as well as varies dosage of probiotics, we could not evaluate the effect of a specific probiotic strain and its dosage; (4) there was no access to raw data such as comorbidities (e.g., diabetes, HIV, hypertension, etc.) to evaluate the impact of these factors in the overall estimates; (5) there was meaningful heterogeneity in the pooled estimates (heterogeneity due to clinical, methodological, and statistical factors); (6) there was a positive publication bias between the eligible studies; (7) no protocol was preregistered for the present study. Factors such as characteristics of included participants, severity grade of TBI, socioeconomic status, body mass index (BMI), as well as comorbidities, all can be considered as clinical heterogeneity. On the other hand, some factors assume as methodological heterogeneity, for example sampling, number of samples, and dosage of probiotic therapy. In addition, inconsistent findings may be due to statistical heterogeneity during subgroup analysis. Therefore, the results should be interpreted with caution.

Taken together, the results of this meta-analysis demonstrated the clinical benefits of the probiotic supplementation on clinical outcomes (e.g. nosocomial infections and mortality) in patients with severe TBI. However, there is considerable heterogeneity, which makes the results less credible. Our study proposed that a combination therapy consisting of probiotics and routine treatment is effective on the improvement of the clinical outcomes of patients with severe TBIs. Nevertheless, the current results are not sufficient to generalize to all populations. Therefore, the results should be interpreted with caution. We believe that present study can help to understand the therapeutic role of probiotics in the treatment of patients with TBI. These findings highlight the position and importance of microbial-based medicine in reducing the poor clinical outcomes of patients with severe TBIs. However, the current results should be strengthened using further large-scale research.

All data generated or analysed during this study are included in this published article.

Traumatic brain injuries

Interleukin-1β

Tumor necrosis factor-α

Central nervous system

Posttraumatic stress disorder

Intensive care unit

Preferred Reporting Items for Systematic Reviews and Meta-analysis

Newcastle-Ottawa Scale

Comprehensive Meta-Analysis

Berwick DM, Downey AS, Cornett EA. A national trauma care system to achieve zero preventable deaths after injury: recommendations from a national academies of sciences, engineering, and medicine report. JAMA. 2016;316(9):927–8.

Article PubMed Google Scholar

Faul M, Coronado V. Epidemiology of traumatic brain injury. Handb Clin Neurol. 2015;127:3–13.

Article PubMed Google Scholar

Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic brain injury: an overview of epidemiology, pathophysiology, and medical management. Med Clin. 2020;104(2):213–38.

Google Scholar

Morganti-Kossmann C, Semple B, Ziebell J, Yan E, Bye N, Kossmann T. Modulation of immune response by head injury. New Insights Neuroimmune Biology 2010:193–220.

Syed-Ahmed M, Narayanan M. Immune dysfunction and risk of infection in chronic kidney disease. Adv Chronic Kidney Dis. 2019;26(1):8–15.

Article PubMed Google Scholar

Pahlavani N, Malekahmadi M, Sedaghat A, Rostami A, Alkadir OKA, Taifi A, Ranjbar G, Sahebkar A, Abdelbasset WK, Beigmohammadi MT. Effects of melatonin and propolis supplementation on inflammation, oxidative stress, and clinical outcomes in patients with primary pneumosepsis: a randomized controlled clinical trial. Complement Med Res. 2022;29(4):275–85.

Article PubMed Google Scholar

Malekahmadi M, Moradi Moghaddam O, Islam SMS, Tanha K, Nematy M, Pahlavani N, Firouzi S, Zali MR, Norouzy A. Evaluation of the effects of pycnogenol (French maritime pine bark extract) supplementation on inflammatory biomarkers and nutritional and clinical status in traumatic brain injury patients in an intensive care unit: a randomized clinical trial protocol. Trials. 2020;21:1–9.

Article Google Scholar

Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, O’Connor DT, Baker DG, Team MRS. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71(4):423–31.

Article PubMed PubMed Central Google Scholar

Karbalaei M, Keikha M. Probiotics and intestinal decolonization of antibiotic-resistant microorganisms; a reality or fantasy? Annals Med Surg 2022, 80.

Mayer EA, Nance K, Chen S. The gut–brain axis. Annu Rev Med. 2022;73:439–53.

Article PubMed Google Scholar

Petrof EO, Dhaliwal R, Manzanares W, Johnstone J, Cook D, Heyland DK. Probiotics in the critically ill: a systematic review of the randomized trial evidence. Crit Care Med. 2012;40(12):3290–302.

Article PubMed Google Scholar

Keikha M, Karbalaei M. Probiotics as the live microscopic fighters against Helicobacter pylori gastric infections. BMC Gastroenterol. 2021;21:1–18.

Article Google Scholar

Mazidi M, Rezaie P, Ferns GA, Vatanparast H. Impact of probiotic administration on serum C-reactive protein concentrations: systematic review and meta-analysis of randomized control trials. Nutrients. 2017;9(1):20.

Article PubMed PubMed Central Google Scholar

Bergold PJ. Treatment of traumatic brain injury with anti-inflammatory drugs. Exp Neurol. 2016;275:367–80.

Article PubMed Google Scholar

Mahmoodpoor A, Hamishehkar H, Asghari R, Abri R, Shadvar K, Sanaie S. Effect of a probiotic preparation on ventilator-associated pneumonia in critically ill patients admitted to the intensive care unit: a prospective double‐blind randomized controlled trial. Nutr Clin Pract. 2019;34(1):156–62.

Article PubMed Google Scholar

Milajerdi A, Mousavi SM, Sadeghi A, Salari-Moghaddam A, Parohan M, Larijani B, Esmaillzadeh A. The effect of probiotics on inflammatory biomarkers: a meta-analysis of randomized clinical trials. Eur J Nutr. 2020;59:633–49.

Article PubMed Google Scholar

Kazemi A, Soltani S, Ghorabi S, Keshtkar A, Daneshzad E, Nasri F, Mazloomi SM. Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: a systematic review and meta-analysis of clinical trials. Clin Nutr. 2020;39(3):789–819.

Article PubMed Google Scholar

Tarsilla M. Cochrane handbook for systematic reviews of interventions. J Multidisciplinary Evaluation. 2010;6(14):142–8.

Article Google Scholar

Kotzampassi K, Giamarellos-Bourboulis EJ, Voudouris A, Kazamias P, Eleftheriadis E. Benefits of a synbiotic formula (Synbiotic 2000Forte®) in critically ill trauma patients: early results of a randomized controlled trial. World J Surg. 2006;30:1848–55.

Article PubMed Google Scholar

Spindler-Vesel A, Bengmark S, Vovk I, Cerovic O, Kompan L. Synbiotics, prebiotics, glutamine, or peptide in early enteral nutrition: a randomized study in trauma patients. J Parenter Enter Nutr. 2007;31(2):119–26.

Article Google Scholar

Giamarellos-Bourboulis EJ, Bengmark S, Kanellakopoulou K, Kotzampassi K. Pro-and synbiotics to control inflammation and infection in patients with multiple injuries. J Trauma Acute Care Surg. 2009;67(4):815–21.

Article Google Scholar

Tan M, Zhu J-C, Du J, Zhang L-M, Yin H-H. Effects of probiotics on serum levels of Th1/Th2 cytokine and clinical outcomes in severe traumatic brain-injured patients: a prospective randomized pilot study. Crit Care. 2011;15:1–10.

Article Google Scholar

Wan G, Wang L, Zhang G, Zhang J, Lu Y, Li J, Yi X. Effects of probiotics combined with early enteral nutrition on endothelin-1 and C-reactive protein levels and prognosis in patients with severe traumatic brain injury. J Int Med Res. 2020;48(3):0300060519888112.

Article PubMed Google Scholar

Habib T, Kassem AB, Ahmed I. Early probiotics in preventing ventilator-associated pneumonia after multiple trauma. Asian J Pharm Clin Res. 2020;13(10):83–5.

Article Google Scholar

Kusmenkov T, Braunstein M, Schneider H, Bidlingmaier M, Prall W, Flatz W, Boecker W, Bogner V. Initial free cortisol dynamics following blunt multiple trauma and traumatic brain injury: a clinical study. J Int Med Res. 2019;47(3):1185–94.

Article PubMed PubMed Central Google Scholar

Şimşek T, Şimşek HU, Cantürk NZ. Response to trauma and metabolic changes: posttraumatic metabolism. Turkish J Surgery/Ulusal Cerrahi Dergisi. 2014;30(3):153.

Google Scholar

Noshadi N, Heidari M, Naemi Kermanshahi M, Zarezadeh M, Sanaie S, Ebrahimi-Mameghani M. Effects of Probiotics supplementation on CRP, IL-6, and length of ICU stay in traumatic brain injuries and multiple trauma patients: a systematic review and Meta‐analysis of Randomized controlled trials. Evidence‐Based Complement Altern Med. 2022;2022(1):4674000.

Google Scholar

Rice MW, Pandya JD, Shear DA. Gut microbiota as a therapeutic target to ameliorate the biochemical, neuroanatomical, and behavioral effects of traumatic brain injuries. Front Neurol. 2019;10:412551.

Article Google Scholar

Hattori N, Yamashiro Y. The gut-brain axis. Annals Nutr Metabolism. 2021;77(Suppl 2):1–3.

Article Google Scholar

Shim JA, Ryu JH, Jo Y, Hong C. The role of gut microbiota in T cell immunity and immune mediated disorders. Int J Biol Sci. 2023;19(4):1178.

Article PubMed PubMed Central Google Scholar

Cénit M, Matzaraki V, Tigchelaar E, Zhernakova A. Rapidly expanding knowledge on the role of the gut microbiome in health and disease. Biochim et Biophys Acta (BBA)-Molecular Basis Disease. 2014;1842(10):1981–92.

Article Google Scholar

Gołąbek-Dropiewska K, Pawłowska J, Witkowski J, Lasek J, Marks W, Stasiak M, Jaskólski D, Kawecka A, Łuczkiewicz P, Baczkowski B. Analysis of selected pro-and anti-inflammatory cytokines in patients with multiple injuries in the early period after trauma. Cent Eur J Immunol. 2018;43(1):42–9.

Article PubMed PubMed Central Google Scholar

Lin YP, Thibodeaux CH, Peña JA, Ferry GD, Versalovic J. Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c-Jun. Inflamm Bowel Dis. 2008;14(8):1068–83.

Article PubMed Google Scholar

Cheng Y, Liu J, Ling Z. Short-chain fatty acids-producing probiotics: a novel source of psychobiotics. Crit Rev Food Sci Nutr. 2022;62(28):7929–59.

Article PubMed Google Scholar

Brenner LA, Forster JE, Stearns-Yoder KA, Stamper CE, Hoisington AJ, Brostow DP, Mealer M, Wortzel HS, Postolache TT, Lowry CA. Evaluation of an immunomodulatory probiotic intervention for veterans with co-occurring mild traumatic brain injury and posttraumatic stress disorder: a pilot study. Front Neurol. 2020;11:546517.

Article Google Scholar

Namas RA, Vodovotz Y, Almahmoud K, Abdul-Malak O, Zaaqoq A, Namas R, Mi Q, Barclay D, Zuckerbraun B, Peitzman AB. Temporal patterns of circulating inflammation biomarker networks differentiate susceptibility to nosocomial infection following blunt trauma in humans. Ann Surg. 2016;263(1):191–8.

Article PubMed Google Scholar

Gu WJ, Deng T, Gong YZ, Jing R, Liu JC. The effects of probiotics in early enteral nutrition on the outcomes of trauma: a meta-analysis of randomized controlled trials. J Parenter Enter Nutr. 2013;37(3):310–7.

Article Google Scholar

Download references

We appreciate from both Iranshahr University of Medical Sciences and Jiroft University of Medical Sciences.

We have not received any funding for this research.

Hanieh Asaadi and Abdolreza Narouiepour Co-first authors.

Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Hanieh Asaadi

Department of Anatomy, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran

Abdolreza Narouiepour

Research Institute for Gastroenterology and Liver Diseases, Imam Reza hospital, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran

Arezo Haji

Department of Microbiology and Virology, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran

Masoud Keikha

Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

Mohsen Karbalaei

Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran

Mohsen Karbalaei

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

1. HA, AN, and MK1 have contributed to design of the work and analysis of data. 2. AH and MK1 have contributed to design of the work. 3. MK2 has drafted the work and substantively revised it. All authors read and approved the final manuscript.

Correspondence to Masoud Keikha or Mohsen Karbalaei.

Not applicable.

Not Applicable.

The authors declare no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Below is the link to the electronic supplementary material

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

Asaadi, H., Narouiepour, A., Haji, A. et al. Probiotic-based therapy as a new useful strategy for the treatment of patients with traumatic brain injury. BMC Infect Dis 24, 1240 (2024). https://doi.org/10.1186/s12879-024-10146-0

Download citation

Received: 10 July 2024

Accepted: 29 October 2024

Published: 04 November 2024

DOI: https://doi.org/10.1186/s12879-024-10146-0

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative