Skip to main content
NCBI home page
Springer logoLink to Springer
. 2024 Oct 13;56(1):60. doi: 10.1007/s00726-024-03420-7

A systematic review and meta-analysis of clinical trials on the effects of glutamine supplementation on gut permeability in adults

Fatemeh Abbasi 1, Mohammad Mehdi Haghighat Lari 2, Gholamreza Reza Khosravi 3, Elahe Mansouri 4, Nastaran Payandeh 5, Alireza Milajerdi 2,✉
PMCID: PMC11471693  PMID: 39397201

Abstract

The gastrointestinal tract's epithelial barrier plays a crucial role in maintaining health. This study aims to investigate the impact of glutamine supplementation on intestinal permeability, considering its importance for immune function and nutrient absorption. The study adhered to the PRISMA protocol for systematic reviews and meta-analyses. A systematic search was performed in four databases (PubMed, Scopus, Web of Science, and Google Scholar) until April 2023 to identify clinical trials on glutamine supplementation and gastrointestinal permeability. Eligibility criteria included randomized placebo-controlled trials measuring gut permeability post-glutamine supplementation. Studies were included regardless of language or publication date. Data extraction involved study characteristics, intervention details, and outcomes. Quality assessment was performed using the Cochrane tool, and statistical analysis utilized mean differences and standard deviations with a random effects model. Subgroup analysis was conducted to explore heterogeneity. The systematic review and meta-analysis included 10 studies from 1998 to 2014 with 352 participants. A total of 216 patients were enrolled in the intervention group, and 212 in the control group. The mean participant age was 46.52 years. The participants had different types of diseases in terms of their health status. Overall, glutamine supplementation did not significantly affect intestinal permeability (WMD: −0.00, 95% CI −0.04, 0.03). Subgroup analysis showed a significant reduction in intestinal permeability with doses over 30g/day (WMD: −0.01, 95% CI −0.10, −0.08). The glutamine supplements were administered orally in all included studies. The meta-analysis demonstrated a significant reduction in intestinal permeability with glutamine supplementation exceeding 30 mg/day for durations of less than 2 weeks. Further investigations with varying dosages and patient populations are warranted to enhance understanding and recommendations regarding glutamine supplementation's effects on gut permeability.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00726-024-03420-7.

Keywords: Glutamine, Intestinal permeability, Supplement, Meta-analysis

Introduction

The gastrointestinal (GI) tract provides a large surface area for digesting and absorbing nutrients and excreting waste products from the body (Wang et al. 2015). This tract is lined by a single layer of epithelial cells, forming a crucial protective barrier against microbial invasion (Madni et al. 2020; Hallajzadeh et al. 2019; Shahinfar et al. 2021). Additionally, the GI tract plays a vital role in maintaining homeostasis and overall immune function (Pugh et al. 2017).

The integrity of the intestinal barrier depends on the turnover of Intestinal Epithelial Cells (IEC) (Arike et al. 2020). The para-cellular space between IECs is responsible for intestinal permeability (Arike et al. 2020). Increased intestinal permeability, due to leakage in the para-cellular space, allows endotoxins and exotoxins to enter the bloodstream, triggering immune responses and systemic inflammation (Wang et al. 2015; Pugh et al. 2017). Moreover, elevated intestinal permeability can impair epithelial cell function and reduce nutrient absorption efficiency (Zuhl et al. 2014; Milajerdi et al. 2022).

Several factors can affect intestinal barrier integrity, including stress, microbial invasion, and immune responses to infections (Camilleri et al. 2012; Arrieta et al. 2006). Dietary intakes of a person might also be influence to his/her gut permeability. For instance, certain dietary components, such as high-fat or high-sugar diets, have been linked to increased intestinal permeability and inflammation (Khademi et al. 2021; Milajerdi et al. 2020). Conversely, diets rich in fiber and specific nutrients like glutamine are believed to support gut health and maintain barrier function. (Zuhl et al. 2014; Marchbank et al. 2011; Shinget al. 2014; Milajerdiet al. 2021). Glutamine is a key amino acid in the plasma, serving as a primary fuel for enterocytes and immune cells such as leukocytes and T lymphocytes (Zuhl et al. 2014). Research has shown that a deficiency in glutamine can impair the ability of leukocytes to produce cytokines in response to bacterial infections (Yaqoob et al. 1998). In addition, some studies have indicated that pre-exercise glutamine supplementation is associated with decreased serum levels of pro-inflammatory cytokines (Paimela et al. 2011; Dokladny et al. 2010). However, findings regarding the impact of glutamine on gut permeability have been inconsistent. For instance, a 2017 study demonstrated that even low doses of oral glutamine (0.25 g/kg) reduced intestinal permeability, with higher doses showing more pronounced effects (Pugh et al. 2017). Conversely, Beutheu et al. found that glutamine supplementation significantly improved impaired intestinal permeability when used alone, not in combination with other amino acids (Beutheu et al. 2014).

To the best of our knowledge, no systematic review and meta-analysis has been conducted to assess the potential effects of glutamine supplementation on gastrointestinal permeability. Given the importance of intestinal barrier integrity for overall health and the inconsistent results of previous studies, this study aims to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of glutamine supplementation on human gastrointestinal permeability.

Methods

This study was conducted according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) protocol.

Literature search

A systematic search was performed in four databases including PubMed, Scopus, Web of Sciences and Google Scholar until April 2023. We searched for clinical trials investigating the effects of glutamine supplementation on gastrointestinal permeability. The electronic search was conducted using suitable MESH and non-MESH terms: (“Glutamine”[tiab] OR “Fd-dependent glutamate synthase”[tiab] OR “glutamine-glutamate cycle”[tiab] OR “ Glycemic control”[tiab] OR “Glucose oxidation”[tiab] OR “Glutamate transporter”[tiab] OR “Glutamine synthetase”[tiab] OR “glutamate”[tiab] OR “glutathione”[tiab] OR “L-glutamine”[tiab]) AND (“Inflammatory bowel disease”[tiab] OR “Inflammatory bowel diseases”[MESH] OR “Crohn disease”[tiab] OR “Crohn disease”[MESH] OR “colitis, ulcerative”[MESH] OR “ulcerative colitis”[tiab] OR “IBD”[tiab] OR “Crohn’s disease”[tiab]). No limitation in terms of the time and language of publications were applied. We also conducted a manual search in reference lists of all relevant studies to avoid missing any eligible study. The literature was evaluated by two independent reviewers who assessed study quality and extracted data based on predefined criteria. Discrepancies between reviewers were resolved through discussion or by consulting a third reviewer.

Eligibility criteria

We included studies that were: randomized placebo-controlled trials with either crossover or parallel design that measured gut permeability following glutamine supplementation.

Exclusion criteria

we excluded articles if they: (1) were animal studies, reviews, in vitro studies, grey literatures including thesis and conference abstract, and those conducted on children (2), were not placebo-controlled trials (3), did not report enough information on the outcomes of interest (4), examined effects of glutamine along with other interventions.

Data extraction

The following data were extracted from each study: name of the first author, publication year, individuals’ characteristics (mean age, sex), randomization, blinding, sample size (control and intervention groups), dosage of glutamine, duration of intervention, and mean (± SDs) changes of outcomes throughout the trial for intervention and control groups. When data were reported in different units, we converted them to the most frequently used unit.

Study quality

We examined risk of bias for all included studies using the Cochrane quality assessment tool designed for clinical trials (Moher et al., 2009). This tool assesses possible sources of bias in randomized trials considering: random sequence generation, concealment of allocation to conditions, inhibition of awareness of the allocated intervention, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Three selections including yes, no, and unclear were available for each above-mentioned item, which are referred to high risk, low risk, and unknown risk of bias, respectively (Supplementary Table 2).

Statistical analysis

Mean change and standard deviation (SD) of the outcomes were used to estimate the mean differences between intervention and control groups. If data were reported in a different format, SD was calculated using suitable formula (Higgins, 2011; Hozo et al., 2005). We also calculated SD change using the following formula: SD change = square root [(SD baseline 2 + SD final 2) − (2×R× SD baseline× SD final)]. The random effects model (using DerSimonian-Laird method) was used to reach in weighted mean difference (WMD) and 95% CI. We conducted subgroup analyses to identify potential sources of heterogeneity among the studies. The subgroup analyses were performed based on the following factors: Outcome Assessment Method (LMR and 51Cr-EDTA), type of Control group (something other than placebo and placebo), Dosage of glutamine (≥ 30 g/d and < 30 g/d), Duration of study (≥ 4 weeks and < 4 weeks), Sample size (> 20 and ≤ 20), and Adjustment (Not Adjusted and Adjusted). The results of these subgroup analyses are presented in Table 1. All statistical analyses were conducted using the Stata software (Stata Corp. College Station, Texas, USA). To assess publication bias, both the funnel plot and Egger's regression test were employed. Also, to assess the robustness of the findings, we conducted sensitivity analyses. These analyses investigated the influence of each individual study on the overall prospective diagnostic instability by omitting one study at a time. The sensitivity analyses were performed using the user-written "metaninf" function in Stata.

Table 1.

Subgroup analyses for the effects of glutamine supplementation on intestinal permeability

Variables Effect Size, n WMD (95% CI)1 P heterogeneity3 I2 (%)4
Overall Effect 12 −0.00(−0.04, 0.03) < 0.001 83.6%
Outcome Assessment Method
 LMR 10 −0.00 (−0.04, −0.03) < 0.001 86.4%
 51 Cr-Edta 2 0.01 (−0.05, 0.06) 0.6 0.0%
Control
 Something Except Placebo 6 0.0 (−0.01, 0.02) 0.89 0.0%
 Placebo 6 −0.01 (−0.08, 0.06) < 0.001 89.9%
Dosage
 ≥ 30 g/d 5 −0.01 (-0.10, -0.08) < 0.001 91.5%
 < 30 g/d 7 0.0 (-0.01, 0.02) 0.85 0.0%
Duration
 ≥ 4Weeks 5 −0.02 (−0.02, 0.06) 0.172 37.4%
 < 4Weeks 7 −0.03 (−0.04, −0.02) < 0.001 87%
Total Number Code
 > 20 7 0.01 (−0.01, 0.03) 0.212 28.3%
 ≤ 20 5 −0.05 (−0.07, −0.04) < 0.001 84.3%
Adjustment
 Not Adjusted 10 −0.01 (−0.05, 0.03) < 0.001 85.4%
 Adjusted 2 0.02 (−0.01, 0.06) 0.59 0.0%
Open in a new tab

WMD weighted mean difference; LMR; CI confidence interval; 51 Cr-Edta;.

1. Obtained from the fixed-effects model.

2. Refers to the mean (95% CI).

3. Obtained from the Q-test.

4. Inconsistency, percentage of variation across studies due to heterogeneity

PICO framework

To guide the systematic review and meta-analysis, we employed the PICO framework to define the key components of our research question. Population (P) includes adults diagnosed with gastrointestinal conditions such as inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis. Intervention (I) refers to the administration of glutamine supplementation, with various dosages considered. The Comparison (C) involves placebo or no treatment, serving as the control condition to assess the relative effectiveness of glutamine. Finally, the Outcome (O) focuses on intestinal permeability, measured by relevant biomarkers such as the lactulose/mannitol ratio or other indicators of gut barrier function. By clearly delineating these elements, the PICO framework helps in systematically evaluating the effects of glutamine supplementation on gut permeability and ensures that the review addresses all critical aspects of the research question. Detailed information on the PICO framework can be found in Supplementary Table 1.

Results

Study characteristics: A total of 11 studies were included in the current systematic review and meta-analysis. Study selection flow-diagram is presented in Fig. 1. These studies were published from 1998 to 2014. Baseline characteristics of included studies are summarized in Table 2. Total patients enrolled in the included studies were 216 in intervention and 212 in control groups. Mean age of participants was 46.52 years. The health status of the study populations varied across the included studies Table 2. Some studies enrolled participants with Crohn's disease (Benjamin et al. 2012; Den Hond et al. 1999), while others included HIV-positive adults (Leite et al. 2013; Noyer et al. 1998). Additionally, other studies had participants with different health conditions, such as advanced or metastatic cancer (Choi et al. 2007), those admitted for gastrointestinal surgery due to nutritional depletion (Hulsewé et al. 2004), severe acute pancreatitis (Singh et al. 2014), critically ill patients admitted to the surgical intensive care unit who were able to start enteral feeding after at least 4 days of internal fasting (Velasco et al. 2001), abdominal surgical patients without severe disease in the liver, kidney, cardiovascular system, or hemopoietic system (Quan et al. 2004), patients with burn size ranging between 50% and 80% of total body surface area (Zhou et al. 2003) and patients with sepsis and multiple organ dysfunction syndrome (Conejero et al. 2002). Studies investigated effects of glutamine supplementation in different dosages on intestinal permeability.

Fig. 1.

Fig. 1

Open in a new tab

Flow diagram of study selection

Table 2.

General characteristics of included studies

Code/Author (yaer) Subjects and gender Age range (y)
And mean		 Intervention type Duration (week/day) Population health status BMI (kg/m2) Types of studies Outcome Assessment Method Outcome Adjustment or matching
Glutamine Dosage Control
(name and composition) 		Intervention
mean ± SD1 (Change) and number		 Control
mean ± SD (Change) and number

1. Jaya Benjamin et al

(2012)

IN2: 15

CON3: 15

M4:20

F5: 10

Total: 30

IN: 35.1 ± 10.8

CON: 33.9 ± 10.4

 0.5 g/kg6 ideal body weight/day Active control group 8-week Crohn's Disease

IN: 21 ± 2.1

CON: 19.8 ± 2.5

 Parallel LMR7 in urine 0.05 ± 0.4 0.05 ± 0.23 –

2. Kwon Choi et al

(2007)

IN: 22

CON: 29

M: 33

F:18

Total: 51

IN: 54 (26–73)

CON: 54 (26–79)

 30 g/day Best supportive care 15 days Advanced or metastatic cancer

IN: -

CON: -

 Parallel 51 Cr-EDTA8 4.69 ± 16.64 8.54 ± 43.46 –

3. Elly Den Hond et al

(1999)

IN: 7

CON: 7

M:4

F: 10

Total: 14

IN: 25 ± 7.9

CON: 38.2 ± 13.4

 7 g three times per day Placebo 4-week Crohn's Disease

IN: 30.0 ± 2.5

CON: 23.8 ± 3.6

 Parallel 51 Cr-E1DT 0.03 ± 0.06 0.02 ± 0.05 1

4. Karel W.E. Hulsew et al

(2004)

IN:

CON:

M: 15

F: 9

Total: 24

Total: 59.8

IN: -

CON: -

 The amino acid solution was mixed with a glucose 50% solution and a lipid solution Isonitrogenous control solution 8–10 days Admitted for gastrointestinal surgery if they were nutritionally depleted

IN: -

CON: -

 Parallel LMR 0.12 ± 0.03 0.12 ± 0.03 –

5. Robério Dias LEITE et al

(2013)

IN: 22

CON: 24

M: 36

F: 10

Total: 46

IN: 34.18 ± 1.66

CON: 40.13 ± 1.89

 (Alanyl-glutamine) 24 g/day Placebo 10 days HIV positive adults

IN: 22.4 ± 0.8

CON: 22.3 ± 0.7

 Parallel LMR 0.015 ± 0.44 0.02 ± 0.26 –

6. Charles M. Noyer et al

(1998)

IN: 8

CON: 8

M: -

F: -

Total: 16

IN: 40 ± 4

CON: 40 ± 3

 4 g/day Placebo 4 weeks HIV positive adults

IN: -

CON: -

 Parallel LMR 0.09 ± 0.17 0.1 ± 0.08 –

7. Charles M. Noyer et al

(1998)

IN: 8

CON: 8

M: -

F: -

Total: 16

IN: 45 ± 3

CON: 40 ± 3

 8 g/day Placebo 4 weeks HIV positive adults

IN: -

CON: -

 Parallel LMR 0.07 ± 0.04 0.1 ± 0.08 –

8. Namrata Singh et al

(2014)

IN: 41

CON: 39

M:49

F: 31

Total: 80

IN: 40.78 ± 15.5

CON: 35.64 ± 13

 20 g/day 20 g/day Whey protein 7 days Severe acute pancreatitis

IN: -

CON: -

 Parallel LMR 0.001 ± 0.03 0.001 ± 0.06 –

9. Nicola´s Velasco et al

(2001)

IN: 8

CON: 7

M: -

F: -

Total: 15

IN: 49.1 ± 7.4

CON: 48.4 ± 5.2

 0.4 g/kg/day 0.15 g/kg/day glutamine 8 days Admitted to surgical intensive care unit if they were critically ill with at least 4 days of internal fasting and able to start enteral feeding by a nasoduodenal tube or jejunostomy

IN: 25.5 ± 0.9

CON: 26.8 ± 1.1

 Parallel LMR 0.1 ± 0.02 0.07 ± 0.06 2

10. Zhu-Fu Quan et al

(2004)

IN: 10

CON: 10

M: 13

F:7

Total: 20

IN: 48.3 ± 10.8

CON: 48.3 ± 12.2

 30 g/day Placebo 7 days Abdominal surgical patient without any severe disease in liver, kidney, cardiovascular system and hemopoietic system

IN: -

CON: -

 Parallel LMR 83.15 ± 11.56 164.42 ± 29.8 –

11. Ye-Ping Zhou et al

(2003)

IN: 20

CON: 20

M: -

F: -

Total: 40

IN: 43.7 ± 3.8

CON: 40 ± 4.3

 0.5 g/kg/day No glutamine diet 12 days Burn size range between 50% and 80% total body surface burn

IN: 21.4 ± 1.7

CON: 21.3 ± 2.2

 Parallel LMR 0.14 ± 0.2 0.13 ± 0.15 –
12. Ramon Conejero et al (2003)

IN: 43

CON: 33

M: 54

F: 22

Total: 76

IN: 57 (18–85)

CON: 54 (21–58)

 30.5 g/day Placebo 28 days Sepsis, septic shock, and multiple organ dysfunction syndrome

IN: -

CON: -

 Parallel LMR 0.163 ± 0.09 0.109 ± 0.06 –
Open in a new tab

Adjustment: 1. Baseline values, 2. initial LMR.

1. Standard Deviation, 2. Intervention Group, 3. Control Group, 4. Male, 5. Female, 6. Gram/Kilogram, 7. Lactulose/Mannitol Ratio, 8. 51-ethylene diaminetetra-acetate.

In some included studies, placebo was used for control group (Conejero et al. 2002; Hond et al. 1999; Leite et al. 2013; Noyer et al 1998; Zhou et al. 2003), whereas others used active control group (Benjamin et al. 2012), best supportive care (Choi et al. 2007), isonitrogenous control solution (Hulsewé et al. 2004), 20 g/day whey protein (Singh et al. 2014), 0.15 g/kg/day glutamine (Velasco et al. 2001), and no glutamine diet (Quan et al. 2004). Most studies used “Lactulose/Mannitol Ratio” (Conejero et al. 2002; Leite et al. 2013; Noyer et al. 1998; Zhou et al. 2003; Benjamin et al. 2012; Hulsewé et al. 2004; Singh et al. 2014; Velasco et al. 2001; Quan et al. 2004) to assess intestinal permeability, while 2 studies used “51 Cr-E1DT” (Hond et al. 1999; Choi et al. 2007). Two studies justified the baseline value (Hond et al. 1999; Velasco et al. 2001), while the others did not justify their findings for the possible confounders (Conejero et al. 2002; Leite et al. 2013; Noyer et al. 1998; Zhou et al. 2003; Benjamin et al. 2012; Choi et al. 2007; Hulsewé et al. 2004; Singh et al. 2014; Quan et al. 2004) Table 2.

Finding from meta-analysis: Combination 11 effect size from 10 studies, no significant effects of glutamine supplementation on intestinal permeability was found [weighted mean difference (WMD): −0.00, 95% Confidence Interval (CI) −0.04, 0.03] Fig. 2. However, in subgroup analysis we found a significant reduction in gut permeability among studies used glutamine in dosages more than 30 g per day [WMD: −0.01, 95% CI −0.10, −0.08]. In contrast, such significant finding did not support at studies with less than 30 g per day of glutamine [WMD: 0.00, 95% CI −0.01, 0.02]. Interestingly, no significant effect was seen in studies with a duration more than 4 weeks [WMD: −0.02, 95%CI−0.02, 0.06], whereas, interventions lasted maximally 2 weeks had significant reducing effect on intestinal permeability [WMD: −0.03, 95%CI −0.04, −0.02] Table 1.

Fig. 2.

Fig. 2

Open in a new tab

Forest plot illustrating the impact of glutamine supplementation, presented as the mean differences between intervention and control groups. The size of each square corresponds to the inverse of the variance of the weighted mean difference (WMD). Horizontal lines indicate 95% confidence intervals (CIs), while diamonds represent pooled estimates derived from random-effects analysis

Other subgroup analyses showed that studies with a sample size of less than 20 had significant finding [WMD: −0.05, 95%CI −0.07, −0.04]. This finding also was reached among studies used lactulose to mannitol ratio as outcome assessment method [WMD: −0.03, 95%CI −0.04, −0.03] and those used placebo for control group [WMD: −0.01, 95%CI: −0.08, 0.06]. No significant findings were reached in studies used 51 Cr-E1DT method to assess intestinal permeability [WMD: −0.01, 95%CI: −0.05, 0.06], those used other control groups other than placebo [WMD: 0.00, 95%CI −0.01, 0.02], and studies adjusted their findings for the baseline values of gut permeability [WMD: 0.02, 95%CI −0.01, 0.06].

Publication bias was assessed through visual inspection of a funnel plot and Egger's test (significant at p < 0.05; Fig. 3). No evidence of publication bias was found for the relationship between glutamine supplementation and the intestinal permeability (p = 0.460 with Egger's test). In addition, the sensitivity analyses demonstrated that the outliers had no significant impact on the meta-analytical estimates Fig. 4.

Fig. 3.

Fig. 3

Open in a new tab

Funnel plot for the association between glutamine supplementation and intestinal permeability

Fig. 4.

Fig. 4

Open in a new tab

Sensitivity analysis effects of glutamine supplementation on intestinal permeability

Discussion

Current meta-analysis showed no significant effect of glutamine supplementation on gut permeability. However, more than 30 mg/day glutamine significantly reduced intestinal permeability. In addition, this significant reduction was also found when we used glutamine for less than 4 weeks. Glutamine administrated at least for 8 days to a maximum duration of 8 weeks. The minimum duration of 8 days was chosen based on preliminary evidence suggesting that short-term supplementation of glutamine can begin to show measurable effects on gut permeability within this period. This duration ensures that even the shortest interventions are long enough to potentially observe significant physiological changes.

In a recent systematic review on 7 clinical trials investigating “the effect of glutamine supplementation on IBD patients”, no significant result was reached for disease course, anthropometric measurements, and intestinal permeability and morphology in patients with IBD, regardless of the route of administration (Severo et al. 2021). In a randomized control trial on athletes received oral glutamine supplementation 2 h before exercise, glutamine attenuated GI permeability in comparison to placebo, even at lower doses, however, larger doses were more effective (Pugh et al. 2017). Achamrah et al. in a review article in 2017 mentioned that depletion of glutamine in villus, decreased expression of tight junction proteins and increased intestinal permeability. Moreover, they claimed that glutamine supplementation can improve gut barrier function in several experimental injury conditions and in some clinical situations (Achamrah et al. 2017). In another study, early enteral glutamine supplementation led to a declined intestinal permeability in critically ill patients (Shariatpanahi et al. 2019). It seems that the effects of glutamine on gut permeability greatly differ between various patients, in different dosages, and also based on the route of administration. Limitation of relevant studies in this issue, forced us to combine all RCTs of glutamine supplementation and gut permeability. It can be considered as a beginning for the future investigations.

Despite overall findings of our study, we found that short time (less than 2 weeks) glutamine supplementation in higher dosages (> 30 mg/day) had significant reductive effect on gut permeability. It seems that more studies with different dosages of glutamine in different durations are required to reach the best recommendation for this supplementation. In addition, its need to do several studies on different populations and patients to prepare a suitable guideline for glutamine supplementation in those patients.

Glutamine as a non-essential amino acid has a vital role in dividing of epithelial cells in the gastrointestinal tract (Van der Hulst et al. 1996). Depletion of glutamine during infection or illness results in atrophy and hyper-permeability of intestinal epithelial cells (Ueno et al. 2011; Ropeleski et al. 2005). Glutamine has been shown to promote the expression of some proteins in tight junctions, such as occluding and claudins, through which it strengthens the barrier function and reduces gut permeability (Zuhl et al. 2014; Rao and Samak 2013). Moreover, glutamine serves as a vital energy substrate for rapidly proliferating cells, including enterocytes lining the intestinal mucosa. During injuries, infections, or metabolic stresses, the elevated demands for glutamine leads to its depletion and subsequent compromise of intestinal barrier function (Windmueller and Spaeth 1974).

To the best of our knowledge, this study is the first systematic review and meta-analysis evaluating influence of glutamine on gut permeability. Ten randomized control trials were included in this study. However, some limitations should also be taken into account. Limited number of studies were available about the effect of different doses of glutamine on gut permeability in different physiological situations. Moreover, included studies had different sample sizes and duration. Only two studies adjusted their findings for baseline values. Moreover, adjustment for other important confounders, including dietary intakes, medical therapies, hormone receptor status and disease progression were not done in most cases. Finally, we included studies that used oral supplementation of Glutamine, and few studies are available about other routes.

In conclusion, glutamine supplementation in doses of more than 30 mg/day for less than 2 weeks, significantly reduced intestinal permeability. Further studies using different doses of glutamine in different patients are required to reach better conclusion.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 14.4 kb) (14.4KB, docx)
Supplementary material 2 (DOCX 19.6 kb) (19.6KB, docx)

Acknowledgment

None.

Author contributions

Fatemeh Abbasi (F.A), Mohammad mehdi Haghighat-Lari (M.H) and Alireza Milajedi (A.M) wrote the main manuscript text. Elahe Mansouri (E.M) prepared figures and tables. Nastaran Payandeh (N.P) revision data analysis. Mohammad Mehdi Haghighat_Lari (M.H) and Gholamreza Reza Khosravi (G.K) revisions responding sent to the journal. In the end, all authors reviewed the manuscript.

Funding

There was no funding or sponsoring organization for this paper.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors do not declare any conflicts of interest.

Footnotes

Publisher’s Note

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

References

  1. Achamrah N, Déchelotte P, Coëffier M (2017) Glutamine and the regulation of intestinal permeability: from bench to bedside. Curr Opin Clin Nutr Metabolic Care 20(1):86–91 [DOI] [PubMed] [Google Scholar]
  2. Arrieta MC, Bistritz L, Meddings JB (2006) Alterations in intestinal permeability. Gut 55(10):1512–1520 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arike L, Seiman A, van der Post S, Rodriguez Piñeiro AM, Ermund A, Schütte A et al (2020) Protein Turnover in Epithelial Cells and Mucus along the Gastrointestinal Tract Is Coordinated by the Spatial Location and Microbiota. Cell Rep 30(4):1077–87e3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benjamin J, Makharia G, Ahuja V, Anand Rajan KD, Kalaivani M, Gupta SD, Joshi YK (2012) Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn's disease: a randomized controlled trial. Dig Dis Sci 57(4):1000–1012 [DOI] [PubMed] [Google Scholar]
  5. Beutheu S, Ouelaa W, Guérin C, Belmonte L, Aziz M, Tennoune N et al (2014) Glutamine supplementation, but not combined glutamine and arginine supplementation, improves gut barrier function during chemotherapy-induced intestinal mucositis in rats. Clin Nutr 33(4):694–701 [DOI] [PubMed] [Google Scholar]
  6. Camilleri M, Madsen K, Spiller R, van Greenwood Meerveld B, Verne GN (2012) Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil: Off J Eur Gastrointest Motil Soc 24(6):503–512 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Choi K, Lee SS, Oh SJ, Lim SY, Lim SY, Jeon WK et al (2007) The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test. Clin Nutr 26(1):57–62 [DOI] [PubMed] [Google Scholar]
  8. Conejero R, Bonet A, Grau T, Esteban A, Mesejo A, Montejo JC et al (2002) Effect of a glutamine-enriched enteral diet on intestinal permeability and infectious morbidity at 28 days in critically ill patients with systemic inflammatory response syndrome: a randomized, single-blind, prospective, multicenter study. Nutrition 18(9):716–721 [DOI] [PubMed] [Google Scholar]
  9. Den Hond E, Hiele M, Peeters M, Ghoos Y, Rutgeerts P (1999) Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn's disease. JPEN J Parenter Enter Nutr 23(1):7–11 [DOI] [PubMed] [Google Scholar]
  10. Dokladny K, Lobb R, Wharton W, Ma TY, Moseley PL (2010) LPS-induced cytokine levels are repressed by elevated expression of HSP70 in rats: possible role of NF-kappaB. Cell stress chaperones 15(2):153–163 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hallajzadeh J, Milajerdi A, Kolahdooz F, Amirani E, Mirzaei H, Asemi Z (2019) The effects of curcumin supplementation on endothelial function: a systematic review and meta-analysis of randomized controlled trials. Phytother Res 33(11):2989–2995 [DOI] [PubMed] [Google Scholar]
  12. Higgins JP et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj 343:d5928 [DOI] [PMC free article] [PubMed]
  13. Hozo SP et al (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5:13 [DOI] [PMC free article] [PubMed]
  14. Hulsewé KW, van Acker BA, Hameeteman W, van der Hulst RR, Vainas T, Arends J-W et al (2004) Does glutamine-enriched parenteral nutrition really affect intestinal morphology and gut permeability? Clin Nutr 23(5):1217–1225 [DOI] [PubMed] [Google Scholar]
  15. Khademi Z, Milajerdi A, Larijani B, Esmaillzadeh A (2021) Dietary intake of total carbohydrates, sugar and sugar-sweetened beverages, and risk of inflammatory bowel disease: a systematic review and meta-analysis of prospective cohort studies. Front Nutr 8:707795 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Leite RD, Lima NL, Leite CAC, Farhat CK, Guerrant RL, Lima AAM (2013) Improvement of intestinal permeability with alanyl-glutamine in HIV patients. Arq Gastroenterol 50:56–63 [DOI] [PubMed] [Google Scholar]
  17. Madni A, Rehman S, Sultan H, Khan MM, Ahmad F, Raza MR et al (2020) Mechanistic Approaches of Internalization, Subcellular Trafficking, and Cytotoxicity of Nanoparticles for Targeting the Small Intestine. AAPS PharmSciTech 22(1):3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Marchbank T, Davison G, Oakes JR, Ghatei MA, Patterson M, Moyer MP, Playford RJ (2011) The nutriceutical bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes. Am J Physiol Gastrointest liver Physiol 300(3):G477–G484 [DOI] [PubMed] [Google Scholar]
  19. Milajerdi A, Larijani B, Esmaillzadeh A (2020) Metaanalysis on obesity and risk of inflammatory bowel disease: Reanalysis is needed. Obes Rev 21(1):e12965 [DOI] [PubMed] [Google Scholar]
  20. Milajerdi A, Abbasi F, Esmaillzadeh A (2022) A systematic review and meta-analysis of prospective studies on obesity and risk of inflammatory bowel disease. Nutr Rev 80(3):479–487 [DOI] [PubMed] [Google Scholar]
  21. Milajerdi A, Ebrahimi-Daryani N, Dieleman LA, Larijani B, Esmaillzadeh A (2021) Association of dietary fiber, fruit, and vegetable consumption with risk of inflammatory bowel disease: a systematic review and meta-analysis. Adv Nutr 12(3):735–743 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Moher D et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097 [DOI] [PMC free article] [PubMed]
  23. Noyer CM, Simon D, Borczuk A, Brandt LJ, Lee MJ, Nehra V (1998) A double-blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Am J Gastroenterol 93(6):972–975 [DOI] [PubMed] [Google Scholar]
  24. Paimela T, Hyttinen JM, Viiri J, Ryhänen T, Karjalainen RO, Salminen A, Kaarniranta K (2011) Celastrol regulates innate immunity response via NF-κB and Hsp70 in human retinal pigment epithelial cells. Pharmacol Res 64(5):501–508 [DOI] [PubMed] [Google Scholar]
  25. Pugh JN, Sage S, Hutson M, Doran DA, Fleming SC, Highton J et al (2017) Glutamine supplementation reduces markers of intestinal permeability during running in the heat in a dose-dependent manner. Eur J Appl Physiol 117(12):2569–2577 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Quan ZF, Yang C, Li N, Li JS (2004) Effect of glutamine on change in early postoperative intestinal permeability and its relation to systemic inflammatory response. World J Gastroenterol 10(13):1992–1994 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Quan Z-F, Yang C, Li N, Li J-S (2004) Effect of glutamine on change in early postoperative intestinal permeability and its relation to systemic inflammatory response. World J Gastroenterology: WJG 10(13):1992 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rao RK, Samak G (2013) Protection and Restitution of Gut Barrier by Probiotics: Nutritional and Clinical Implications. Curr Nutr Food Sci 9(2):99–107 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ropeleski MJ, Riehm J, Baer KA, Musch MW, Chang EB (2005) Anti-apoptotic Effects of L-Glutamine—Mediated Transcriptional Modulation of the Heat Shock Protein 72 During Heat Shock. Gastroenterology 129(1):170–184 [DOI] [PubMed] [Google Scholar]
  30. Severo JS, da Silva Barros VJ, da Silva ACA, Parente JML, Lima MM, Lima AÂM et al (2021) Effects of glutamine supplementation on inflammatory bowel disease: A systematic review of clinical trials. Clin Nut ESPEN 42:53 [DOI] [PubMed] [Google Scholar]
  31. Shahinfar H, Payandeh N, ElhamKia M, Abbasi F, Alaghi A, Djafari F et al (2021) Administration of dietary antioxidants for patients with inflammatory bowel disease: A systematic review and meta-analysis of randomized controlled clinical trials. Complement Ther Med 63:102787 [DOI] [PubMed] [Google Scholar]
  32. Shariatpanahi ZV, Eslamian G, Ardehali SH, Baghestani A-R (2019) Effects of early enteral glutamine supplementation on intestinal permeability in critically ill patients. Indian J Crit care Med: Peer-Rev Off Publ Indian Soc Crit Care Med 23(8):356 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Singh N, Mishra SK, Sachdev V, Sharma H, Upadhyay AD, Arora I, Saraya A (2014) Effect of oral glutamine supplementation on gut permeability and endotoxemia in patients with severe acute pancreatitis: a randomized controlled trial. Pancreas 43(6):867–873 [DOI] [PubMed] [Google Scholar]
  34. Shing CM, Peake JM, Lim CL, Briskey D, Walsh NP, Fortes MB et al (2014) Effects of probiotics supplementation on gastrointestinal permeability, inflammation and exercise performance in the heat. Eur J Appl Physiol 114(1):93–103 [DOI] [PubMed] [Google Scholar]
  35. Ueno PM, Oriá RB, Maier EA, Guedes M, de Azevedo OG, Wu D et al (2011) Alanyl-glutamine promotes intestinal epithelial cell homeostasis in vitro and in a murine model of weanling undernutrition. Am J Physiol-Gastrointestinal Liver Physiol 301(4):G612–G22 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Van der Hulst R, Von Meyenfeldt M, Soeters P (1996) Glutamine: an essential amino acid for the gut. Nutrition 12(11–12 Suppl):S78–S81 [DOI] [PubMed] [Google Scholar]
  37. Velasco N, Hernandez G, Wainstein C, Castillo L, Maiz A, Lopez F et al (2001) Influence of polymeric enteral nutrition supplemented with different doses of glutamine on gut permeability in critically ill patients. Nutrition 17(11–12):907–911 [DOI] [PubMed] [Google Scholar]
  38. Wang B, Wu G, Zhou Z, Dai Z, Sun Y, Ji Y et al (2015) Glutamine and intestinal barrier function. Amino Acids 47(10):2143–2154 [DOI] [PubMed] [Google Scholar]
  39. Windmueller HG, Spaeth AE (1974) Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 249(16):5070–5079 [PubMed] [Google Scholar]
  40. Yaqoob P, Calder PC (1998) Cytokine production by human peripheral blood mononuclear cells: differential senstivity to glutamine availability. Cytokine 10(10):790–794 [DOI] [PubMed] [Google Scholar]
  41. Zuhl MN, Lanphere KR, Kravitz L, Mermier CM, Schneider S, Dokladny K, Moseley PL (2014) Effects of oral glutamine supplementation on exercise-induced gastrointestinal permeability and tight junction protein expression. J Appl Physiol 116(2):183–191 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zhou YP, Jiang ZM, Sun YH, Wang XR, Ma EL, Wilmore D (2003) The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe burns: a randomized, double-blind, controlled clinical trial. JPEN J Parenter Enter Nutr 27(4):241–245 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material 1 (DOCX 14.4 kb) (14.4KB, docx)
Supplementary material 2 (DOCX 19.6 kb) (19.6KB, docx)

Data Availability Statement

No datasets were generated or analysed during the current study.

Articles from Amino Acids are provided here courtesy of Springer

RESOURCES