380 Asia Pac J Clin Nutr 2012;21 (3):380-385
Glutamine for chemotherapy induced diarrhea: a meta-
Juxian Sun MD1, Hui Wang MD2, Heping Hu MD2
1Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical
University, Shanghai, China
2Department of Liver disease, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical
University, Shanghai, China
The clinical efficacy of glutamine in the control of chemotherapy-induced diarrhea remains controversial. We
conducted a meta-analysis, including as many randomized control trails (RCTs) as possible, to clarify the effec-
tiveness of prophylactic glutamine in patients requiring chemotherapy. Methods: the Embase, MEDLINE, Coch-
rane Library, and BIOSIS databases were searched, and the included studies were RCTs that compared the use of
prophylactic glutamine versus placebo in patients receiving chemotherapy. The main outcomes were diarrhea se-
verity and duration. Results: a total of 298 patients in eight RCTs were reviewed (147 patients who received
glutamine, and 151 patients who received placebo). There was a statistically significant difference in the duration
of diarrhea (weighted mean difference (WMD), -1; 95% confidence interval (CI), -1.73, -0.26) between the two
groups, but there was no significant difference in the severity of diarrhea (WMD, -0.49; 95% CI, -1.36, 0.39) be-
tween the groups. Conclusion: we concluded that glutamine could reduce the duration of diarrhea but could not
improve its severity.
Key Words: glutamine, diarrhea, chemotherapy, meta-analysis, prophylactic
Most commonly, chemotherapy is a systemic therapy,
which means that it affects the entire body via the blood-
stream. Chemotherapy targets rapidly dividing cells,
meaning that it also harms normal cells with high turn-
over rates such as those lining the digestive tract. Many of
the major adverse effects of chemotherapy are related to
the loss of the mucosal integrity of the gut epithelium,
which might be associated with increased risks of bac-
teremia and endotoxemia.1,2 The primary clinical mani-
festation of this adverse effect is diarrhea. To prevent
chemotherapy-induced diarrhea and improve the quality
of life of patients, it is important to promptly provide
powerful treatment. Traditionally, medical treatment of
chemotherapy-induced diarrhea has included the use of
nonspecific agents, such as the opiate preparations pare-
goric, atropine, and loperamide.
Glutamine is the major energy source for rapidly divid-
ing cells such as enterocytes3 and plays important roles in
gut integrity and immunologic responses. It might be use-
ful in healing the gastrointestinal mucosa after chemo-
therapy-induced damage and may ameliorate the clinical
manifestation of this damage.4 In addition, a number of
clinical studies have attempted to clarify its anti-diarrheal
However, the clinical efficacy of glutamate in the con-
trol of chemotherapy-induced diarrhea remains controver-
sial; some investigators have reported the efficacy of
glutamine in alleviating diarrhea to be disappointing,1, 5, 8-
12 whereas others found it to be ineffective.2,13 The com-
mon shortcoming of these studies has been small sample
sizes, making these trials less representative. Therefore,
we conducted the current meta-analysis, including as
many randomized control trails (RCTs) as possible, to
clarify the effectiveness of prophylactic glutamine in pa-
tients requiring chemotherapy. Bone marrow transplant
(BMT) patients were also included in our protocol.
A meta-analysis of relevant RCTs comparing the effects
of glutamine and placebo on chemotherapy-induced diar-
rhea was undertaken. The Embase, MEDLINE, Cochrane
Library, and BIOSIS databases were searched using the
following combinations of search terms: glutamine/Gln,
chemotherapy or BMT, diarrhea, RCTs, and human sub-
jects. Only studies written English or Chinese were
searched. The papers were retrieved to identify relevant
studies for inclusion in the meta-analysis.
The criteria for inclusion in the meta-analysis were as
follows: the patients were randomized; the groups dif-
fered in that one group received glutamine and the other
group served as control; and the results were reported
clearly. All studies were examined to identify parameters
Corresponding Author: Dr Heping Hu, Department of Liver
disease, Eastern Hepatobiliary Surgery Hospital, The Second
Military Medical University, No.225 Changhai Road, Shanghai,
Tel: +862181875254; Fax: +862165566851
Manuscript received 7 October 2011. Initial review completed
18 January 2012. Revision accepted 29 February 2012.
Glutamine for post-chemotherapy diarrhea 381
that could be compared. The data were extracted from the
text and tables within the studies. Data from the studies
were independently examined by the authors of this study.
If data were not available in the original publication, the
authors of those studies were contacted via email to re-
quest this information.
The eligible studies were graded using a 5-point scale
in which a score of 1 was given for each of the following
components, as described by Jadad et al14: the description
of the study as randomized; the description of an appro-
priate method of randomization; the description of the
study as double-blind; the description of an appropriate
method of double-blinding; and a statement of withdraw-
als. As non-randomized studies were excluded, the mini-
mum score was 1, and the maximum score was 5. All
studies were scored individually, compared and discussed
where the scores were different. We were able to compare
the therapeutic results between the studies.
Quantitative analyses were performed using Review
Manager software (RevMan for Windows, version 5.0;
The Cochrane Collaboration, Oxford, UK, 2008), which
calculates the odds ratio for dichotomous data or the
weighted mean differences (WMDs) for continuous data
between the experimental and control groups for each
study, with an overall estimate of the pooled effect. Re-
view Manager was used to perform heterogeneity analy-
ses; data that were not significantly heterogeneous
(p>0.05) were analyzed using a fixed effects model, and
heterogeneous data (p<0.05) were analyzed using a ran-
dom effects model.
There were 20 English research studies identified by our
search strategies. All full-text articles were reviewed.
Finally, eight studies2,5,8-13 were included in the meta-
analysis. A total of 298 patients were included in these
eight RCTs: 147 patients received glutamine, and 151
patients received placebo. The characteristics of the in-
cluded studies are shown in Table 1. Based on the overall
results of the meta-analysis, we found that glutamine
nificantly reduced the duration of diarrhea compared with
placebo (WMD, −1; 95% confidence interval (CI), −1.73,
−0.26; Figure 1). In the subgroup analysis, we found that
oral glutamine significantly reduced the duration of diar-
rhea (WMD, −1.06; 95% CI, −2.01, −0.11; Figure 1), but
intravenous glutamine was ineffective in this regard
(WMD, −0.89; 95% CI, −2.07, 0.28; Figure 1).
The common toxicity criteria grades for diarrhea were
defined as follows: grade 0, none; grade 1, increase of <4
stools/day over pretreatment; grade 2, increase of 4–6
stools/day or nocturnal stools; grade 3, increase of >7
stools/day, incontinence, or the need for parenteral sup-
port for dehydration; and grade 4, physiological conse-
quences requiring intensive care or hemodynamic col-
lapse. Our findings suggested that glutamine could not
improve the severity of diarrhea (WMD, −0.49; 95% CI,
−1.36, 0.39; Figure 2). Statistical heterogeneity was iden-
tified for overall rates (p<0.00001), and thus, a random
effects model was utilized (p<0.00001).
It has been proven that chemotherapy can induce bacterial
translocation and intestinal barrier dysfunction in animal
studies.15 Glutamine is the most abundant free amino acid
in the human body, and it is essential for the growth of
normal and rapidly proliferating cells. Maintaining the the
integrity of the intestine.13,16 During episodes of cata-
bioenergetics of these cells is fundamental to maintaining
Table 1. Controlled prospective trials of the effects of glutamine on chemoradiotherapy-induced diarrhea
Li Y et al2
(Jadad score 4)
Gln§ 20 g/d I.V¶
Sornsuvit C et al5
(Jadad score 2)
T 8 Gln 30 g/d I.V
P 8 1.1± 1.4 4.3±5.7
Pytlík R et al8
(Jadad score 4)
T 21 Gln 20 g/d I.V
P 19 NA 4.3±3
Daniele B et al13
(Jadad score 4)
Gln 18 g/d Oral
Coghlin Dickson TM
et al 9
(Jadad score 4)
Bozzetti F et al12
(Jadad score 2)
T 29 Gln 30 g/d Oral
P 29 Placebo NA 3±2.25
Gln 30 g/d I.V
Jebb SA et al11
(Jadad score 2)
van Zaanen HC et al10
(Jadad score 2)
Data are shown as the mean ± SD; †T, treatment; ‡P, placebo; §Gln: Glutamine; ¶IV: Intravenously; ††d, days.
Gln 16 g/d Oral
Gln 40 g IV
1994 3 weeks
382 J Sun, H Wang and H Hu
bolic stress, there is a marked intracellular depletion of
Glutamine has been demonstrated in numerous studies
to reduce intestinal permeability, which can be increased
by chemotherapy.2,18 Therefore, we believe that glutamine
would be effective for controlling chemotherapy-induced
diarrhea. However, the effects of glutamine in patients
with diarrhea induced by chemotherapy remain contro-
versial. Many RCTs have discussed this topic, but the
findings have been inconsistent for a number of reasons.
Thus, we conducted this meta-analysis, which included
eight RCTs, to clarify this issue. In this study, we con-
cluded that glutamine can reduce the duration of diarrhea,
but it could not improve its severity.
Li et al.2 evaluated the use of glutamine for chemother-
apy-induced diarrhea in gastrointestinal cancer patients in
a randomized cross-over study. In this study, patients
with gastric or colorectal cancer who exhibited grade 2 or
higher side effects according to the WHO side-effect
grading system were randomly assigned to receive a dose
of 20 g of glutamine or placebo intravenously. According
to their findings, glutamine reduced plasma endotoxin
levels and the severity of diarrhea. One serious concern of
this trial was that endotoxin levels were used to assess
intestinal permeability instead of the lactulose-mannitol
test. Another clinical study1 conducted by this group
demonstrated that oral glutamine could not ameliorate
stomatitis and diarrhea, although it did reverse chemo-
therapy-induced increases in intestinal permeability.
Sornsuvit et al 5 used a somewhat higher dose of
glutamine (30 g, IV) for diarrhea prevention in acute
myeloid leukemia patients receiving chemotherapy. The
prophylactic use of glutamine did not significantly reduce
the severity or duration of diarrhea, although it enhanced
neutrophil phagocytic function and maintain nutritional
status. However, this study only included eight patients in
each group, which decreased its reliability.
A study by Pytlík et al.8 evaluated the effects of gluta-
mine in autologous transplant patients. Their study was a
randomized trial of 20 g per day of parental glutamine
given at the start of chemotherapy. Although patients in
the glutamine group had a longer hospital stay, more se-
vere oral mucositis, and a more costive condition, they
had fewer days with diarrhea. In addition, this study in-
cluded a heterogeneous patient population. Other studies
also discussed the use of glutamine in BMT patients;
however, we were primarily concerned with its diarrhea-
preventing effects. Despite the mostly disappointing re-
sults, the data from these studies tended to support the
idea that parenteral glutamine supplementation reduced
the duration of diarrhea. The small number of patients in
these trials is a possible cause of the lack of significant
Bozzetti et al 12 assessed the efficacy of glutamine in
Figure 1. Meta-analysis of the duration of diarrhea in randomized controlled trials comparing glutamine and placebo. The results revealed a
benefit of glutamine in reducing the duration of diarrhea, particularly in the oral glutamine subgroup. CI, confidence interval. Chi2, Chi-
Figure 2. Meta-analysis of diarrhea scores in randomized controlled trials comparing glutamine and placebo. The results indicated that
glutamine did not improve the severity of diarrhea. CI, confidence interval. Chi2, chi-square.
Glutamine for post-chemotherapy diarrhea 383
preventing doxifluridine-induced diarrhea in a double-
blind randomized trial including 65 patients. Patients re-
ceived 30 g of glutamine per day (divided into three doses
of 10 g each) or placebo for 8 consecutive days between
chemotherapy. The glutamine group tended to have fewer
days with diarrhea. Although this article assessed the se-
verity of diarrhea in these patients, no accurate data were
found or calculated, and thus, we were unable to include
the data of this study in Figure 2.
Daniele et al 13 evaluated the efficacy of glutamine in
preventing FU(fluorouracil)-induced intestinal toxicity in
a double-blind, placebo-controlled, randomized trial. Pa-
tients treated with fluorouracil were randomly assigned to
receive either 18 g of oral glutamine per day or placebo 5
days before chemotherapy. Though the duration and se-
verity of diarrhea were not statistically different between
the two groups, the researchers found that glutamine
could prevent FU-induced changes in intestinal absorp-
tion and permeability, supporting the protective effect of
glutamine on chemotherapy-induced diarrhea.
The four randomized controlled trials 2,5,10,13 assessing
the effects of glutamine on the severity of diarrhea dif-
fered significantly from each other, suggesting that com-
bining them for statistical analysis may not be valid.
These trials differed in terms of the internalizing standard,
the doses used, and the routes and duration of glutamine
administration. Ultimately, our results were disappointing.
We cannot precisely explain why glutamine decreased
the duration of diarrhea without improving its severity,
but a possibility is that although glutamine could not pre-
vent the death of enterocytes induced by chemotherapy, it
did accelerate mucosal regeneration. Leitão et al 19 also
revealed that glutamine accelerates mucosal recovery,
increasing mucosal tissue glutathione stores and hasten-
ing re-epithelization. Other mechanisms by which gluta-
mate improves gastrointestinal toxicity have been investi-
gated, such as its down regulation of Toll-like receptor-4
and myeloid differentiation gene 88 expression and im-
provement of intestinal recovery after intestinal mucosal
damaged caused by LPS endotoxemia.20
In the subgroup analysis, oral glutamine, but not intra-
venous glutamine, significantly reduced the duration of
diarrhea. This finding does not appear to be related to the
small numbers of clinical trials and patients included in
this meta-analysis It is well established that the presence
of food in the gut lumen is an important stimulus for mu-
cosal cell growth, and MacFie21 reported that the energy
source of enterocytes was primarily located in the intesti-
nal lumen and not in blood. Glutamine can exert an atro-
phic effect on mucosal cells, and oral glutamine reduced
the severity of enterocolitis induced by toxic doses of
methotrexate in rats.22 Another paper reported that intra-
venous glutamine could not preserve small-bowel muco-
sal height.23 The aforementioned reason might be the
cause of this finding, but there is not sufficient clinical
evidence to support the view that oral glutamine would be
better. Additional clinical trials comparing the effects of
oral and intravenous glutamine on chemotherapy-induced
diarrhea are necessary.
Studies have provided limited evidence that glutamine
supplementation has a benefit for patients with radiation-
induced diarrhea.24 Studies of high-quantity with large
sample sizes should be conducted in the future; however,
glutamine should not be used at present to prevent diar-
rhea during radiotherapy, but this agent can be adminis-
tered prophylactically to patients receiving chemotherapy.
It can reduce the duration of diarrhea, thus reducing hos-
Human hepatoma cells consume glutamine at a 5–10-
fold faster rate than normal hepatocytes.25 This finding
indicated that parental glutamine would stimulate tumor
growth. However, RCTs revealed that glutamine did not
have any impact on the tumor response to chemother-
Allocation concealment, an important source of bias,
was commonly unclear, whereas many studies did not
utilize double-blinding. Negative studies are less likely to
be submitted or accepted for publication, and consider-
able variation can exist between studies in terms of inter-
ventions and clinical circumstances. Quantitative meta-
analyses are limited by heterogeneity in study design and
small study sizes. However, despite these weaknesses,
meta-analysis is considered a reliable source of evidence.
Furthermore, a large, well-designed, prospective, random-
ized trial is necessary to confirm these findings.
We concluded that glutamine could reduce the duration of
diarrhea, but it could not improve its severity.
The authors report no conflicts of interest.
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