Introduction
Crohn's disease is a chronic gastrointestinal
disease mainly related to eating habits and autoimmune function,
and clinical statistical analysis found that the incidence of this
disease in China is increasing (1–3). Crohn's
disease can cause systemic symptoms, such as lesions in mouth,
eyes, skin, and gastrointestinal tract. Occurrence site of Crohn's
disease is mainly the gastrointestinal tract, and highest incidence
is found in ileum and colon (4,5).
Clinically, Crohn's disease is mainly treated with antibiotics,
immunosuppressive agents and other drugs (6–9).
Antibiotics may cause the development of intestinal flora
resistance, and the immunosuppressive agents are not affordable for
most patients. At present, probiotics and glucocorticoid are
incresingly widely used to treat this disease (2,10,11). In
this study, probiotics combined with glucocorticoid therapy was
used to treat Crohn's disease. The clinical treatment effects were
observed and compared.
Patients and methods
Materials
A total of 83 patients with Crohn's disease were
selected from March 2015 to December 2017 in PLA Army General
Hospital (Beijing, China). Patients were randomly divided into the
control group and treatment group. The treatment group included 23
males and 20 females, with an average age of 43.43±5.43 years and
an average disease duration of 2.12±1.09 years. The control group
included 20 males and 20 females, with an average age of 48.43±5.43
years and an average disease duration of 2.01±1.02 years. The
healthy group included 19 males and 21 females, with an average age
of 44.76±4.99 years. There was no significant difference between
the three groups in general information such as age, sex and
disease duration.
Inclusion criteria were: patients who met the
criteria for ‘diagnosis and treatment of inflammatory bowel
disease’; patients who were not suffering from heart, liver or
other vital organ injuries; patients without mental diseases;
patients who could cooperate with the researchers.
Exclusion criteria were: patients who were allergic
to probiotics and glucocorticoids; patients who were pregnant or in
lactation; patients with other intestinal diseases.
The study was approved by the Ethics Committee of
PLA Army General Hospital (Beijing, China). Patients who
participated in this study, signed an informed consent and had
complete clinical data. Signed informed consents were obtained from
the patients or guardians.
Methods
Patients in the control group were treated with
routine treatment of oral sulfasalazine at a dose of 1 g each time,
4 times per day. Besides oral sulfasalazine, patients in the
treatment group were treated with probiotics combined with
glucocorticoids. Probiotics: Bifidobacterium Lactobacillus
triple tablets, at the dose of 4 × 500 mg per time, 2 times per
day. Glucocorticoids: prednisone, at the initial dose of 0.75–1.0
mg/kg/day and gradually stopped in3-4 months.
Efficacy evaluation and observation
indicators
The levels of inflammatory cytokines C-reactive
protein (CRP, TNF-α and IL-10) were measured before and after
treatment. The inflammatory cytokines were determined by using
ELISA kit (Beyotime, Shanghai, China).
Determination of intestinal flora: fresh feces was
collected from patients and healthy individuals, and yeast,
peptococcus, lactobacilli and enterococci were
isolated, cultured and detected.
Clinical efficacy: recovery, clinical symptoms and
signs disappeared after treatment, stool routine examination was
negative, microscopic ulcer was healed, mucosal recovery was
observed; markedly effective, clinical symptoms and signs
disappeared after treatment, stool routine examination was
negative, microscopic ulcer was mostly healed; effective, clinical
symptoms and signs disappeared after treatment, stool routine
examination was negative and mild inflammation was observed by
microscopic examination; ineffective, clinical symptoms and signs
were not improved or aggregated. Total effective rate = (recovered
cases + apparent effective cases + effective cases)/total number
×100%.
Statistical analysis
Statistical software SPSS 17.0 (SPSS Inc., Chicago,
IL, USA) was used to analyze the data. Enumeration data were
expressed as mean ± standard deviation. Enumeration data were
recorded as a number. Comparison between multiple groups was done
using One-way ANOVA test followed by a post hoc test (Least
Significant Difference). P<0.05 was considered to indicate a
statistically significant difference.
Results
Comparison of general clinical data
between the two groups of patients
There were 23 males and 20 females in the treatment
group, including 19 patients with ileocolic, 17 patients with
ileum, 7 patients with colon, and 21 patients with stenosis and 15
patients with penetration type and 7 patients with non-penetration
type. There were 20 males and 20 females in the control group,
including 15 patients with ileocolic, 16 patients with ileum, 9
patients with colon, and 19 patients with stenosis and 14 patients
with penetration type and 7 patients with non-penetration type.
There was no significant difference in sex, lesion location and
type of lesion between the two groups (Table I).
 | Table I.Comparison of general clinical data
between two groups of patients (n). |
Table I.
Comparison of general clinical data
between two groups of patients (n).
|
|
| Sex | Lesion
localization | Lesion type |
|---|
|
|
|
|
|
|
|---|
| Groups | Cases | Male | Female | Ilecolon | Ileum | Colon | Stenosis | Penetration type | Non-penetration
type |
|---|
| Treatment | 43 | 23 | 20 | 19 | 17 | 7 | 21 | 15 | 7 |
| Control | 40 | 20 | 20 | 15 | 16 | 9 | 19 | 14 | 7 |
Comparison of inflammatory cytokines
between the two groups of patients
Before treatment, the levels of CRP, TNF-α and IL-10
in the treatment group were 13.39±0.93 ng/ml, 2.45±0.21 ng/ml and
14.35±1.67 pg/ml, respectively. No significant differences in the
levels of CRP, TNF-α and IL-10 were found between the two groups.
After treatment, the levels of these inflammatory factors in both
groups were significantly decreased, and the levels of the
inflammatory factors in the treatment group were significantly
lower than those in the control group (P<0.05). The levels of
the inflammatory factors in the treatment group reached the levels
of that in the control group (Table
II).
| Table II.Comparison of inflammatory cytokines
between two groups of patients (mean ±SD). |
Table II.
Comparison of inflammatory cytokines
between two groups of patients (mean ±SD).
| Groups | Time-points | CRP (ng/ml) | TNF-α (ng/ml) | IL-10 (pg/ml) |
|---|
| Treatment | Before treatment | 13.39±0.93 | 2.45±0.21 | 14.35±1.67 |
|
| After treatment | 7.21±0.89 | 0.72±0.08 | 10.23±1.86 |
|
| P valuea | <0.001 | <0.001 | <0.001 |
| Control | Before treatment | 13.51±1.21 | 2.61±0.21 | 14.98±1.45 |
|
| After treatment | 10.56±1.09 | 1.72±0.11 | 13.25±1.75 |
|
| P valueb | <0.001 | <0.001 | <0.001 |
|
| P valuec | <0.001 | <0.001 | <0.001 |
| Healthy
individuals |
| 6.23±0.65 | 0.69±0.08 | 9.81±0.99 |
|
| P valued | <0.001 | <0.001 | <0.001 |
Comparison of intestinal flora between
the groups of patients and healthy individuals
Before treatment, no significant differences in
number of yeast, enterococci, lactobacilli and
peptococcus intestinal flora were found between the two
groups. After treatment, the levels of yeast, enterococci
and peptococcus of the groups of patients were significantly
decreased, while the level of lactobacillus was
significantly increased in both groups, and the changes were more
significant in the treatment group than those in the control group.
After treatment, the number of intestinal flora in the treatment
group reached that of the healthy individuals (Table III).
| Table III.Comparison of intestinal flora between
two groups of patients and healthy individuals (mean ±SD). |
Table III.
Comparison of intestinal flora between
two groups of patients and healthy individuals (mean ±SD).
| Groups | Time-points | Yeast |
Enterococci |
Lactobacilli |
Peptococcus |
|---|
| Treatment | Before treatment | 2.23±0.21 | 6.73±0.65 | 5.63±0.53 | 6.23±0.63 |
|
| After treatment |
1.03±0.01a |
5.32±0.43a |
8.31±0.82a |
3.89±0.32a |
| Control | Before treatment | 2.42±0.21 | 6.79±0.62 | 5.73±0.51 | 6.29±0.61 |
|
| After treatment |
1.59±0.12a,b |
6.21±0.60a,b |
6.93±0.62a,b |
5.79±0.59a,b |
| Healthy
individuals |
| 0.92±0.08 | 5.24±0.52 | 8.23±0.80 | 3.93±0.34 |
Comparison of clinical efficacy of the
two groups of patients
In the treatment group, 15 patients recovered, 21
were markedly effective, 6 were effective, and the total effective
rate was 97.6%. In the control group, 8 patients recovered, 15 were
markedly effective, and 11 patients were effective, and the total
effective rate was 85.3%. Therapeutic efficiency of the the
treatment group was significantly higher than that of the control
group (P<0.05) (Table IV).
| Table IV.Comparison of clinical efficacy of two
groups of patients (n). |
Table IV.
Comparison of clinical efficacy of two
groups of patients (n).
| Groups | Cases | Recovery | Markedly
effective | Effective | Ineffective | Total effective
rate (%) |
|---|
| Treatment | 43 | 15 | 21 | 6 | 1 | 42 (97.6) |
| Control | 40 | 8 | 15 | 11 | 6 | 34
(85.3)a |
Comparison of incidence of infection
between the two groups of patients
In the treatment group, 8 patients developed
infectious abdominal distension and diarrhea, 9 patients developed
abdominal abscess, 4 patients developed pulmonary infection, 1
patient developed sepsis, and the overall incidence was 51.1%. In
the control group, 12 patients developed infectious abdominal
distension and diarrhea, 11 patients developed abdominal abscess, 8
patients developed pulmonary infection, 5 patients developed
sepsis, and the overall incidence was 92.7%. The infection rate of
the control group was significantly higher than that of the
treatment group (P<0.05) (Table
V).
| Table V.Comparison of incidence of infection
between two groups of patients (n). |
Table V.
Comparison of incidence of infection
between two groups of patients (n).
| Groups | Cases | Infectious
abdominal distension and diarrhea | Abdominal
abscess | Pulmonary
infection | Sepsis | Incidence (%) |
|---|
| Treatment | 43 | 8 | 9 | 4 | 1 | 22 (51.1) |
| Control | 40 | 12 | 11 | 8 | 5 | 36
(92.7)a |
Discussion
Crohn's disease is an inflammatory bowel disease
that can cause serious complications of infection. Antibiotics are
generally used in the treatment of Crohn's disease, while long-term
use of antibiotics may lead to the development of resistance, which
in turn may affect treatment outcomes (12,13). In
this study, probiotics combined with glucocorticoid was used to
treat Crohn's disease, so as to explore the clinical efficacy of
this treatment effect and the impact on intestinal flora.
Treatment with probiotics is safe for the intestine,
and can provide nutrients for the intestine, improve the level of
intestinal flora and maintain the balance of flora (14,15).
Glucocorticoids can rapidly diffuse into the cytoplasm after
entering the body and bind to hormone receptors in cells.
Glucocorticoid can bind to corresponding reactants and activate the
expression of relevant genes to exert anti-inflammatory effects
(16,17).
TNF-α as the major inflammatory and immune function
factor in the body is mainly produced by activated monocytes and
megakaryocytes. When inflammation occurs, the level of TNF-α
significantly increases, thereby inducing the secretion of a
variety of inflammatory factors and adhesion molecules. IL-10 as an
important inflammatory factor in Crohn's disease is mainly produced
by activated monocytes. IL-10 inhibits the secretion of
inflammatory mediators by monocytes, and has a strong
anti-inflammatory effect. In Crohn's disease, intestinal flora is
imbalanced mainly due to the proliferation of yeast. At the same
time, the numbers of enterococcus and peptococcus
were significantly increased, while the number of
lactobacillus was decreased, seriously affecting the
intestinal digestive function (18,19).
This study showed that the effective rate of the
treatment group was significantly higher than that of the control
group (97.6 vs. 85.3%), indicating the use of probiotics combined
with glucocorticoid treatment can improve treatment effect and
effectively alleviate clinical symptoms. After treatment, the
levels of inflammatory factors in the treatment group were
significantly lower than those in the control group. After entering
the human body, probiotics can improve intestinal damage, protect
intestinal wall permeability, thereby reducing the levels of
proinflammatory substances such as inflammatory cytokines and
endotoxin in lamina propria, thereby inhibiting inflammation.
Glucocorticoids reduce the secretion of arachidonic acid, which is
a proinflammatory precursor in the body, thereby inhibiting the
production and secretion of inflammatory cytokines. After
treatment, intestinal flora was improved, the levels of yeast,
enterococci and peptococcus were significantly
decreased, and the level of lactobacillus was increased. The
improvement is more significant in the treatment group than that in
the control group, indicating the probiotics combined with
glucocorticoid treatment can play a better role than conventional
methods in protecting intestinal flora. Results also showed that
probiotics combined with glucocorticoid treatment can reduce the
incidence of infection, abdominal distension, diarrhea and other
side effects.
In conclusion, the use of probiotics combined with
glucocorticoid in the treatment of Crohn's disease can improve
clinical efficacy, reduce infection rate, improve the protective
effect of intestinal flora, and effectively control the production
and secretion of inflammatory cytokines. Therefore, this treatment
should be popularized in clinical practice.
Acknowledgements
Not applicable.
Funding
This study was supported by National Science and
Technology Support Program (2014BAI09B05) and The Special Fund of
Capital Health Research and Development (starting fund no.
2018-1-5091).
Availability of data and materials
The datasets used and/or analyzed during the present
study are available from the corresponding author on reasonable
request.
Authors' contributions
HS, QK and RF conceived and designed the
experiments, and performed the statistical analysis. HS, QK and HW
performed most of the experiments. HS contributed to the writing of
the manuscript. QK and HW helped to draft the manuscript. HY, LD
and YL contributed to the acquisition of data. All the authors have
read and approved the final version of this study.
Ethics approval and consent to
participate
The study was approved by the Ethics Committee of
PLA Army General Hospital (Beijing, China). Patients who
participated in this study, signed an informed consent and had
complete clinical data. Signed informed consents were obtained from
the patients or guardians.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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