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Abstract

Objective: To investigate the clinical value of Clostridium butyricum powders combined with zinc gluconate in the treatment of infectious diarrhea in children, clinical data of 86 children with infectious diarrhea were retrospectively analyzed. Methods: Both groups received routine treatments to reduce symptoms, among which the control group (n = 40) was given Clostridium butyricum powders, and the experiment group (n = 46) was given Clostridium butyricum powders and zinc gluconate. Patients in both groups were treated for 5 days. The clinical efficacy, recovery time, safety, serum levels of inflammatory markers (interleukin-6, interleukin-17, C-reactive protein), indicators of the intestinal mucosal function (diamine oxidase, D-lactate) and indicators to intestinal microecology (bifidobacteria, lactobacillus) before and after treatment were compared between the two groups. Results: The clinical efficacy in the experiment group (95.65%) was higher than that in the control group (77.50%, p < 0.05). The time of recovery from symptoms including diarrhea, abdominal pain and vomiting, and to normal body temperature in the experiment group were shorter than those in the control group (all p < .001). After treatment, the serum IL-6, IL-17, CRP levels and DAO, D-lactate levels in both groups were lower than those before treatment, and were lower in the experiment group than in the control group (all p < .001). After treatment, the intestinal bifidobacteria and lactobacillus levels in both groups were higher than those before treatment, and were higher in the experiment group than in the control group (all p < .01). There was no significant difference in the incidence of adverse reactions between the experiment group (8.70%) and the control group (2.50%). Conclusion: In this open-label study, Clostridium butyricum powders combined with zinc gluconate are significantly effective in treating children with infectious diarrhea, which is conducive to relieving early symptoms, downregulating serum inflammatory factor levels, improving intestinal mucosal function, regulating intestinal microecology, and ensuring the safety of patients.

Keywords

Infectious diarrhea clostridium butyricum powders zinc gluconate inflammatory factor

Introduction

Infectious diarrhea is a common disease frequently occurring in pediatrics. Long-term diarrhea can lead to pediatric malnutrition, poor growth and development, severe dehydration or electrolyte imbalance and is even life- and health-threatening. Its prevention and treatment have been widely drew attention from clinical pediatricians.¹ At present, fluid replacement, antidiarrheal, antibacterial or antiviral methods are mostly adopted to treat pediatric infectious diarrhea in western medicine. However, some children still present some symptoms of digestive disorders after treatment, affecting growth and development, and the reasons may be related to intestinal microecological disorders and dysbacteriosis caused by multiple factors such as diarrhea and treatment of anti-infection.² Therefore, in the treatment of infectious diarrhea in children, it is of vital importance to supplement probiotics, regulate bacterial metabolism, correct intestinal microecological disorders, and reconstruct intestinal natural protective barriers.³ In addition, zinc, as an essential trace element for human body, has multiple effects, including promoting growth and development, improving immune function and mucosal function.⁴ Studies have pointed out that blood zinc levels in children with diarrhea are significantly lower than those in healthy ones, suggesting that diarrhea is closely related to zinc deficiency. Diarrhea can lead to zinc deficiency, and vice versa, so zinc supplementation is particularly important in the treatment of diarrhea.⁵

Clostridium butyricum powders have multiple effects such as promoting intestinal mucosal repair and regeneration, nourishing intestinal tract, eliminating inflammation, and regulating intestinal bacteria balance, which is beneficial for restoring normal physiological function of the intestine.⁶ Study of Fu et al. has shown that the application of Clostridium butyricum powder plus antidiarrheal in the treatment of infectious diarrhea in children can significantly improve efficacy, accelerate the improvement of symptoms, effectively reduce the level of serum inflammatory factors, and is safer.⁷ Zinc gluconate can meet the needs of the human body for zinc, promote the repair of damaged intestinal mucosa, enhance intestinal absorption of water and nutrients, improve immunity, and enhance disease resistance.⁸ Study of Zhang et al. has shown that conventional treatment combined with zinc gluconate in the treatment of infantile diarrhea can improve clinical efficacy, relieve symptoms, and strengthen the function of humoral immunity, cellular immunity, and red blood cell immunity. These results suggest that adjuvant therapy with the drugs mentioned above can improve the clinical efficacy in children with diarrhea.⁹ A study by Guo et al. has shown that Clostridium butyricum powders combined with zinc gluconate have a prominent effect in treating acute diarrhea in children, which can effectively improve symptoms and reduce inflammatory responses, thereby reducing the pain of children.¹⁰ However, its effects on intestinal mucosal function and intestinal bacteria have not been reported. It has also been reported in a study that the treatment of antibiotic-associated diarrhea with Combined Clostridium Butyricum and Bifidobacterium powders can effectively shorten the diarrhea and hospital stay of children, significantly increase the number of intestinal bacteria in children, and reduce inflammatory response.¹¹ The therapeutic effect of Clostridium Butyricum powder combined with zinc gluconate on infantile diarrhea is significant, and whether the synergistic effect of the two has a regulatory effect on intestinal bacteria has become the topic of this study. To find out this, we analyzed the clinical data of 86 children with infectious diarrhea to explore the clinical value of Clostridium butyricum powders combined with zinc gluconate.

Materials and methods

Clinical data

In this open-label study, clinical data of 86 children (aged 1–3 years old) with infectious diarrhea admitted to the hospital from February 2019 to November 2020 were retrospectively analyzed. 40 children were included in the control group (guardians of this group of children refused zinc gluconate supplementation) and 46 children in the experiment group according to the treatment methods. Both groups received routine treatments to reduce symptoms, among which patients in the control group were treated with Clostridium butyricum powders, and patients in the experiment group were treated with Clostridium butyricum powders plus zinc gluconate. See Table 1 for baseline data of two groups. This study conformed to the ethical standards of the World Medical Association Declaration of Helsinki, was reviewed and approved by the hospital ethics committee (Approval No. 2020A-209). Since the included subjects were too young to understand the research, written informed consent was obtained from legally authorized representatives (the guardians of the included children) before the study.

Table 1.

Comparison of clinical data between the two groups [n%; ( $\bar{x}$ ± SD)].

Characteristics	Experiment group (n = 46)	Control group (n = 40)	χ2 and t value	p value
Gender (Male/Female, case)	22/24	20/19	0.101	0.751
Age (years)	2.4 ± 0.4	2.3 ± 0.5	1.029	0.306
Disease course (d)	1.44 ± 0.38	1.51 ± 0.42	0.811	0.420
Degree of dehydration [case (%)]			0.187	0.665
Mild	24 (52.17)	19 (47.50)
Moderate	22 (47.83)	21 (52.50)

Inclusion and exclusion criteria

Inclusion criteria¹²: Patients were included in the study if they (1). were clinically diagnosed with infectious diarrhea and presented with symptoms including diarrhea, abdominal pain, vomiting and fever; (2). had an acute onset, with a course of disease ≤3 days; (3). did not take probiotics or zinc within 1 week before enrollment. Exclusion criteria: Patients were excluded if they (1). presented with severe fever or dehydration; (2). had dysfunction in the heart, liver, or kidney; (3). combined with disorders of the immune system, endocrine system, and blood system; (4). adhered poorly to or could not cooperate with the treatment during study.

Treatment regimen

Both groups were given conventional symptomatic and supportive treatments including fluid replacement, montmorillonite powder (Simcere Pharmaceutical Co., Ltd., China) for diarrhea, anti-infective therapy, and dietary control. Based on the treatments above, children in the control group were given Clostridium butyricum powders (Qingdao Eastsea Pharmaceutical Co., Ltd.; Approval No. S200440088; specification: 500 mg/sachet, each sachet containing at least 7.5 * 10⁶ CFU of viable bacteria), and each time, those under 1 year old were given half a sachet while those aged one year old or above were given 1 sachet, three times a day. Besides the same regime as the control group, children in the experiment group were also given zinc gluconate oral solution (Henan Tongyuan Pharmaceutical Co., Ltd.; Approval No. H41025018; specification: 10 mL per bottle, each bottle containing 3.5 mg of active ingredient per milliliter), and those under 1 year old were given 5 mL each time, while those aged one year old or above were given 10 mL each time, once a day. Both groups were treated for 5 days.

Outcome measures

(1) Clinical efficacy

After treating for 5 days, the clinical efficacy was defined as follows: a. Ineffective: the children’s symptoms and signs were not significantly improved, and stool frequency and consistency were not recovered; b. Effective: the children’s symptoms and signs were significantly improved, and the stool frequency and consistency were significantly recovered; c. Markedly effective: the children’s symptoms and signs basically disappeared, and the stool frequency and consistency returned to normal.¹² Overall response rate = (the number of effective cases + the number of markedly effective cases)/total number of cases * 100%.

(2) Recovery time of symptoms and signs

The improvement of diarrhea, abdominal pain, vomiting and body temperature was recorded during treatment, and the time of recovery from these symptoms and to normal body temperature were compared between the two groups.

(3) Inflammatory factors

Serum interleukin-6 (IL-6), interleukin-17 (IL-17), and C-reactive protein (CRP) levels were compared between the two groups before and after treatment: 4 mL of blood samples were drawn from the patient and centrifuged at 3000 rpm for 10 min (centrifugal radius: 6.5 cm). Then the serum was collected for the detection of inflammatory factors using an enzyme-linked immunosorbent assay (Shanghai Enzyme-linked Biotechnology Co., Ltd).¹³

(4) Intestinal mucosal function

Before and after treatment, the levels of diamine oxidase (DAO) and D-lactate were compared between the two groups: 4 mL of fasting blood was drawn at the cubital vein from the patients in the morning. Subsequently, the serum was separated using the same method as above. Then the levels of DAO and D-lactate were measured and compared by spectrophotometry.¹⁴

(5) Intestinal microecological indicators

Before and after treatment, 0.2 g of fresh stool was obtained and detected by viable plate counting for the contents of intestinal bifidobacteria and lactobacillus, which were compared between the two groups.

(6) Safety

The incidences of nausea, vomiting, constipation and other adverse reactions were statistically compared between the two groups. Incidence of adverse reactions = number of adverse reactions/total number of cases * 100%.¹⁰

Statistical methods

SPSS 22.0 software was used to process all data. Measurement data were analyzed by Bartlett's test of homogeneity of variance and Kolmogorov-Smirnov test, and those confirmed for homogeneity of variance and following approximately normal distribution were expressed as ( $\bar{x}$ ± sd). An independent sample t-test was used for comparison between two groups. Paired t-test was used for within-group comparison. Enumeration data were expressed as n (%). The exact probability test was used for the number of cases <40 or a theoretical frequency T ≤ 1. A chi-squared test was used for the number of cases ≤40 and a theoretical frequency T > 5 or 1 < T < 5. Statistical significance was defined when a p-value is less than 0.05.

Results

Clinical data

There was no significant difference in clinical data between the two groups, including gender, age, disease course, and degree of dehydration (all p > .05), which were comparable. See Table 1.

Clinical Efficacy

The overall response rate in the experiment group (95.65%) was significantly higher than that in the control group (77.50%) (p < .05). See Table 2.

Table 2.

Comparison of clinical efficacy between two groups [n (%)].

Group	Ineffective	Effective	Markedly effective	Overall response rate (%)
Experiment group (n = 46)	2 (4.35)	13 (28.26)	31 (67.39)	44 (95.65)
Control group (n = 40)	9 (22.50)	10 (25.00)	21 (52.50)	31 (77.50)
χ² value				6.320
p value				0.012

Recovery time of symptoms and signs

Time of recovery from symptoms including diarrhea, abdominal pain and vomiting, and to normal body temperature in the experiment group was significantly shorter than those in the control group (all p < .001). This result suggests that Clostridium butyricum powders combined with zinc gluconate can significantly promote the recovery of clinical symptoms in children with infectious diarrhea. (all p < .001). See Table 3.

Table 3.

Recovery time of symptoms and signs in the two groups ( $\bar{x}$ ± SD, h).

Group	Diarrhea	Abdominal pain	Vomiting	Body temperature
Experiment group (n = 46)	48.52 ± 10.63	41.25 ± 8.54	24.38 ± 5.29	32.75 ± 8.57
Control group (n = 40)	62.93 ± 14.22	53.69 ± 10.72	36.45 ± 7.55	45.84 ± 10.26
T value	5.322	5.952	8.586	6.421
p value	<.001	<.001	<.001	<.001

Inflammatory factor

There was no significant difference in serum levels of IL-6, IL-17 and CRP between the two groups before treatment (all p > .05), which were lower than those before treatment (all p < .001), and were lower in the experiment group than in the control group (all p < .001). These results suggest that Clostridium butyricum powders combined with zinc gluconate can significantly improve the inflammatory response of children with infectious diarrhea. See Table 4 and Figure 1.

Table 4.

Comparison of serum IL-6, IL-17, and CRP levels between the two groups ( $\bar{x}$ ± SD).

Group	Experiment group (n = 46)	Control group (n = 40)	T value	p value
IL-6 (μg/L)			0.849	0.398
Before treatment	16.69 ± 4.32	17.43 ± 3.67
After treatment	7.11 ± 1.59^***	10.72 ± 2.63^***	7.815	<0.001
IL-17 (pg/mL)
Before treatment	27.69 ± 5.42	28.33 ± 6.01	0.519	0.605
After treatment	9.26 ± 2.33^***	14.82 ± 3.58^***	8.536	<0.001
CRP (mg/L)
Before treatment	13.42 ± 3.53	14.17 ± 2.89	1.068	0.289
After treatment	7.52 ± 2.41^***	9.69 ± 2.12^***	4.433	<0.001

Note: IL-6: interleukin-6; IL-17: interleukin-17; CRP: C-reactive protein. Compared with that before treatment, ^***p < .001.

Figure 1.

Comparison of serum IL-6, IL-17, and CRP levels between the two groups. Note: A: IL-6 (μg/L); B: IL-17 (pg/mL); C: CRP (mg/L). Compared with that before treatment, ***p < .001; compared with the control group after treatment, ^###p < .001.

Intestinal mucosal function

Before treatment, there was no significant difference in DAO and D-lactate levels between the two groups (all p > 0.05). However, after treatment, both indicators were downregulated, and were lower in the experiment group than in the control group (all p < .001). Such result suggests that Clostridium butyricum powders combined with zinc gluconate can significantly improve DAO and D-lactate levels in children with infectious diarrhea. See Table 5.

Table 5.

Comparison of DAO and D-lactate levels between the two groups ( $\bar{x}$ ± SD).

Group	DAO (U/L)		D-lactate (mg/L)
Group	Before treatment	After treatment	Before treatment	After treatment
Experiment group (n = 46)	12.42 ± 3.17	4.53 ± 1.24^***	9.78 ± 2.83	4.31 ± 1.32^***
Control group (n = 40)	13.01 ± 2.86	7.22 ± 1.79^***	10.22 ± 3.11	6.84 ± 2.14^***
T value	0.901	8.184	0.687	6.706
p value	.370	<.001	.494	<.001

Note: DAO: diamine oxidase. Compared with that before treatment, ^***p < .001.

Indicators to intestinal microecology

There was no significant difference in the levels of intestinal bifidobacteria and lactobacillus between the two groups before treatment (all p > .05), which were elevated after treatment, and were higher in the experiment group than in the control group. This result indicates that Clostridium butyricum powders combining zinc gluconate can significantly improve the levels of intestinal bifidobacteria and lactic acid bacteria in children with infectious diarrhea. See Table 6 and Figure 2.

Table 6.

Comparison of intestinal bifidobacteria and lactobacillus levels between the two groups ( $\bar{x}$ ± SD, log CFU/g).

Group	Bifidobacterium		Lactobacillus
Group	Before treatment	After treatment	Before treatment	After treatment
Experiment group (n = 46)	6.88 ± 1.36	10.69 ± 2.05	9.46 ± 2.41	12.51 ± 3.55
Control group (n = 40)	7.06 ± 1.42	8.22 ± 1.64	8.85 ± 2.36	10.46 ± 2.43
T value	0.009	6.101	1.182	3.077
p value	.993	<.001	.241	.003

Figure 2.

Comparison of intestinal bifidobacterial and lactobacillus levels between the two groups. Note: A: Bifidobacterium (log CFU/g); B: Lactobacillus (log CFU/g). Compared with that before treatment, ***p < .001; compared with the control group after treatment, ^##p < .01, ^###p < .001.

Safety

There was no significant difference in the incidence of adverse reactions between the experiment group (8.70%) and the control group (2.50%) (p > .05). See Table 7.

Table 7.

Comparison of incidence of adverse reactions between the two groups [n (%)].

Group	Nausea	Vomiting	Constipation	Overall response rate
Experiment group (n = 46)	1 (2.17)	1 (2.17)	2 (4.63)	4 (8.70)
Control group (n = 40)	0 (0.0)	0 (0.0)	1 (2.50)	1 (2.50)
χ² value				0.075
p value				.784

Discussion

Presently, fluid replacement, antidiarrheal and antiinfective therapies are the most basic methods for clinical treatment of infectious diarrhea in children. Although these measures can correct electrolyte imbalance, improve dehydration and relieve diarrhea symptoms, some children are still difficult to completely get their benefits, leading to poor efficacy and clinical results.¹⁵ Therefore, it has become a research priority for clinical pediatricians to select a safe and effective regimen for the treatment of pediatric infectious diarrhea.

The results of this study showed that the clinical efficacy, recovery time of symptoms and signs of the experiment group were better than those of the control group, and there was no significant difference in the incidence of adverse reactions between the two groups. The study by Lu Haimei et al. showed that the combination of probiotics and zinc supplements in the treatment of diarrhea in children could significantly shorten the length of hospital stay, and recovery time of stool frequency, stool property and body temperature, which was consistent with the results of this study.¹⁶ These results suggest that Clostridium butyricum powders combining zinc gluconate in treating pediatric infectious diarrhea can effectively improve diarrhea symptoms and promote disease outcomes.^17–20

The results of this study showed that after treatment, the serum IL-6, IL-17 and CRP levels, DAO, D-lactate levels, intestinal bifidobacteria, and lactobacillus levels in the experiment group were lower than those in the control group, suggesting that this regimen is beneficial to reduce inflammatory responses, improve intestinal mucosal function, and promote recovery of intestinal microecology. A study by Zhang Lianfeng et al. has revealed that Clostridium butyricum powders combined with ribavirin can significantly reduce the levels of TNF-α, IL-6, and CRP in children with hand-foot-mouth disease and improve clinical efficacy, which is consistent with the results of this study.²¹ This result suggests that Clostridium butyricum powders combined with zinc gluconate can synergistically exert a prominent therapeutic effect through a multi-target action. This may be related to the fact that, on the one hand, Clostridium butyricum powders combined with zinc gluconate activates the immune system and improves immunity as well as the body’s anti-inflammatory ability. Meanwhile, this regime can promote the reproduction of intestinal bifidobacteria and lactobacilli, enhance bacteria activity and selectively remove intestinal harmful bacteria, thus promoting the growth of probiotics, and rapidly balances intestinal environment. On the other hand, Clostridium butyricum powders can directly promote the absorption of trace elements such as calcium, iron and zinc, vitamin K, folic acid and other nutrients in children, while appropriate supplementation of zinc gluconate helps to improve malnutrition caused by diarrhea and facilitates the recovery of the disease.

Also, the results of our study demonstrated that there was no significant difference in the incidence of adverse reactions between the experiment group (8.70%) and the control group (2.50%), which suggests that the combination of the two drugs does not increase adverse reactions and is safe and effective in clinical practice. However, tolerable side effects were found in both groups, this may be related to the fact that the sample size is rather small, which needs to be expanded in further studies.

This study is a preliminary study, which is limited to small sample size. At the same time, the follow-up time of this study is short, and we did not conduct a multicenter, double-blind, randomized controlled trial requiring a large sample size. Therefore, we will focus on a multicenter study using a larger sample size to further clarify the effects of Clostridium butyricum powders combined with zinc gluconate in the treatment of pediatric infectious diarrhea.

In addition, this study also has certain limitations. The potential confounding factors in the initial selection of treatment were not specified, and the initial content of zinc was not measured. Besides, only the children who refused zinc supplementation were selected as the control, which may lead to some bias in the results and will be considered in future study.

Conclusion

The use of Clostridium butyricum powders combined with zinc gluconate in the treatment of children with infectious diarrhea can effectively relieve clinical symptoms, down-regulate the level of serum inflammatory factors, regulate intestinal microecology, improve intestinal mucosal function, and enhance overall therapeutic effect without increasing the risk of adverse reactions, which guarantees medication safety of the patients.

Footnotes

Acknowledgements

The authors thank the reviewers for their useful comments.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

Ethical approval for this study was obtained from Lanzhou University Second Hospital, (Approval Number 2020A-209).

Informed consent

Written informed consent was obtained from legally authorized representatives before the study.

ORCID iD

Xiaonan Xu

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Clostridium butyricum powders combined with zinc gluconate on inflammatory factors and intestinal microecology in children with infectious diarrhea

Abstract

Keywords

Introduction

Materials and methods

Clinical data

Inclusion and exclusion criteria

Treatment regimen

Outcome measures

Statistical methods

Results

Clinical data

Clinical Efficacy

Recovery time of symptoms and signs

Inflammatory factor

Intestinal mucosal function

Indicators to intestinal microecology

Safety

Discussion

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

Ethics approval

Informed consent

ORCID iD

References