GUT MICROBIOTA AND THE USE OF PROBIOTICS IN CONSTIPATION IN CHILDREN AND ADOLESCENTS: SYSTEMATIC REVIEW

Gomes, Daiane Oliveira Vale San; Morais, Mauro Batista de

doi:10.1590/1984-0462/2020/38/2018123

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Brasil

Revista Paulista de Pediatria

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Brasil

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REVIEW ARTICLE • Rev. paul. pediatr. 38 • 2020 • https://doi.org/10.1590/1984-0462/2020/38/2018123 copy

GUT MICROBIOTA AND THE USE OF PROBIOTICS IN CONSTIPATION IN CHILDREN AND ADOLESCENTS: SYSTEMATIC REVIEW

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To perform a systematic review of literature data on gut microbiota and the efficacy of probiotics for the treatment of constipation in children and adolescents.

Data source:

The research was performed in the PubMed, the Scientific Electronic Library Online (SciELO) and the Latin American and Caribbean Health Sciences Literature (LILACS) databases in English, Portuguese and Spanish. All original articles that mentioned the evaluation of the gut microbiota or the use of probiotics in children with constipation in their title and abstract were selected.

Data synthesis:

559 articles were found, 47 of which were selected for reading. From these, 12 articles were included; they studied children and adolescents divided into two categories: a gut microbiota evaluation (n=4) and an evaluation of the use of probiotics in constipation therapy (n=8). The four papers that analyzed fecal microbiota used different laboratory methodologies. No typical pattern of gut microbiota was found. Regarding treatment, eight clinical trials with heterogeneous methodologies were found. Fifteen strains of probiotics were evaluated and only one was analyzed in more than one article. Irregular beneficial effects of probiotics have been demonstrated in some manifestations of constipation (bowel frequency or consistency of stool or abdominal pain or pain during a bowel movement or flatulence). In one clinical trial, a complete control of constipation without the use of laxatives was obtained.

Conclusions:

There is no specific pattern of fecal microbiota abnormalities in constipation. Despite the probiotics’ positive effects on certain characteristics of the intestinal habitat, there is still no evidence to recommend it in the treatment of constipation in pediatrics.

Keywords:
Constipation; Probiotics; Microbiota; Child; Adolescent

Authors, year, reference, location	n (age) division of groups	Definition of constipation	Analysis of fecal microbiota	Results of children with constipation compared to controls
Zoppi et al., 1998⁸8. Zoppi G, Cinquetti M, Luciano A, Benini A, Muner A, Bertazzoni Minelli E. The intestinal ecosystem in chronic functional constipation. Acta Paediatr. 1998;87:836-41. Italy	42 (5-14 years old) 28 with constipation 14 healthy controls	Bowel movement frequency: <1 every 48 hours and hard stools	Material analyzed: a stool sample. Culture in selective and non-selective media supplemented by biochemical assay	- Similar anaerobic total count in individuals with and without constipation. In those with constipation, we observed: - a higher number of anaerobes of the genera Clostridia (p <0.001) and Bifidobacteria (p <0.02); - a greater number of Clostridium than Bacterioides; - a greater number of Clostridium than Escherichia coli. In the control group, the counts of Clostridia, Bacteroides and E. coli were similar.
Zhu et al., 2014 ⁹9. Zhu L, Liu W, Alkhouri R, Baker RD, Bard JE, Quigley EM, et al. Structural changes in the gut microbiome of constipated patients. Physiol Genomics. 2014;46:679-86. https://doi.org/10.1152/physiolgenomics.00082.2014 https://doi.org/https://doi.org/10.1152/... United States	22 (10-13 years old) eight obese patients with constipation 14 obese controls without constipation	NASPGHAN Guideline (2006):³⁹39. Constipation Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Evaluation and treatment of constipation in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr . 2006;43:e1-13. https://doi.org/10.1097/01.mpg.0000233159.97667.c3 https://doi.org/https://doi.org/10.1097/... delay or difficulty having a bowel movement for more than two weeks	Material analyzed: a stool sample. Pyrosequencing of the 16S rRNA gene	In those with constipation, we observed: - a decrease in the filament Bacteroidetes, especially genus Prevotella (0.010); - an increase in Firmicutes, especially Lachnospiraceae (p = 0.042) and Ruminococcaceae (p = 0.024); Constipation was not associated with a decrease in Lactobacillus and Bifidobacteria.
Meij et al., 2016 ¹³13. de Meij TG, de Groot EF, Eck A, Budding AE, Kneepkens CM, Benninga MA , et al. Characterization of microbiota in children with chronic functional constipation. PLoS One. 2016;19;11:e0164731. https://doi.org/10.1371/journal.pone.0164731 https://doi.org/https://doi.org/10.1371/... Holland	137 (4-18 years old) 76 with constipation 61 healthy controls	Rome III Criterion (2006) for functional constipation	Material analyzed: a stool sample. Microbiota profile based on IS-pro multiplex PCR method	- No differences were found in phyla and bacterial diversity according to Shannon’s index. In those with constipation, the following were found: - an increase in Bacteroides fragilis, Bacteroides ovatus, Bifidobacterium longum, Proteus mirabilis, a species of Parabacteroides; - a decrease in Alistipes finegoldii andRuminococcus species.
Moraes et al., 2016 ¹⁵15. de Moraes JG, Motta ME, Beltrão MF, Salviano TL, de Silva GA. Fecal microbiota and diet of children with chronic constipation. Int J Pediatr. 2016;2016:6787269. https://doi.org/10.1155/2016/6787269 https://doi.org/https://doi.org/10.1155/... Brazil	79 (3-36 months) 39 with constipation 40 healthy controls	Rome III Criterion (2006) for functional constipation	Material analyzed: a stool sample. Total Bacterial Count, Lactobacillus and Bifidobacterium by real time PCR	- No difference was observed in the counts for total bacterial and bifidobacterium. - In those with constipation, a lower (p = 0.022) concentration of Lactobacillus per milligram of stool was observed.

Study, year, reference	Patients		Probiotic		Comparison (n)/presentation	Duration	Allocation concealment/blind analysis/intention to treat/follow-up losses
Study, year, reference	n (age)	Definition of constipation	Genus, species and strain (n)	Dose/presentation	Comparison (n)/presentation	Duration
Banaszkiewicz et al., 2005¹⁸18. Banaszkiewicz A, Szajewska H. Ineffectiveness of Lactobacillus GG as an adjunct to lactulose for the treatment of constipation in children: a double-blind, placebo-controlled randomized trial. J Pediatr. 2005;146:364-9. https://doi.org/10.1016/j.jpeds.2004.10.022 https://doi.org/https://doi.org/10.1016/...	(2-16 years old)	Less than three bowel movements/wk. for at least 12 weeks	L. rhamnosus GG ATCC 531032 + Lactulose (n=43)	2x/day 10 ⁹ CFU/capsules	placebo + lactulose (n = 41)/capsules	26 weeks (12 weeks of treatment)	yes/yes/yes/yes
Bu et al., 2007²¹21. Bu LN, Chang MH, Ni YH, Chen HL, Cheng CC. Lactobacillus casei rhamnosus Lcr35 in children with chronic constipation. Pediatr Int. 2007;49:485-90. https://doi.org/10.1111/j.1442-200X.2007.02397.x https://doi.org/https://doi.org/10.1111/...	45 (1-4 years old)	Less than three bowel movements/wk. for more than two months and anal fissure with bleeding or faecal leak or hard/large stools	L. casei rhamnosus Lcr35 (n = 18)	2x/day 8 × 10⁸ CFU/capsules	MgO (n = 18) Placebo (n = 9)/capsules	4 weeks	yes/yes/yes/yes
Coccorullo et al., 2010¹⁶16. Coccorullo P, Strisciuglio C, Martinelli M, Miele E, Greco L, Staiano A. Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study. J Pediatr. 2010;157:598-602. https://doi.org/10.1016/j.jpeds.2010.04.066 https://doi.org/https://doi.org/10.1016/...	44 (5-10 months old)	Rome III Criterion (2006) for functional constipation	Lactobacillusreuteri DSM 17938 (n = 22)	1x/day 10⁸ CFU/oily suspension in drops	Placebo (n = 22)/oily suspension in drops	eight weeks	yes/yes/yes/yes
Tabbers et al., 2011²⁰20. Tabbers MM , Chmielewska A, Roseboom MG, Crastes N, Perrin C, Reitsma JB, et al. Fermented milk containing Bifidobacterium lactis DN-173 010 in childhood constipation: a randomized, double-blind, controlled trial. Pediatrics. 2011;127:e1392-9. https://doi.org/10.1542/peds.2010-2590 https://doi.org/https://doi.org/10.1542/...	148 (3-16 years old)	Rome III Criterion (2006) for functional constipation	Bifidobacterium lactis DN-173 010 (n=74)	2x/day 4.25 x 10⁹ CFU/fermented milk	Placebo (n=74)/Low lactose non-fermented dairy	five weeks (three weeks of treatment)	yes/yes/yes/yes
Guerra et al., 2011²²22. Guerra PV, Lima LN, Souza TC, Mazochi V, Penna FJ, Silva AM, et al. Pediatric functional constipation treatment with Bifidobacterium-containing yogurt: a crossover, double-blind, controlled trial. World J Gastroenterol. 2011;17:3916-21. https://doi.org/10.3748/wjg.v17.i34.3916 https://doi.org/https://doi.org/10.3748/...	59 (5-15 years old)	Rome III Criterion (2006) for functional constipation	Bifidobacterium longum (n = 29)	1x/day 10⁹ CFU/goat yogurt	Placebo (n = 30)/goat yogurt	ten weeks (crossover after five weeks)	yes/yes/yes/yes
Sadeghzadeh et al., 2014²³23. Sadeghzadeh M, Rabieefar A, Khoshnevisasl P, Mousavinasab N, Eftekhari K. The effect of probiotics on childhood constipation: a randomized controlled double blind clinical trial. Int J Pediatr . 2014;2014:937212. https://doi.org/10.1155/2014/937212 https://doi.org/https://doi.org/10.1155/...	48 (4-12 years old)	Rome III Criterion (2006) for functional constipation	Protexin^* (n = 24)	1x/day 10⁹ CFU + lactulose/sachet	placebo + lactulose (n = 24)/sachet	four weeks	yes/yes/yes/yes
Russo et al., 2017¹⁷17. Russo M, Giugliano FP, Quitadamo P, Mancusi V, Miele E , Staiano A . Efficacy of a mixture of probiotic agents as complementary therapy for chronic functional constipation in childhood. Ital J Pediatr. 2017;43:24. https://doi.org/10.1186/s13052-017-0334-3 https://doi.org/https://doi.org/10.1186/...	55 (4-12 years old)	Rome III Criterion (2006) for functional constipation	Probiotic Mix^** + PEG 4000 (n = 27)	1 sachet/day	PEG 4000 (n = 28)/sachet	eight weeks	yes/no/yes/yes
Wojtyniak et al., 2017¹⁹19. Wojtyniak K, Horvath A, Dziechciarz P, Szajewska H . Lactobacillus casei rhamnosus Lcr35 in the management of functional constipation in children: a Randomized Trial. J Pediatr. 2017;184:101-5. https://doi.org/10.1016/j.jpeds.2017.01.068 https://doi.org/https://doi.org/10.1016/...	81 (1-4 years old)	Rome III Criterion (2006) for functional constipation	Lactobacillus casei rhamnosus Lcr35 (n=46)	2x/day 8 × 10 8 CFU/capsules	Placebo (n = 48)/capsules	four weeks	yes/yes/yes/yes

Author, year, reference and place	Probiotic	Results of children with constipation compared to control group
Banaszkiewicz et al., 2005¹⁸18. Banaszkiewicz A, Szajewska H. Ineffectiveness of Lactobacillus GG as an adjunct to lactulose for the treatment of constipation in children: a double-blind, placebo-controlled randomized trial. J Pediatr. 2005;146:364-9. https://doi.org/10.1016/j.jpeds.2004.10.022 https://doi.org/https://doi.org/10.1016/... Poland	L. rhamnosus GG (ATCC 531032)	Treatment success^a was similar (p> 0.05) at the 12^th week (experimental group=72% and control group=68%) and at the 24^th week (experimental group =64% and control group=65%). There was no difference between the groups regarding weekly number of bowel movements, the force of the bowel movement, fecal escape and the number of required doses of laxatives.
Bu et al., 2007²¹21. Bu LN, Chang MH, Ni YH, Chen HL, Cheng CC. Lactobacillus casei rhamnosus Lcr35 in children with chronic constipation. Pediatr Int. 2007;49:485-90. https://doi.org/10.1111/j.1442-200X.2007.02397.x https://doi.org/https://doi.org/10.1111/... Taiwan	L. casei rhamnosus Lcr35	Greater (p=0.01) treatment success^a in the magnesium oxide (72.2%) and probiotic (77.8%) groups compared to the placebo (11.1%). The magnesium oxide and probiotic groups presented a higher (p = 0.03) frequency of bowel movement, a lower (p = 0.01) frequency of hardened stools and a lower (p = 0.04) frequency of glycerin enema use in comparison to the placebo. Episodes of abdominal pain were less frequent (p = 0.03) in the probiotic group compared to the magnesium oxide and placebo groups. There was an increase in the percentage of lactobacilli in anaerobic microbiota after probiotic treatment (p = 0.03) and when compared to the magnesium oxide and placebo groups (p = 0.02), there was no correlation with bowel movement frequency. There was no difference between the groups regarding the frequency of lactulose use, bowel movement episodes and appetite alteration.
Coccorullo et al., 2010¹⁶16. Coccorullo P, Strisciuglio C, Martinelli M, Miele E, Greco L, Staiano A. Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study. J Pediatr. 2010;157:598-602. https://doi.org/10.1016/j.jpeds.2010.04.066 https://doi.org/https://doi.org/10.1016/... Italy	Lactobacillusreuteri DSM 17938	No definition of therapeutic success. Higher frequency of probiotic bowel movements in the second (p = 0.042), fourth (p = 0.008) and eighth (p = 0.027) weeks of treatment versus the control. There was no difference between groups with regard to stool consistency. There was an increase (p = 0.02) of inconsolable crying episodes in the probiotic group. In the control group, an increase in inconsolable crying was also observed, however, it did not reach statistical significance (p = 0.08).
Tabbers et al., 2011²⁰20. Tabbers MM , Chmielewska A, Roseboom MG, Crastes N, Perrin C, Reitsma JB, et al. Fermented milk containing Bifidobacterium lactis DN-173 010 in childhood constipation: a randomized, double-blind, controlled trial. Pediatrics. 2011;127:e1392-9. https://doi.org/10.1542/peds.2010-2590 https://doi.org/https://doi.org/10.1542/... Holland and Poland	Bifidobacterium lactis DN-173 010 (n=74)	Treatment success^b was higher in the probiotic group (38%) compared to the placebo group (24%), but there was no significant difference (p=0.06). In the probiotic group, a reduction (p = 0.02) in flatulence frequency was observed. There was no difference between the probiotic and control groups regarding bowel movement frequency, stool consistency, fecal incontinence, pain during bowel movements, abdominal pain and bisacodil use. Higher bisacodil intake was observed in the control group (p=0.0069).
Guerra et al., 2011²²22. Guerra PV, Lima LN, Souza TC, Mazochi V, Penna FJ, Silva AM, et al. Pediatric functional constipation treatment with Bifidobacterium-containing yogurt: a crossover, double-blind, controlled trial. World J Gastroenterol. 2011;17:3916-21. https://doi.org/10.3748/wjg.v17.i34.3916 https://doi.org/https://doi.org/10.3748/... Brazil	Bifidobacterium longum (n = 29)	They do not present total data obtained in the two intervention periods with probiotic or control. They mention that in the probiotic group, considering all the results, there was a significant difference in the frequency of bowel movements, pain in bowel movements and abdominal pain.
Sadeghzadeh et al., 2014²³23. Sadeghzadeh M, Rabieefar A, Khoshnevisasl P, Mousavinasab N, Eftekhari K. The effect of probiotics on childhood constipation: a randomized controlled double blind clinical trial. Int J Pediatr . 2014;2014:937212. https://doi.org/10.1155/2014/937212 https://doi.org/https://doi.org/10.1155/... Iran	Protexin^®	No definition of therapeutic success. At the end of the fourth week it was found that the probiotic group had a higher (p = 0.042) bowel movement frequency and an improvement (p = 0.049) in stool consistency when compared to the placebo group. In the first week of intervention, a lower (p=0.030) frequency of fecal incontinence, a lower frequency (p=0.017) of abdominal pain and a greater weight gain (p=0.002) was found. These variables were similar in the fourth week of the study.
Russo et al., 2017¹⁷17. Russo M, Giugliano FP, Quitadamo P, Mancusi V, Miele E , Staiano A . Efficacy of a mixture of probiotic agents as complementary therapy for chronic functional constipation in childhood. Ital J Pediatr. 2017;43:24. https://doi.org/10.1186/s13052-017-0334-3 https://doi.org/https://doi.org/10.1186/... Italy	Brief bifidobacterium M-16 V^® , Infant Bifidobacterium M-63^® and Bifidobacterium longum BB536^®. Bifidobacterium longum BB536^®	In the second week of the study, treatment success^c was higher with PEG (72%) compared to the PEG + probiotic mixture group (59%) (p=0.02). After one month (the fourth week), there was no difference in treatment success between the PEG group (88%) and the PEG + probiotic mixture group (81.8%). There was no difference between groups regarding bowel movement frequency, stool consistency, abdominal pain, fecal incontinence and rectal bleeding after two months (eighth week) of study. One month after the end of the study (12^nd week), a clinical remission rate was observed in the PEG + probiotic mixture group in 64% of patients and 52% in the PEG-only group (p=0.28).
Wojtyniak et al., 2017¹⁹19. Wojtyniak K, Horvath A, Dziechciarz P, Szajewska H . Lactobacillus casei rhamnosus Lcr35 in the management of functional constipation in children: a Randomized Trial. J Pediatr. 2017;184:101-5. https://doi.org/10.1016/j.jpeds.2017.01.068 https://doi.org/https://doi.org/10.1016/... Poland	Lactobacillus casei rhamnosus Lcr35	There was no difference in treatment success^a between the groups. In the probiotic group, there was a lower (p = 0.005) bowel movement frequency in allof the studied weeks compared to the placebo group. Comparing from the baseline to the fourth week of study, there was an increase (p<0.001) in bowel movement frequency and an improvement (p<0.001) in stool consistency in both groups.

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[1] *Corresponding author. E-mail: maurobmorais@gmail.com (M.B. de Morais)