The use of probiotics and prebiotics in decolonizing pathogenic bacteria from the gut; a systematic review and meta-analysis of clinical outcomes

Figures & data

Table 1. Inclusion and exclusion criteria for the Probiotics study.

PICOS Criteria	Inclusion criteria	Exclusion criteria
Population	Adult population (> 18 years). Confirmed colonization of pathogenic(, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, multidrug-resistant (MDR) Escherichia coli, MDR gram-negative Bacillus, Staphylococcus aureus, Clostridium difficile, Helicobacter pyroli, Vancomycin-resistant Enterococci (VRE), Multi-drug resistant Pseudomonas aeruginosa and Carbapenemase-producing Klebsiella pneumonia.) bacteria through PCR, plate culture methods, 16S rRNA sequencing, breath tests, etc.	Patients who had repeated or stubborn C. difficile infections (other studies solely focus on this issue). Studies on VRE and C. difficile that have already been reviewed.^Citation19,Citation20 Children (Age <18 years) (since the gut microbiota of children is still evolving and does not resemble the adults.^Citation21 People infected with pathogens other than bacteria.
Intervention	Probiotics were concomitant with conventional therapy (Table in decolonizing pathogens. Distinct types of probiotics with no restriction of dosages based on bacteria or yeast Different types of probiotics and prebiotics delivery materials were considered, such as capsules, tablets, sachet powder, yoghurt, milk drinks, etc. Instead of focusing on a specific type, we included all the delivery methods since the study is still rare.	We excluded all the studies other than probiotics to decolonize pathogens. Focusing on any drugs other than conventional therapy concomitant with probiotics.
Comparison	Probiotics with or without conventional medicine (experimental group) compared with only traditional therapy or a placebo (control group).	Studies with no control or placebo group
Outcome	The primary outcome was decolonizing pathogens from the gut within one month (30 days) or the end of the study, whichever is earliest, confirmed by PCR or plate culture method.	Not applicable
Study design	Randomized control trials (RCTs) and other clinical studies with a distinct control arm comparing combined therapy with (Placebo). Limited to original articles.	Observation studies, case reports, experimental studies, pilot studies, etc.

Table 2. Inclusion and exclusion criteria for the Prebiotics study.

PICOS Criteria	Inclusion criteria	Exclusion criteria
Population	Adult population (>18 years) Any other animals, including mice, chicken, etc., are also included since only probiotics studies on humans are scarce. Confirmed colonization of pathogenic bacteria (Salmonella enteritidis, S. typhimurium, S.enterica, Acinetobacter, Clostridium perfringens, Helicobacter, etc.) through PCR, plate culture methods, 16S rRNA sequencing, breath tests, etc.	Children (Age <18 years) as the gut microbiota of children do not resemble the adults. People or animals infected with pathogens other than bacteria.
Intervention	Prebiotics or a combination of prebiotics with no restriction of dose and types. Different types of prebiotic delivery materials were considered.	All the studies other than prebiotics to decolonize pathogens were excluded. Focusing on any drugs other than prebiotics.
Comparison	Prebiotic treatment was compared with the baseline pathogenic load in the gut.	Studies with no comparison.
Outcome	The primary outcome was decolonizing or reducing pathogens compared to the initial challenge confirmed by PCR or plate culture.	Not applicable
Study design	Due to the scarcity of human-based RCTs for the efficacy of prebiotic treated cohort, we considered clinical control trials and case studies on animals or humans where prebiotics or a combination of prebiotics are used to decolonize or reduce pathogenic burdens (CFU reduction). Limited to original articles.	Observation studies, case reports, experimental studies, pilot studies, etc.

Figure 1. PRISMA flow diagram showing the systematic review process with the bibliometric assessment, including article attrition and study selection.

Table 3. Types and dosages of probiotics.

Reference	Type of probiotics	Dosage (CFU/day)	Formulation ofprobiotic
Alberda 2018^Citation26	Lactobacillus casei sp. paracasei CNCM I-1518	2 x 10^10	yogurt drink,
Barker 2017^Citation27	L. acidophilus NCFM, ATCC 700,396; L. paracasei Lpc-37, ATCC SD5275; Bifidobacterium lactis Bi-07, ATCC SC5220;	1.7 x 10^10	Capsule
Dall 2019^Citation28	L. rhamnosus GG	6 x 10^9	Tablet
De Regt 2015^Citation29	B. bifidum, B. lactis, Enterococcus faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, and L. salivarius	1 x 10^9	Powder
Doron 2015^Citation30	L. rhamnosus GG	2 x 10^10	Capsule
Eggers 2018^Citation31	L. rhamnosus HN001	1 x 10^10	Capsule
Gerding 2015^Citation32	Nontoxigenic Clostridium difficile strain M3 (VP20621; NTCD-M3	1 x 10^7	Liquid drink
He 2022^Citation33	Lyophilized Saccharomyces boulardii	1 x 10^9	Powder
Klarin 2008^Citation34	L. plantarum 299v	8x 10^8	Capsule
Kwon 2015^Citation35	L. rhamnosus GG	1 x 10^10	Capsule
Ljungquist 2020^Citation13	Probiotic Vivomixx®, a mixture of 8 different living bacterial strains	9 x 10^11	Sachet
Manely 2007^Citation36	L. rhamnosus GG (LGG)	1 x 10^9	Yogurt
Mc Farland 1994^Citation37	S. boulardii	3 × 10^10	Capsule
Nouvenne 2015^Citation38	Not declared	2.4 × 10^10	Capsule
Rauseo 2022^Citation39	L. rhamnosus GG (LGG)	2 x 10^10	Capsule
Rubin 2022^Citation40	L. rhamnosus GG	3 × 10^10	Capsule
Salomao 2016^Citation41	L. bulgaricus and L. rhamnosus	4 x 10^10	Suspension
Sullivan 2004^Citation42	L. paracasei ssp. paracasei F19	1 x 10^10	Milk Powder
Lawrence 2005^Citation43	Lyophilized S. boulardii	1 x 10^9	Capsule
Surawicz 2000^Citation44	L. rhamnosus GG	1 x 10^9	Capsules
Szachta 2011^Citation45	L. rhamnosus GG	3 x 10^9	Sachet powder
Tang 2021^Citation46	E. faecium and Bacillus subtilis	1.3 x 10^9	Capsule
Tannok 2011^Citation16	Escherichia coli Nissle 1917	2 x 10^11	Capsule
Viazis 2022^Citation47	L. acidophilus LA-5, L. plantarum, Bifidobacterium lactis BB-12, and S. boulardii.	5.5 x 10^9	Capsule
Warrak 2014^Citation48	L. rhamnosus HN001	1 x 10^9	Capsule
Wieers 2021^Citation49	L. acidophilus NCFM, L. paracasei Lpc-37, B. lactis Bl-04, and B. lactis Bi-07 (Bactiol duo®)	1.4 x 10^10	Capsule
Wullt 2003^Citation50	L. plantarum 299v	5 x 10^10	Fruit drink
Yang 2021^Citation51	L. reuteri DSM17648	1 x 10^10	Sachet
OH 2015^Citation52	Streptococcus faecium and Bacillus subtilis	9 x 10^10	Capsule

Figure 2. Forest plot for the intervention group (probiotics) vs. placebo for the decolonization success at the end of the study or at a 1-month time point. The I² values are interpreted as low, moderate, and high levels of heterogeneity, where I² = 0–49%, I²= 50–75%, and I² > 75%.^19,53 A 5% significance level (p<0.05) was used to determine the significant difference between the treatment efficacies. The events consist of the persistence of bacteria.

Figure 3. Forest plot of the sub-group analysis for the efficacy of probiotics concomitant with or without conventional medicine. The I² values are interpreted as low, moderate, and high levels of heterogeneity, where I² = 0–49%, I²= 50–75%, and I²> 75%, respectively.^19,53 A 5% significance level (p<0.05) was used to determine the significant difference between the treatment efficacies. The events consist of the persistence of bacteria.

Figure 4. Forest plot of the sub-group analysis for the efficacy of specific probiotics Lactobacillus, Mixed probiotics, S. boulardii, and other probiotics vs placebo. The I² values are interpreted as low, moderate, and high levels of heterogeneity, where I² = 0–49%, I²= 50–75%, and I²> 75%, respectively.^19,53 A 5% significance level (p<0.05) was used to determine the significant difference between the treatment efficacies. The events consist of the persistence of bacteria.

Figure 5. Forest plots for sub-group analysis of the efficacy of the intervention (Probiotics) vs. Placebo on C. difficile, MDR-Enterobacteriaceae, VRE, and H. pylori. The I² values are interpreted as low, moderate, and high levels of heterogeneity, where I² = 0–49%, I²= 50–75%, and I²> 75%, respectively.^19,53 A 5% significance level (p<0.05) was used to determine the significant difference between the treatment efficacies. The events consist of the persistence of bacteria.

Figure 6. Results of the meta-regression of the covariates, dosages of probiotics, and types of probiotics and types of bacteria on the decolonization of pathogens.

Table 4. Moderation effect of the covariates of probiotic intervention, types of probiotics, pathogens, regions, and dosages of probiotics on the effect size of pathogenic decolonization.

Moderator (k* =29)	Estimates	Standard error (SE)	p-value
Types of probiotics	−0.0486	0.0265	0.018
Types of pathogens	0.0514	0.0174	0.003
Region of studies	0.00648	0.0326	0.842
Probiotics dose	0.0109	0.0325	0.737

Figure 7. Funnel plot of comparison: efficacy of pathogenic bacteria decolonization.

Table 5. Publication bias summary.

Egger’s test
Estimates of measure		−0.7512
Significance level		p = 0.2573
Begg’s test (Rank Correlation Test for Funnel Plot Asymmetry)
Kendall’s Tau estimates	−0.1138
Significance level	p = 0.4148
Regression Test for Funnel Plot Asymmetry
Z	−1.098
Significance level	p = 0.272

Table 6. GRADEpro summary of findings for assessing the quality of evidence as assessed separately by two independent reviewers.

Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Pathogens decolonization by probiotics	placebo	Relative (95% CI)	Absolute (95% CI)
Overall probiotic effect (follow-up: mean 1 month; assessed with placebo)
29	RCTs	not serious	serious^a	not serious	not serious	none	982/1343 (73.1%)	1011/1508 (67.0%)	OR 0.59 (0.42 to 0.81)	125 fewer per 1,000 (from 210 fewer to 48 fewer)	⨁⨁⨁◯ Moderate	Critical
Groupwise probiotic effect - Lactobacillus (follow-up: range 4 weeks to 6 weeks; assessed with placebo)
15	RCTs	not serious	serious^a	not serious	not serious	none	254/422 (60.2%)	239/451 (53.0%)	OR 0.72 (0.50 to 1.04)	82 fewer per 1,000 (from 169 fewer to 10 more)	⨁⨁⨁◯ Moderate	Important
Groupwise probiotic effect - Mix probiotics (follow-up: range 4 weeks to 6 weeks; assessed with placebo)
5	RCTs	not serious	serious^a	not serious	not serious	none	413/514 (80.4%)	574/759 (75.6%)	OR 0.83 (0.59 to 1.16)	36 fewer per 1,000 (from 110 fewer to 26 more)	⨁⨁⨁◯ Moderate	Important
Groupwise probiotic effect - Saccharomyces boulardii (follow-up: range 4 weeks to 6 weeks; assessed with placebo)
4	RCTs	not serious	not serious	not serious	not serious	none	122/160 (76.3%)	95/164 (57.9%)	OR 0.34 (0.23 to 0.49)	260 fewer per 1,000 (from 339 fewer to 176 fewer)	⨁⨁⨁⨁ High	Important
Subgroup analysis based on types of bacteria - Clostridium difficile (follow-up: mean 1 month; assessed with placebo)
8	RCTs	not serious	not serious	serious^b	not serious	none	206/268 (76.9%)	94/190 (49.5%)	OR 0.25 (0.17 to 0.36)	298 fewer per 1,000 (from 352 fewer to 234 fewer)	⨁⨁⨁◯ Moderate	Critical
Subgroup analysis based on types of bacteria - MDR Enterobacteriaceae (follow-up: mean 1 month; assessed with placebo)
5	RCTs	not serious	not serious	serious^b	not serious	none	34/116 (29.3%)	27/112 (24.1%)	OR 0.39 (0.19 to 0.80)	131 fewer per 1,000 (from 184 fewer to 38 fewer)	⨁⨁⨁◯ Moderate	Critical
Subgroup analysis based on types of bacteria - Vancomycin-resistant Enterococcus (VRE) (follow-up: mean 1 month; assessed with placebo)
4	RCTs	not serious	serious^a	not serious	not serious	none	43/70 (61.4%)	23/75 (30.7%)	OR 0.40 (0.12 to 1.34)	156 fewer per 1,000 (from 256 fewer to 65 more)	⨁⨁⨁◯ Moderate	Critical
Subgroup analysis based on types of bacteria - Helicobacter pylori (follow-up: mean 1 month; assessed with placebo)
4	RCTs	not serious	serious^a	not serious	not serious	none	521/583 (89.4%)	498/584 (85.3%)	OR 0.69 (0.49 to 0.98)	53 fewer per 1,000 (from 113 fewer to 3 fewer)	⨁⨁⨁◯ Moderate	Critical
Prebiotics in reducing or eradicating pathogens (follow-up: range 3 weeks to 4 weeks; assessed with baseline)
10	Observational studies	serious^c	serious^d	serious^e	not serious	none	Some groups were missing the control or placebo group for comparison of intervention. There was no defined event in the intervention and control group. Therefore, no meta-analysis was done to make a comparison.				⨁◯◯◯ Very low	Important

CI: confidence interval; OR: odds ratio.

Explanations

a. Some studies showed that probiotics have excellent results in decolonising multi-drug resistant pathogens, whereas, in some studies, a placebo works best.

b. The treatment was different. The same probiotics were not used in all the studies to decolonise the pathogens.

c. Some studies did not have a control group; therefore, it is difficult to conclude the results.

d. No meta-analysis was done to determine heterogeneity.

e. No patient and control group can compare the data for a direct assessment.

Grading of evidence

High certainty: We are highly confident that the true effect lies closer to that of the estimate of the effect

Moderate certainty: We are moderately confident that the true effect is likely to be close to the estimate of the effect. However, there is the possibility of a difference between the true effect and measures of estimate.

Low certainty:We are not confident that the true effect will likely be close to the effect size. There might be a substantial difference between the true effect and the estimate of the effect.

Very low certainty: The true effect is likely to differ substantially from the mesure estimate (effect size).

Table 7. Types and dosages of prebiotics.

Reference	Type of prebiotics	Dosage/day	Study subjects
Lin et al., 2016^Citation59	Xylooligosaccharides (XOS)	1.2 gm	Human
Mao et al., 2018^Citation56	Fructooligosaccharide (FOS)	5–25% of the regular diet	Rat
Adhikari et al., 2018^Citation54	Fructooligosaccharide (FOS)	1% of the regular diet	Poultry
Monteagudo-Mera et al., 2016^Citation58	Galactooligosaccharides (GOS)	1% of the regular diet	Mice
Ribeiro et al., 2007^Citation57	Mannan oligosaccharide – Bio Mos	2.5 mg	Poultry
Pourabedin et al., 2017^Citation61	Xylooligosaccharides and mannose-oligosaccharides	2 gm	Poultry
Spring et al., 2000^Citation62	Mannanoligosaccharides (MOS)	4,000 ppm of dietary MOS	Poultry
Lowry et al., 2005^Citation63	Beta-glucan	Not mentioned	Poultry
Rajani et al., 2016^Citation60	Galactoglucomannan oligosaccharides (GGMs)	0.3% of the regular diet	Poultry
Matsumoto et al., 2017^Citation55	Fructooligosaccharide (FOS)	5% of the regular diet	Mice

Table 8. Metagenomic analysis outcome on alpha diversity for probiotic intervention.

Reference					Metagenomic analysis outcome (probiotics vs placebo)
	Colonized bacteria	Types of probiotics and dose	Antibiotics/conventional treatment	Trial period (days) Probiotics +antibiotics	Status of Alpha diversity	p-value	Status of Beta diversity	p-value
Chen et al., 2021^Citation65	H. pylori	L. acidophilus and L. rhamnosus (one sachet containing 3 × 10^Citation9 CFU per sachet, twice a day for 28 days)	No antibiotics, only a placebo	28	Alpha diversity changed significantly	Shannon index (p= 0.097), Chao index (p = 0.05)	No significant difference was observed	PERMANOVA (p = 0.76)
Oh et al., 2016^Citation52	H. pylori	Streptococcus faecium 9x10^Citation8 CFU/day, Bacillus subtilis 1x10^Citation8 CFU/day	500 mg of clarithromycin, 1 g amoxicillin, and 30 mg of lansoprazole	14+14	Alpha diversity increased in the probiotics group	Shannon diversity (p<0.05)	Not analyzed
Piewngam et al.,2018^Citation64	S. aureus	Bacillus subtilis spores	No antibiotics	14	Alpha diversity did not change.	Shannon index (p value not mentioned) Chao index, p value not mentioned	Beta diversity changed but not significant
Yang et al., 2021^Citation51	H. pylori	Non-viable L. reuteri DSM17648 L. reuteri DSM17648 (1 × 1010/day)	Standard triple therapy (esomeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg)	28 +14	Alpha diversity changed significantly	Chao index (p = 0.001), Shannon index (p =0.001)	Beta diversity significantly increased in the probiotics group	(p = 0.002)
Tang et al., 2021^Citation46	H. pylori	Enterococcus faecium 4.5 x 10^Citation8 and B. subtilis 5.0 x 10^Citation7 (three times a day for four weeks)	14-day BQT (esomeprazole 20 mg, amoxicillin 1000 mg, furazolidone 100 mg, bismuth potassium citrate 220 mg, all given twice daily	28 +14	Alpha diversity increased after the treatment	Shannon diversity (p > 0.05) is not significant	Significant difference observed at 4 weeks	(p = 0.03)

Table 9. Metagenomic analysis outcome on the microbiome composition for probiotic intervention.

Study	Probiotics Treatment	Changes in the phyla after treatment		Changes in the genera after treatment
		Probiotics group	Placebo	Probiotics (Genera increased)	Probiotics (Genera decreased)	Placebo (Genera increased)	Placebo (Genera decreased)
Chen et al., 2021^Citation65	L. acidophilus and L. rhamnosus (one sachet containing 3 × 10^Citation9 CFU per sachet, twice a day for 28 days)	Firmicutes reduced, Actinobacteria and Bacteroidetes reduced but not significant.	Firmicutes and Bacteroides increased, Proteobacteria and Actinobacteria decreased	Stackia Eubacterium Mitsuokella Xylanophilum Pseudoflavonifactor	Prevotelleceae Peptococcus Enterococcus Paludecola Selimonas	Succinatimonas Gordonibacter Sangubacteroids Anaerostipes Erysipeletoclostridium Lactobacillus Hydrogenoanaerobacterium UCG-011	Pseudomonas Oxalobacter Roultella Dielma Frisingicoccus Lachanospiraceae Mitsuokella Hungatella
OH 2015^Citation52	Streptococcus faecium 9x10^Citation8 CFU/day, Bacillus subtilis 1x10^Citation8 CFU/day for 14 days	Firmicutes were reduced, Proteobacteria were increased The number of OTUs reduced from 231 to 186	Proteobacteria were increased, Firmicutes increased The number of OTUs reduced from 219 to 120		Drug-resistant Citrobacter, Klebsiella, PseudomonasEscherichia	Drug-resistant Klebsiella Citrobacter
He et al., 2022^Citation33	Saccharomyces boulardii (14 days)	Not analyzed	Not analyzed	Bifidobacterium Lactobacillus Bacteroides	Enterococcus Enterobacter	Enterococcus Enterobacter	Bifidobacterium Lactobacillus Bacteroids
Yang et al., 2021^Citation51	Non-viable L. reuteri DSM17648 L. reuteri DSM17648 (1 × 1010/day) (28 days)	Firmicutes Actinobacteria Bacteroides increased and Proteobacteria decreased	Only proteobacteria increased	Fecalibacterium Bifidobacterium Subdoligranulum Prevotella Collinsella Fuscicatenibacter Baceroids	Blautia Shigella Escherichia	Blautia Shigella Escherichia	Fecalibacterium Bifidobacterium Subdoligranulum Prevotella Collinsella Fuscicatenibacter Bacteroides
Tang et al., 2021^Citation46	Enterococcus faecium 4.5 x 10^Citation8 and B. subtilis 5.0 x 10^Citation7 (three times a day for 28 days)	Proteobacteria increased. Actinobacteria, Firmicutes, Bacteroidetes, and Fusobacteria remained the same.	Proteobacteria reduced, and Other phyla remained the same.	Shigella, Klebsiella, Streptococcus, Veillonella, Bacteroides, Faecalibacterium,	Roseburia, Phascolarctobacterium, Blautia	Shigella, Klebsiella, Streptococcus, Veillonella	Bacteroides, Faecalibacterium Roseburia, Phascolarctobacterium, Blautia
Piewngam et al., 018^Citation64	Bacillus subtillis spores	Actinobacteria, Firmicutes increased and Bacteroidetes, Proteobacteria decreased	Proteobacteria and Bacteroidetes increased and Firmicutes, Actinobacteria decreased	Not analyse	Not analyse

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