Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: A systematic review

Nora C Carpay; Kim Kamphorst; Tim G J de Meij; Joost G Daams; Arine M Vlieger; Ruurd M van Elburg

doi:10.1371/journal.pone.0277405

. 2022 Nov 9;17(11):e0277405. doi: 10.1371/journal.pone.0277405

Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: A systematic review

Nora C Carpay ^1,^*,^#, Kim Kamphorst ^1,^#, Tim G J de Meij ², Joost G Daams ³, Arine M Vlieger ^4,^‡, Ruurd M van Elburg ^1,^‡

Editor: Ozra Tabatabaei-Malazy⁵

PMCID: PMC9645654 PMID: 36350926

Abstract

Background and aims

Disruption of the developing microbiota by Caesarean birth or early exposure to antibiotics may impact long-term health outcomes, which can potentially be prevented by nutritional supplements. This systematic review aimed to summarise the evidence regarding the effects of prebiotics, probiotics and synbiotics on the intestinal microbiota composition of term infants born by Caesarean section or exposed to antibiotics in the first week of life.

Methods

A systematic search was performed from inception to August 2022 in Medline and Embase. Two researchers independently performed title and abstract screening (n = 12,230), full-text screening (n = 46) and critical appraisal. We included randomised controlled trials which included term-born infants who were born following Caesarean section or who were exposed to postpartum antibiotics in the first week of life, pre-, pro- or synbiotics were administered <6 weeks after birth and outcome(s) consisted of microbiota analyses.

Results

Twelve randomised controlled trials investigating Caesarean born infants and one randomised controlled trial including infants exposed to antibiotics were included. Group sizes varied from 11 to 230 with 1193 infants in total. Probiotic (n = 7) or synbiotic (n = 3) supplementation significantly increased the abundance of the supplemented bacterial species (of the Bifidobacterium and Lactobacillus genus), and there was a decrease in Enterobacteriaceae, especially <4 weeks of age. At phylum level, Actinobacteria (two studies), Proteobacteria (one study) and Firmicutes (one study) increased after probiotic supplementation. In three studies on prebiotics, two studies reported a significant increase in Bifidobacteria and one study found a significant increase in Enterobacteriaceae.

Discussion

Prebiotic, probiotic and synbiotic supplements seem to restore dysbiosis after Caesarean section towards a microbial signature of vaginally born infants by increasing the abundance of beneficial bacteria. However, given the variety in study products and study procedures, it is yet too early to advocate specific products in clinical settings.

Introduction

The human gastrointestinal microbiota is a collection of all microorganisms (bacteria, viruses, fungi, protozoa) residing in the gastrointestinal tract. Together, these microorganisms affect processes such as metabolism [1,2] and inflammatory and immunological responses[2], and also influence the integrity and structure of the gastrointestinal tract [2]. The normal gastrointestinal microbiota develops rapidly after birth and is highly dynamic until it shifts towards an adult-like composition around the age of three years [3]. This development is driven by exposure to microbes from maternal, environmental, and dietary sources [4] and can be disrupted by many factors, especially when they occur early in this developmental process.

Caesarean section is one of the most important causes of disrupted microbiota development due to reduced vertical mother-infant transmission of beneficial intestinal bacteria (specifically of the Lactobacillus and Bifidobacterium genus). It has been suggested that the prenatal antibiotic exposure during a Caesarean section also affects the infant’s microbiota development, but a recent randomised controlled trial (RCT) reported that prenatal exposure to antibiotics during caesarean section does not further disrupt the microbiota colonisation [5]. During and after a Caesarean section, the infant becomes predominantly colonised with bacteria from the hospital environment (e.g. Staphylococcus, Corynebacterium and Propionibacterium species) [1,2,6,7]. Dysbiosis after Caesarean section can persist for as long as seven years and is associated with a higher risk of obesity, atopy, and type 1 diabetes mellitus [6].

In addition to Caesarean deliveries, exposure to antibiotics in early life has been associated with dysbiosis [8]. Early life antibiotics have been shown to decrease the abundance of Bifidobacteria [9] and Bacteroidetes [10] and increase the amount of Clostridia [8] and Enterobacteriaceae [9]. Antibiotics are the most frequently prescribed drugs in neonates with 8% of all European infants exposed to antibiotics in the first week of life [11]. The effect of antibiotic exposure, specifically in the first week of life, has been associated with an altered gut microbiota[9,12] a higher risk of wheezing [13], infantile colic [13], gastrointestinal disorders [14], impaired growth [12,15], allergies [16], and asthma [17].

These short- and long-term health effects linked to early dysbiosis through Caesarean delivery and neonatal antibiotic exposure illustrate the need for interventions aimed at restoration of this dysbiosis, and consequently prevention of related health consequences. Supplementation with prebiotics, probiotics or synbiotics has been described as a promising intervention to reduce some of the risks associated with early microbiota disruption. Probiotics are live microorganisms such as Bifidobacteria and Lactobacilli [7], while prebiotics are nutrients that promote growth and activity of bacteria that already exist in the gut [18]. Synbiotics are a combination of pre- and probiotics [18].

The aim of this systematic review is to identify all studies investigating the effects of a pre-, pro- or synbiotic supplement on the gut microbiota of term-born infants born by Caesarean section or exposed to antibiotics in the first week of life.

Methods

Literature search

OVID Medline and Embase were systematically searched from inception to August 10, 2022. The search strategy was constructed in collaboration with a medical librarian (JD) and was composed of the following components:

([c section] OR ([antibiotic treatment] AND [first week of life] OR [first week antibiotics])) AND

[pre- pro- synbiotics]

[dietary supplements] AND [microbiome]

[dietary supplements brands]

In order to reduce recall bias and enhance search results precision VOS-viewer was used to identify terms for NOTing out irrelevant records from databases searched [19]. No other filters or limits were used. The full search term including the specific keywords and combinations of search components can be found in the S1 Table.

Eligibility criteria

The following inclusion criteria were applied, all criteria had to be met for inclusion:

study participants were term-born infants who were born following Caesarean section or exposed to antibiotics in the first week of life (born vaginally or following Caesarean section),
administration of pre-, pro- or synbiotic dietary supplements was started within six weeks after birth,
reported outcome(s) consisted of microbiota analyses,
study design was a randomised controlled trial.

Exclusion criteria were:

studies including infants with major congenital malformations,
studies written in a language other than English,
animal studies,
for the Caesarean-analyses: studies which included both vaginally and Caesarean-delivered infants but performed no subgroup analyses for only the Caesarean-delivered infants

Data collection

All records found in the search were exported into Rayyan after deduplication [20]. Two researchers (NC and KK) independently performed title and abstract screening, as well as full-text screening. Titles and abstracts were screened by determining whether the article could meet the in- and exclusion criteria stated above. After consensus on the included articles, relevant data was extracted by NC in consultation with the other co-authors. Reference lists of the included articles were hand-searched to look for additional relevant studies.

All significant outcomes provided in the main text or supplemental information were summarised in a table, and non-significant results from studies investigating the same outcomes were reported in separate bar charts.

If both “per protocol” and “(modified) intention to treat” analyses were available, only the results from the “(modified) intention to treat” analysis were included in the table.

Critical appraisal

To assess the risk of bias in the included articles, the Cochrane risk-of-bias tool for randomised controlled trials (RoB 2) [21] was used. The RoB 2 assesses the risk of bias of studies in five domains: bias arising from the randomisation process, bias due to deviations from the intended intervention, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported results. Risk of bias was independently assessed by two researchers (NC and KK) and any discrepancies were discussed until a consensus was reached. The guidance document of the RoB 2 was used to determine whether articles had a high, some or a low risk of bias. If a study included both vaginally and Caesarean-delivered infants and performed a subgroup analysis on the Caesarean-delivered infants, only the methods used for the relevant subgroup analyses were assessed.

The review and protocol were not registered. This systematic review was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses [22].

Results

Of the 15,756 records, 12,230 remained after deduplication. After title and abstract screening, 56 articles were deemed suitable for full-text screening. Finally, 13 articles were included for analysis (Fig 1). Hand-searching the reference lists of these articles did not result in any more inclusions.

Study characteristics

In total, 13 articles were included, based on 12 randomised controlled trials (Fig 1); Lay et al [23] published results of a subgroup analysis based on the RCT by Chua et al. [24].

The 12 microbiota studies investigated the effect of prebiotics [23–26] (n = 3), synbiotics [23,24,27,28] (n = 3) and probiotics [29–35] (n = 7) (Table 1). The interventions were started between birth and the first three weeks of life, and treatment duration varied between five days after birth and six months of age. All studies investigated the effect of these interventions on infants born via Caesarean section, except for one study which included infants who received antibiotic treatment within three days after birth [35].

Table 1. General characteristics of the included randomised controlled trials.

First author	Country	Study period (year published)	# Participants¹			AB or CS SG?	Feeding method	Intervention	Control	Start of intervention	Duration intervention	Outcomes (relevant subgroup)	Follow-up	Comments
First author	Country	Study period (year published)	I	C	T	AB or CS SG?	Feeding method	Intervention	Control	Start of intervention	Duration intervention	Outcomes (relevant subgroup)	Follow-up	Comments
Chua [24]	Singapore & Thailand	2011–2013 (2017, 2021)	52 + 51	50	153	CS	Mixed (FF + BF)	Prebiotic (scGOS/lcFOS) or synbiotic (scGOS/ICFOS and Bifidobacterium breve M-16V)	Control formula	1–3 D	16 W	Total faecal Bifidobacterium, Bifidobacterium species abundance, other members of the gut microbiota, pH, sc fatty acids, lactate	3, 5 D 2, 4, 8, 12, 16, 22 W	Infants born via CS were also exposed to intrapartum AB prophylaxis. Lay et al.: some results were based on a SG
Lay [23]	Singapore & Thailand	2011–2013 (2017, 2021)	39 + 44	44	127	CS	Mixed (FF + BF)		Control formula	1–3 D	16 W		3, 5 D 2, 4, 8, 12, 16, 22 W
Berger [25]	Italy & Belgium	2012–2015 (2020, 2017)	19	24	43	CS SG	Exclusive FF	Prebiotics: 2 HMOs (2’-fucosyllactose and lacto-N-neotetraose)	Control formula	0–14 D	6 M	Stool microbiota diversity	3, 12 M	-
Korpela [29]	Finland	2000–2003 (2018, 2018, 2009, 2017)	35	44	79	CS SG	Exclusive BF, mixed feeding or FF	Probiotic: Lactobacillus rhamnosus LC705, Bifidobacterium breve Bb99, Propionibacterium freudenreichii spp., shermanii JS	Placebo (micro-crystalline cellulose)	36 W gestation + from birth	6 M	Microbiota composition	3 M	Infants had to be at risk for atopic disease (at least one parent with asthma, allergic rhinitis or eczema) and this intervention was initiated prenatally (36 W gestation)
Baglatzi [30]	Greece	2009–2011 (2016)	84	80	164	CS	Exclusive or mixed FF	Probiotic: regular dose of Bifidobacterium lactis	Low dose of B. lactis	Birth	6 M	Detection of B. lactis	12 M	No control group that was fed formula without pre-, pro-, or synbiotics
Cooper [27]	South Africa	2008–2013 (2016)	92	101	193	CS SG	Exclusive FF	Synbiotic: BMOs (containing GOS and MOS such as 3’- and 6’ sialyllactose) + Bifidobacterium lactis CNCM-I-3446	Control formula	Birth (≤3 D)	6 M	Faecal (bifido)bacteria, anthropometrics, faecal pH, lean mass, fat mass and bone mineral content, digestive tolerance, immune parameters, HIV infection status, frequency of morbidity episodes	1 Y	All included infants had HIV+ mothers and all mothers and infants received antiretroviral medication. Infants who tested positive for HIV were excluded
Estorninos [26]	Philippines	2016–2018 (2022)	115	115	230	CS SG	Exclusive FF	Prebiotic: bovine MOS (GOS and sialylated-oligosaccharides)	Control formula	3 W	6 M	Phylogenetic distance/microbiota composition, Bifidobacteria abundance	4 M	At the 2.5 month time point, only a subgroup of 75 infants for each group provided a faecal sample
Frese [31]	USA	2015–2016 (2017)	11	9	20	CS SG	Any	Probiotic: Bifidobacterium infantis EVC001	None	7 D	27 D	Microbiota composition, relative abundances of the most abundant taxonomic groups	60 D	Significantly more mothers in the control group were primiparous
Garcia Rodenas [32]	Greece	2010–2011 (2016)	11	10	21	CS SG	Exclusive FF	Probiotic: Lactobacillus reuteri DSM 17938	Control formula	<72 H	6 M	Relative abundance of OTUs, weighted UniFrac distances, relative abundance of Bifidobacterium	4 M	-
Hurkala [33]	Poland	2014–2017 (2020)	71	77	148	CS	Exclusive FF	Probiotic: Bifidobacterium breve PB04 and Lactobacillus rhamnosus KL53A	None	<1 H	Until discharge (5 or 6 D)	Abundance of lactobacilli in faeces, populations of Bifidobacterium in faeces, populations of potentially pathogenic bacteria	1 M	Significantly more missing stool samples from the control group (29 compared to 13 in the intervention group)
Roggero [34]	Italy	2015–2016 (2020)	16	16	32	CS SG	Exclusive FF	Probiotic: Lactobacillus paracasei CBA L74	Control formula	<7 D	3 M	sIgA production, antimicrobial peptides, microbiota diversity, metabolome, abundance of bacterial genera	90 D	Infants may have been breastfed for a few days before enrolment
Yang [28]	China	2018 (2021)	7 + 7	9	23	CS	BF	Synbiotic: high and low dose of Bifidobacterium lactis Bi-07 and Lactobacillus rhamnosus HN001 + GOS	No probiotic	Birth	28 D	Diversity of gut microbiota, gut microbiota composition, COGs	28 D	-
Zhong [35]	China	2017–2018 (2021)	25 + 13	17	55	1 week AB	Any	Probiotic: Bifidobacterium longum, Lactobacillus acidophilus and Enterococcus faecalis during or after AB treatment	None	Beginning or end of AB treatment (AB treatment started <3 D after birth)	42 D	Gut microbiota, relative abundance of OTUs	42 D	Children were not necessarily born via CS, but received AB in the first week of life

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¹ # participants in a subgroup, if applicable.

I Intervention.

C Control.

T Total.

CS Caesarean section.

SG subgroup.

BF breastfeeding.

FF formula feeding.

HMOs human milk oligosaccharides.

(sc) GOS: (short chain) galactooligosaccharides.

(lc) FOS: (long chain) fructooligosaccharides.

Spp. Several species.

BMOs bovine milk oligosaccharides.

MOS: Milk oligosaccharides.

D days.

M months.

W weeks.

H hours.

Y year.

AB antibiotic.

LRTI lower respiratory tract infection.

URTI upper respiratory tract infection.

OTU operational taxonomic unit.

sIgA secretory Immunoglobulin A.

COG: Clusters of orthologous groups of proteins.

Critical appraisal

The assessment of the risk of bias of the included studies is provided in Table 2. Of the 12 studies, 10 were determined to have a high risk of bias, mainly due to issues in adhering to the intervention. Most studies did not address the extent to which participants adhered to the intervention, and if they did, the appropriate analyses necessary to estimate the effect of the non-adherence to the intervention were not applied.

Table 2. Risk of bias of the included studies.

First author	Domains of the Cochrane risk-of-bias tool for randomised controlled trials (RoB-2)
First author	Domain 1	Domain 2	Domain 3	Domain 4	Domain 5	Total
Chua [24]
Lay [23]
Berger [25]
Estorninos [26]
Korpela [29]
Baglatzi [30]
Cooper [27]
Frese [31]
Garcia Rodenas [32]
Hurkala [33]
Roggero [34]
Yang [28]
Zhong [35]

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Green: Low risk of bias, yellow: Some risk of bias, red: High risk of bias.

Domain 1: Risk of bias arising from the randomisation process.

Domain 2: Risk of bias due to deviations from the intended interventions (effect of adhering to intervention).

Domain 3: Missing outcome data.

Domain 4: Risk of bias in measurement of the outcome.

Domain 5: Risk of bias in selection of the reported result.

The effect of pre-, pro- and synbiotics after antibiotics in the first week of life

The effects of the interventions were divided in three time clusters: 0–1 weeks, 1–4 weeks, or >4 weeks. The only study during or after antibiotic treatment in the first week of life investigated the effect of a probiotic supplement containing Bifidobacterium longum, Lactobacillus acidophilus and Enterococcus faecalis [35]. At the phylum level they found a significant increase in abundance of Actinobacteria and Proteobacteria at 0–1 weeks and >4 weeks and an increase in Actinobacteria at 1–4 weeks. At the genus level, they reported a significant increase in the relative abundance of Bifidobacterium at 0–1 weeks and >4 weeks (Table 3).

Table 3. Effects of pre-, pro- or synbiotic interventions on microbiota composition.

First author	Intervention			# Participants¹			Analysis techniques	Time points	Outcomes: microbiota composition
First author	Pre-/pro-/synbiotic	Start	Duration	I	C	T	Analysis techniques	Time points	Diversity + Compositional differences	Phylum level	Family level	Genus level	Species level	Other
0–1 Week
Cooper [27]	Synbiotic: BMOs (containing GOS and MOS such as 3’- and 6’ sialyllactose) + B. lactis CNCM-I-3446	Birth (≤3 D)	6 M	92	101	193	PCR, FISH	3 D	n.s.
Chua [24]	Prebiotic (scGOS/lcFOS)	1–3 D	16 W	39	45	84	16S rRNA sequencing + FISH + qPCR	3/5 D				% Bifidobacteria: ↑
Chua [24]	Synbiotic (scGOS/ICFOS and B. breve M-16V)	1–3 D	16 W	45	45	90	16S rRNA sequencing + FISH + qPCR	3/5 D			% Enterobacteriaceae: ↓	Estimated mean of total Bifidobacterium gene count: ↑ % Bifidobacteria: ↑ Bifidobacteria count: ↑	B. breve M-16V [intervention] detected in infant: ↑	Acetate: ↑ pH: ↓
Lay [23]	Prebiotic (scGOS/lcFOS)	1–3 D	16 W	39	44	83	Shotgun 16S rRNA sequencing of the V3-V6 region, shotgun metagenomics, metatranscriptomics and metabolomics	3/5 D	n.s.
	Synbiotic (scGOS/ICFOS and B. breve M-16V)	1–3 D	16 W	44	44	88		3 D	Compositional difference		Relative abundance of strict anaerobes^: ↑ Relative abundance of facultative anaerobes/aerobes^: ↓ Bifidobacteriaceae*: ↑	Bifidobacterium: ↑	Abundance of B. breve [intervention]: ↑
	Synbiotic (scGOS/ICFOS and B. breve M-16V)	1–3 D	16 W	44	44	88		5 D	Compositional difference		Relative abundance of strict anaerobes^: ↑ Relative abundance of facultative anaerobes/aerobes^: ↓ Bifidobacteriaceae*: ↑	Bifidobacterium: ↑ Haemophilus: ↓	Abundance of B. breve [intervention]: ↑
Yang [28]	High dose of synbiotic: B. lactis Bi-07 and L. rhamnosus HN001 + GOS	Birth	28 D	7	9	16	16S rRNA gene sequencing of the V3-V4 region + PCR	3 D				Relative abundance of Bifidobacterium: ↑ Relative abundance of Lactobacillus: ↑
				6	8	14		7 D				Relative abundance of Lactobacillus: ↑
	Low dose of synbiotic: B. lactis Bi-07 and L. rhamnosus HN001 + GOS			7	9	16		3 D				Relative abundance of Bifidobacterium: ↑ Relative abundance of Lactobacillus: ↑
				5	8	13		7 D				Relative abundance of Lactobacillus: ↑
Hurkala [33]	Probiotic: B. breve PB04 and L. rhamnosus KL53A	<1 H	5 or 6 D	71	77	148	PCR	5/6 D				Abundance of Lactobacilli: ↑ Abundance of Bifidobacterium: ↑	L. rhamnosus [intervention]: ↑ B. breve [intervention]: ↑
Zhong [35]	Probiotic: B. longum, L. acidophilus and E. faecalis during AB treatment	<3 D	42 D	25	17	42	16S rRNA gene sequencing of the V3-V4 region + PCR	1 W		Relative abundance Actinobacteria: ↑ Relative Abundance Proteobacteria: ↑		Relative abundance of Bifidobacterium: ↑
Zhong [35]	Probiotic: B. longum, L. acidophilus and E. faecalis after AB treatment	7 D	42 D	13	17	30	16S rRNA gene sequencing of the V3-V4 region + PCR	1 W	n.s.
1–4 Weeks
Cooper [27]	Synbiotic: BMOs (containing GOS and MOS such as 3’- and 6’ sialyllactose) + B. lactis CNCM-I-3446	Birth (≤3 D)	6 M	92	101	193	PCR, FISH	10 D				Faecal Bifidobacterium counts: ↑ Faecal detection rate of Bifidobacteria: ↑ Faecal detection rate of Bacteroides: ↑	Faecal detection of B. lactis CNCM I-3446 [intervention]: ↑	Mean faecal pH: ↓
Cooper [27]		Birth (≤3 D)	6 M	92	101	193	PCR, FISH	1 M				Faecal Bifidobacterium counts: ↑ Faecal detection rate of Bifidobacteria: ↑ Faecal detection rate of Lactobacillus: ↑	Faecal detection of B. lactis CNCM I-3446 [intervention]: ↑	Mean faecal pH: ↓
Chua [24]	Prebiotic (scGOS/lcFOS)	1–3 D	16 W	39	45	84	16S rRNA sequencing + FISH + qPCR	2 W			% Enterobacteriaceae: ↑
	Prebiotic (scGOS/lcFOS)			39	45	84		4 W						pH: ↓
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			45	45	90		2 W			% Enterobacteriaceae: ↓	Estimated mean of total Bifidobacterium gene count: ↑ % Bifidobacteria: ↑ Bifidobacteria count: ↑	B. breve M-16V [intervention] detected in infant: ↑	pH: ↓
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			45	45	90		4 W			% Enterobacteriaceae: ↓	Estimated mean of total Bifidobacterium gene count: ↑ % Bifidobacteria: ↑ Bifidobacteria count: ↑	B. breve M-16V [intervention] detected in infant: ↑	pH: ↓
Lay [23]	Prebiotic (scGOS/lcFOS)	1–3 D	16 W	39	44	83	Shotgun 16S rRNA sequencing of the V3-V6 region, shotgun metagenomics, metatranscriptomics and metabolomics	2 + 4 W	n.s.
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			44	44	88		2 W	Compositional difference		Relative abundance of strict anaerobes^: ↑ Relative abundance of facultative anaerobes/aerobes^: ↓ Bifidobacteriaceae*: ↑	Bifidobacterium: ↑	Abundance of B. breve [intervention]: ↑
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			44	44	88		4 W			Clostridiaceae: ↓		Abundance of B. breve [intervention]: ↑
Garcia Rodenas [32]	Probiotic: L. reuteri DSM 17938	<72 H	6 M	11	10	21	16S rRNA gene sequencing of the V1- V3 regions + PCR	2 W	Compositional difference	Relative abundance of Actinobacteria: ↑ Relative abundance of Firmicutes: ↑	Relative abundance of Enterobacteriaceae: ↓ Relative abundance of Bifidobacteriaceae: ↑ Relative abundance of Lactobacillaceae: ↑	Detectable Bifidobacterium: ↑ Relative abundance of Lactobacillus: ↑	Abundance of L. reuteri [intervention]: ↑
Zhong [35]	Probiotic: B. longum, L. acidophilus and E. faecalis during AB treatment	<3 D	42 D	25	17	42	16S rRNA gene sequencing of the V3-V4 region + PCR	2 W	n.s.
Zhong [35]	Probiotic: B. longum, L. acidophilus and E. faecalis after AB treatment	7 D	42 D	13	17	30	16S rRNA gene sequencing of the V3-V4 region + PCR	2 W		Relative abundance of Actinobacteria: ↑
Hurkala [33]	Probiotic: B. breve PB04 and L. rhamnosus KL53A	<1 H	5 or 6 D	58	48	106	PCR	1 M				Abundance of Lactobacilli: ↑
Yang [28]	High dose of synbiotic: B. lactis Bi-07 and L. rhamnosus HN001 + GOS	Birth	28 D	6	5	11	16S rRNA gene sequencing of the V3-V4 region + PCR	1 M	n.s.
Yang [28]	Low dose of synbiotic: B. lactis Bi-07 and L. rhamnosus HN001 + GOS	Birth	28 D	7	5	12	16S rRNA gene sequencing of the V3-V4 region + PCR	1 M	n.s.
>4 weeks
Zhong [35]	Probiotic: B. longum, L. acidophilus and E. faecalis during AB treatment	<3 D	42 D	25	17	42	16S rRNA gene sequencing of the V3-V4 region + PCR	42 D		Relative abundance of Actinobacteria: ↑ Relative abundance of Proteobacteria: ↑		Relative abundance of Bifidobacterium: ↑
Zhong [35]	Probiotic: B. longum, L. acidophilus and E. faecalis after AB treatment	7 D	42 D	13	17	30	16S rRNA gene sequencing of the V3-V4 region + PCR	42 D	n.s.
Chua [24]	Prebiotic (scGOS/lcFOS)	1–3 D	16 W	39	45	84	16S rRNA sequencing + FISH + qPCR	12 W	n.s.
	Prebiotic (scGOS/lcFOS)			39	45	84		16 W			% Enterobacteriaceae: ↑
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			45	45	90		12 W			% Enterobacteriaceae: ↓	Bifidobacteria count: ↑	B. breve M-16V detected in infant: ↑
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			45	45	90		16 W					B. breve M-16V detected in infant: ↑
Lay [23]	Prebiotic (scGOS/lcFOS)	1–3 D	16 W	39 44	44 44	83 88	Shotgun 16S rRNA sequencing of the V3-V6 region, shotgun metagenomics, metatranscriptomics and metabolomics	8 W			Staphylococcaceae: ↓
	Prebiotic (scGOS/lcFOS)			39 44	44 44	83 88		12, 16, 22 W	n.s.
	Synbiotic (scGOS/ICFOS and B. breve M-16V)			10	10	20		8 W	Shannon diversity: ↑				B. longum: ↓
								12, 16 W	n.s.
								22 W					V. dispar: ↑
Estorninos [26]	Prebiotic: bovine MOS (GOS and sialylated-oligosaccharides)	3 W	6 M	75	75	150	16S rRNA gene sequencing of the V3-V4 region	2.5 M	Compositional difference
Estorninos [26]	Prebiotic: bovine MOS (GOS and sialylated-oligosaccharides)	3 W	6 M	114	112	226	16S rRNA gene sequencing of the V3-V4 region	4 M	Compositional difference			Abundance of Bifidobacterium: ↑
Berger [25]	Prebiotics: 2 HMOs (2’-fucosyllactose and lacto-N-neotetraose)	0–14 D	6 M	19	24	43	16S rRNA gene sequencing of the V3-V4 region	3 M	n.s.
Korpela [29]	Probiotic: L. rhamnosus LC705, B. breve Bb99, P. freudenreichii spp., shermanii JS and GOS	36 W gest. + from birth	6 M	35	44	79	16S rRNA gene amplicon sequencing of the V3-V4 region	3 M			Bifidobacteriaceae: ↑ Coriobacteriaceae: ↑ Porphyromonadaceae: ↑ Bacteroidaceae: ↑
Cooper [27]	Synbiotic: BMOs (containing GOS and MOS such as 3’- and 6’ sialyllactose) + B. lactis CNCM-I-3446	Birth (≤3 D)	6 M	92	101	193	PCR, FISH	3 M				Faecal Bifidobacteria counts: ↑ Faecal detection rate of Clostridium/Eubacterieum: ↓	Faecal detection of B. lactis CNCM I-3446 [intervention]: ↑	Mean faecal pH: ↓
Roggero [34]	Probiotic: L. paracasei CBA L74	<7 D	3 M	16	16	32	16s RNA gene sequencing of the V3 region	3 M						sIgA production: ↑
Baglatzi [30]	Probiotic: regular dose of B. lactis	Birth	6 M	84	80	164	PCR	4 M					Positive detection of B. lactis [intervention]: ↑
Garcia Rodenas [32]	Probiotic: L. reuteri DSM 17938	<72 H	6 M	11	10	21	16S rRNA gene sequencing of the V1- V3 regions + PCR	4 M					Abundance of L. reuteri [intervention]: ↑

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*: g. bifidobacterium, o. pseudomonadales, f. actinomycetaceae, k. bacteria, g. staphylococcus, g. streptococcus, f. streptococcaceae, f. bifidobacteriaceae, o. enterobacteriales, f. Enterobacteriaceae.

**: f. Prevotellaceae, f. peptostreptococcaceae, f. ruminococcaceae, o. clostridiales, f. porphyromonadaceae, f. clostridiaceae, f. lachnospiraceae, f. veillonellaceae, f. bacteroidaceae, f. bifidobacteriaceae.

***: o. lactobacillales, o. bacillales, f. pasteurellaceae, f. staphylococcaceae, f. lactobacillaceae, f. enterococcaceae, o. enterobacteriales, f. streptococcaceae, f. Enterobacteriaceae.

¹ # participants in a subgroup, if applicable.

I Intervention.

C Control.

T Total.

CS Caesarean section.

SG subgroup.

HMOs human milk oligosaccharides.

(sc) GOS: (short chain) galactooligosaccharides.

(lc) FOS: (long chain) fructooligosaccharides.

BMOs bovine milk oligosaccharides.

MOS: Milk oligosaccharides.

D days.

M months.

W weeks.

H hours.

Y year.

AB antibiotics.

The effect of pre-, pro- and synbiotics after Caesarean section

Fig 2 summarises the number of statistically significant and non-significant differences that were found in the three time clusters. The significant microbiota changes in the experimental groups compared to the control groups (described in Table 1) are discussed in further detail below.

Diversity and compositional differences

One study [23] found compositional differences (using a distance-based redundancy analysis) at 0–1 weeks, 1–4 weeks and >4 weeks in the infants who received a synbiotic compared to those who received a prebiotic or placebo, and an increased diversity at 8 weeks using the Shannon diversity index. Researchers of two other studies [26,32] also measured compositional differences (phylogenetic distance) at 1–4 weeks [32] and >4 weeks [26] and reported a significantly different microbiota composition in infants who received a probiotic [32] or prebiotic [26] compared to a placebo.

Phylum level

Only one study [32] investigated the effect of a probiotic after Caesarean delivery on the phylum level. At 1–4 weeks, they found an increase in both Actinobacteria and Firmicutes in the probiotic group.

Family level

At 0–1 weeks, Chua et al. [24] found a significant decrease in the percentage of Enterobacteriaceae present in the stool of infants who received the synbiotic, but not those who received the prebiotic. Lay et al. [23], who analysed a subgroup of infants from the same study, reported an increase in relative abundance of strict anaerobes, a decrease in relative abundance of facultative anaerobes/aerobes and an increase in Bifidobacteriaceae in the synbiotic group.

At 1–4 weeks, Chua et al. again report a significant decrease in the percentage of Enterobacteriaceae in the synbiotic group, but a significant increase in the prebiotic group [24]. In a subgroup analysis by Lay et al., no significant differences were found in the prebiotic group, but an increase in strict anaerobes, decrease in facultative anaerobes/aerobes and Clostridiaceae and an increase in Bifidobacteriaceae was observed after a synbiotic supplement [23]. In line with their findings, another study[32] also found a significant increase in Bifidobacteriaceae. Additionally, they found a significant increase in Lactobacillaceae. Furthermore, they reported a significant decrease in the percentage of Enterobacteriaceae in their probiotic group, which is similar to Chua et al.’s findings in their synbiotic intervention group.

At >4 weeks, Chua et al. found the same results as at 1–4 weeks: a significant decrease in the percentage of Enterobacteriaceae in the synbiotic group, and a significant increase in the prebiotic group [24]. Moreover, in a subgroup a decrease in Staphylococcaceae was reported [23]. Another study found an increase in Bifidobacteriaceae, Coriobacteriaceae, Porphyromonadaceae and Bacteroidaceae [29].

Genus level

At 0–1 weeks, four articles [23,24,28,33] based on three RCTs reported a significant increase in abundance of the Bifidobacterium genus after administration of a probiotic[33], prebiotic [24], and synbiotic [23,24,28]. Two studies [28,33] also found an increase abundance of the Lactobacillus genus [28,33], and one study [23] reported a decrease of the Haemophilus genus.

At 1–4 weeks, four articles [23,24,27,32] from three RCTs found an increase in the Bifidobacterium genus after administration of a probiotic [27,32] or synbiotic [23,24]. Three [27,32,33] reported an increased (relative) abundance of Lactobacillus and one of these [27] also observed an increased abundance of Bacteroides.

At >4 weeks, three studies [23,26,27] reported an increased Bifidobacterium genus abundance, and one of the two [27] also found a decreased faecal detection rate of Clostridium/Eubacterium.

Species level

At 0–1 weeks, Chua et al. [24] and Lay et al. [23] (based on the same RCT) reported a significant increase of Bifidobacterium breve M-16V detected in the infants who received a synbiotic, which included this Bifidobacterium species.

At 1–4 weeks, three studies [24,27,32] found an increase in the faecal detection of the bacterial species they included in their intervention: Bifidobacterium lactis CNCM I-3446 [27], Bifidobacterium breve [23] and Lactobacillus reuteri [32].

At >4 weeks, three studies again reported an increase in faecal detection of their intervention: Bifidobacterium lactis [27,30] and Lactobacillus reuteri [32]. Another study also found a decreased abundance of Bifidobacterium longum and an increase in Veillonella dispar [23].

Intestinal microenvironment

At 0–1 weeks, one article [24] found a decreased faecal pH and increased acetate after administration of a synbiotic. At 1–4 weeks, the same study [24] and another [27] both reported a decreased faecal pH after administration of a synbiotic [24,27] or prebiotic [24]. At >4 weeks, one of the studies [27] still found a decreased faecal pH in the synbiotic-group [27], and another article [34] observed an increased secretory IgA (sIgA) production in infants who received a probiotic.

Discussion

The aim of this systematic review was to describe the effects of a pre-, pro- or synbiotic supplement on the gut microbiota following Caesarean section or exposure to antibiotics in the first week of life. Only one article investigated the effect of a probiotic on antibiotic-exposed infants; a mixture of three probiotics resulted in an increase in Actinobacteria, Proteobacteria and Bifidobacterium. For the Caesarean-born infants, the key finding was an increase in the supplemented bacterial species (of the Bifidobacterium and Lactobacillus genus) after probiotic or synbiotic supplements, and a decrease in Enterobacteriaceae after synbiotic but an increase after prebiotic supplementation. Furthermore, there were significant increases in Actinobacteria, Proteobacteria and Firmicutes in the probiotic groups compared to the control groups. Moreover, the microbiota composition of the probiotic or synbiotic group was significantly different from the control group in two studies, and bacterial species diversity was increased in one study after administration of a synbiotic.

Prebiotics are less extensively studied, and only few outcome parameters reached statistical significance. However, according to one included study, prebiotics increased the abundance of Enterobacteriaceae, which has been associated with potentially negative health effects such as an increased risk of atopic eczema [36], food allergy [37] and delayed colonisation of beneficial bacterial species [36]. Three articles based on two prebiotic studies reported an increase in Bifidobacteria [23,24,26] and two of the three also found a significantly different microbiota composition [23,26].

Because of the heterogeneity in the interventions in terms of study design and composition of the supplement, it is difficult to compare their efficacy. Generally, probiotics and synbiotics seem more effective in increasing the abundance of beneficial bacteria. Bifidobacteria and Lactobacilli, which were increased in the intervention groups of eight and five studies respectively, are associated with various health effects: both Bifidobacteria and Lactobacilli seem to protect from allergies [38,39] and infantile colic [38] and they are associated with healthy microbiota development [38]. Several species of the Bifidobacterium genus are commonly present in the infant gut, and their function is to digest sugars in human milk, reduce intestinal pH and improve the integrity of the intestinal wall [40]. Delivery via Caesarean section, which was the case in five [23,24,26,28,33] of the six studies investigating the microbiota at the genus level, results in a disrupted vertical transmission of Bifidobacterium [40]. The results in Table 3 indicate that a pro- or synbiotic intervention can alleviate this disruption and shift the neonatal microbiota composition towards that of vaginally born infants. Human milk oligosaccharides present in breast milk can also stimulate colonisation by Bifidobacteria [40]. Interestingly, all five articles that reported a significant increase of Bifidobacterium levels at 0–1 weeks included infants that were (also) breastfed. However, at the time points after this first week, other studies that included infants who were exclusively formula fed also show significant increases in Bifidobacterium levels. Moreover, three studies on pro- and synbiotics also found a significantly different microbiota composition or a more diverse microbiota in the intervention groups. Birth following Caesarean section or exposure to antibiotics in the first week of life reduces bacterial diversity, which makes these infants susceptible to colonisation by bacteria usually found on the mother’s skin such as Staphylococcus, Corynebacterium and Propionibacterium spp., which is associated with an increased risk of gastrointestinal and systemic disorders, including eczema allergies, later in life [41]. The results in Table 3 show that this diversity may (partially) be restored by supplementation with pro- or synbiotics and possibly prebiotics.

To our knowledge, this is the first systematic review evaluating the effects of pre-, pro- and synbiotics specifically in both Caesarean born and antibiotic-exposed infants. While another systematic review about the effects of pre-, pro- and synbiotics on the microbiota of children born via Caesarean section was published recently [42], we identified four additional relevant articles that were not included by Martin-Pelaez et al. Furthermore, some of their included articles did not perform a separate subgroup-analysis for children born via Caesarean section.

It is crucial to analyse these Caesarean born infants separately from vaginally born infants who were not exposed to antibiotics, because the effect of pre-, pro- and synbiotics may differ in infants with a disrupted microbiota from those who were born vaginally. Illustratively, in one of the trials included in our review, the effects of pre-, pro- and synbiotics on the microbiota was only significant in the Caesarean born subgroup [32]. Additionally, Frese et al. [31] did not perform a statistical subgroup analysis for the Caesarean born infants but the differences in the microbiota composition of their cohort seems to be largely driven by Caesarean born infants. Specifically, in their intervention group, they found a significant increase in faecal Bifidobacteriaceae and Bifidobacterium infantis, and a clear decrease in the relative abundances of Enterobacteriaceae, Clostridiaceae, Erysipelotrichaceae, Pasteurellaceae, Micrococcaceae and Lachnospiraceae. These findings suggest that especially infants with a disrupted microbiota might benefit most from an intervention with pre-, pro or synbiotics.

Important strengths of this review are the elaborate search strategy developed in collaboration with a medical librarian to include all relevant articles. We also looked for any subgroup analyses of Caesarean-born infants in the full texts, even when the title or abstract did not explicitly state that these were performed. We only included articles that performed analyses on Caesarean-born infants, and not articles that only analysed the total group of participants with vaginally born infants included.

Limitations of this study are that many articles that included a subgroup analysis of Caesarean-born infants reported only a selection of the outcomes for this subgroup. It is unclear whether more analyses were performed and only the significant results were published, which would result in publication bias. Similarly, many articles did not adjust for multiple testing. This is also reflected in the critical appraisal of the articles, which showed that 11 of the 13 included studies had a high risk of bias. Lastly, while some trials mentioned in this review included a reference group with vaginally born and/or exclusively breastfed infants, we chose to focus on analyses between intervention and placebo-controlled groups instead of also comparing the intervention groups to the reference group. For further research, it would be interesting to evaluate whether pre-, pro- and synbiotic interventions could restore the microbiota of infants born through Caesarean section or infants exposed to antibiotics to that of a healthy reference group.

Other recommendations for future research are firstly that, in order to be able to compare the results of different studies, studies should standardise their methods of faecal sample collection, storage, isolation and analyses. Furthermore, microbiota studies should increase their follow-up time to see whether any differences that were found between intervention and control groups persist beyond the duration of the intervention and to search for associations with long-term health outcomes. In addition, since the effect of a pre-, pro- or synbiotic on infants after antibiotic treatment in the first week of life was only investigated by one study [35], more RCTs are necessary in this group of infants. Moreover, to assess the clinical potential of pre-, pro- or synbiotic supplementation, it is crucial that high quality RCTs with predetermined clinical outcomes are conducted. Lastly, only one study [34] explored the effects of their intervention on the metabolome. The metabolome gives an indication of the function of the microbiota, and how the microbiota affects metabolites in urine, faeces and blood serum [43]. While most included studies focused their microbiota analysis on the microbiota composition, the metabolome might reveal important information on the mechanics by which the microbiota influences its host.

Conclusion

Supplementation of pre-, pro- or synbiotics in Caesarean-born infants and infants who received antibiotics early in life mostly increased the phyla, families, genera and species that corresponded to the pro- or synbiotic intervention that was administered, while the effects of a prebiotic generally did not reach statistical significance. Supplementation of these at-risk children to restore the microbiota to a composition more similar to vaginally born infants (i.e. predominant colonisation by Bifidobacteria and Lactobacilli) may alleviate some of the negative consequences of a disrupted microbiota. However, more high-quality research is needed to explicate the clinical effects of such microbiota changes and to determine which pre-, pro- or synbiotic products are most effective.

Supporting information

S1 Table. Full search strategy.

(DOCX)

Click here for additional data file.^{(24KB, docx)}

S2 Table. PRISMA checklist.

(DOCX)

Click here for additional data file.^{(31.6KB, docx)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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43.Brink LR, Mercer KE, Piccolo BD, Chintapalli SV, Elolimy A, Bowlin AK, et al. Neonatal diet alters fecal microbiota and metabolome profiles at different ages in infants fed breast milk or formula. Am J Clin Nutr. 2020;111(6):1190–202. Epub 2020/04/25. doi: 10.1093/ajcn/nqaa076 [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0277405.r001

Decision Letter 0

Ozra Tabatabaei-Malazy

4 Aug 2022

PONE-D-22-18775Microbial effects of supplemented prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: a systematic reviewPLOS ONE

Dear Dr. Carpay,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Ozra Tabatabaei-Malazy

Academic Editor

PLOS ONE

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2. We note that this manuscript is a systematic review or meta-analysis; our author guidelines therefore require that you use PRISMA guidance to help improve reporting quality of this type of study. Please upload copies of the completed PRISMA checklist as Supporting Information with a file name “PRISMA checklist”.

Additional Editor Comments:

Reviewer#1:

In the current manuscript, the authors summarize the evidence regarding the effects of prebiotics, probiotics, and symbiotics on the intestinal microbiota composition of term infants born by Caesarean section or exposed to antibiotics in the first week of life. The authors have focused on an important and interesting clinical question and covered elements that are necessary for a systematic review; the patient, group of patients, or problem being evaluated; the intervention; comparison interventions; and specific outcomes. The discussion section provides appropriate clarification from the authors whenever it is suspected. Authors have commented on the limitations of the review itself, including those of the included studies. Authors have considered fatal flaw(s) and performed risk of bias assessments. I think the current manuscript is acceptable.

Reviewer#2:

The topic of the systematic review is very interesting and useful for the scientific community. However, authors present a review that in my opinion needs to be worked in depth. I am concern specifically on important errors in methodology and discussion. Some of the most important issues I consider should be corrected for future applications are:

1. Authors included studies until August 2021, which is almost one year ago. I would recommend to the authors to check for the new articles that fill their selection criteria published during the last year.

2. The searching strings are not clear. Authors don´t indicate which are their keywords for their searching. Neither do they present the combinations of this keywords. A first consequence of this lack of accuracy in the searching strategy is the vast number of articles obtained (11248), leading to an unnecessary amount of screening work (title and abstract). The use of filters would have also helped them.

3. Besides the high amount of information give in the 2 tables, these results have been very poorly discussed in the discussion section. The results obtained must be always discussed in the discussion section. If those are not discussed, it does not make any sense to present them.

Other observations are:

Abstract: Selection criteria should be presented in the abstract. It is important to state the design of the studies selected for the review. Bifidobacterium and Lactobacillus are not species. Please define them or re-write the sentence. When reporting variations in gut microbial populations, please indicate the group of comparison.

Introduction: Why are authors naming “microbiome” to the “collection of microorganisms”? I am aware that many researchers use the term “gut microbiota” and “gut microbiome” indistinctly, but in essence, these terms don´t mean the same. Please explain.

The lack of vertical mother-to-infant transmission is not only the possible cause of microbial dysbiosis in the newborn. Please complete.

When authors write about antibiotic exposure, they seem to present this as an issue independent of caesarean section. However, they should bear in mind that antibiotic administration to the mother also occurs during caesarian section.

The definitions of pre, pro and synbiotics should be presented.

Results

Authors should indicate the reasons of the elimination of the articles in the first step of the screening (11193).

Table 1: The interventions must be given in detail regarding the CFU of the probiotics (alone or in combination with prebiotics in symbiotic preparations) the bacterial strains used in the probiotics and in the synbiotic formulations, the prebiotic amount provided per dose, the dairy dose, and the administration route.

Footnote of table one present two times “I”, for “Intervention” and for OUT.

Critical appraisal: authors should indicate what each color means.

Please check for mistakes in the bacterial nomenclature of bacteria (specially the use of italics) throughout the manuscript, including the tables.

Authors state that “this is the first systematic review evaluating the effects of pre-, pro- and synbiotics specifically in both Caesarean born and antibiotic-exposed infants”. However only 1 out of the 12 studies are actually dealing with antibiotics.

Reviewr#3:

Dear Authors,

The manuscript is in interesting filed. However, there are some major concerns.

Overall, whole manuscript is required to English language editing.

Then, please consider following comments.

Title:

-It is better to brief.

Abstract:

-Methods section: Please insert inclusion/exclusion criteria, main keywords, update the search, and insert grey literature

Introduction:

-Nearly, more than half of Ref. are addressed in this section, please reduce Ref.

-Please address past systematic reviews and then the novelty of the current study.

Methods:

-It is better to update search, insert grey literature, and confirm the method is based on PRISMA.

-Did you search ref. lists? It is essential to hand search Ref. list of the included studies when conducting a systematic review.

-In eligibility criteria, clarify characteristics of control group, they should receive which one? prebiotics, placebo, or none of them?

-The second inclusion criteria “six weeks after birth” is ambiguous. In table 1 is observed using intervention more than 6w. What is your reason?

-In critical appraisal; the last sentence “Several studies included…..”should move to discussion.

-Please delete “the review and protocol were not registrated”.

Results:

-First line: correct dictation “deduplication”.

-“ Lay et al.[33] published results of a subgroup analysis based on the RCT by Chua et al.[34]” Why included this study? It is a duplication publication. Please describe.

-Zhong et al study is included vaginal/cesarean delivery. Please recheck the data with original paper and correct them in your tables.

Discussion:

-This section needs to revise by adding more details and discussion about your results.

Best Regards,

Eic#:

Dear Authors,

Please consider following important points:

-Prepare a response letter point by point to each comment and highlight all corrections and changes by yellow color in whole manuscript.

-Consider Language Editing.

Best Regards,

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In the current manuscript, the authors summarize the evidence regarding the effects of prebiotics, probiotics, and symbiotics on the intestinal microbiota composition of term infants born by Caesarean section or exposed to antibiotics in the first week of life. The authors have focused on an important and interesting clinical question and covered elements that are necessary for a systematic review; the patient, group of patients, or problem being evaluated; the intervention; comparison interventions; and specific outcomes. The discussion section provides appropriate clarification from the authors whenever it is suspected. Authors have commented on the limitations of the review itself, including those of the included studies. Authors have considered fatal flaw(s) and performed risk of bias assessments. I think the current manuscript is acceptable.

Reviewer #2: The topic of the systematic review is very interesting and useful for the scientific community. However, authors present a review that in my opinion needs to be worked in depth. I am concern specifically on important errors in methodology and discussion. Some of the most important issues I consider should be corrected for future applications are:

Other observations are:

The lack of vertical mother-to-infant transmission is not only the possible cause of microbial dysbiosis in the newborn. Please complete.

The definitions of pre, pro and synbiotics should be presented.

Results

Authors should indicate the reasons of the elimination of the articles in the first step of the screening (11193).

Footnote of table one present two times “I”, for “Intervention” and for OUT.

Critical appraisal: authors should indicate what each color means.

Please check for mistakes in the bacterial nomenclature of bacteria (specially the use of italics) throughout the manuscript, including the tables.

Reviewer #3: Dear Authors,

The manuscript is in interesting filed. However, there are some major concerns.

Overall, whole manuscript is required to English language editing.

Then, please consider following comments.

Title:

-It is better to brief.

Abstract:

-Methods section: Please insert inclusion/exclusion criteria, main keywords, update the search, and insert grey literature

Introduction:

-Nearly, more than half of Ref. are addressed in this section, please reduce Ref.

-Please address past systematic reviews and then the novelty of the current study.

Methods:

-It is better to update search, insert grey literature, and confirm the method is based on PRISMA.

-Did you search ref. lists? It is essential to hand search Ref. list of the included studies when conducting a systematic review.

-In eligibility criteria, clarify characteristics of control group, they should receive which one? prebiotics, placebo, or none of them?

-The second inclusion criteria “six weeks after birth” is ambiguous. In table 1 is observed using intervention more than 6w. What is your reason?

-In critical appraisal; the last sentence “Several studies included…..”should move to discussion.

-Please delete “the review and protocol were not registrated”.

Results:

-First line: correct dictation “deduplication”.

-“ Lay et al.[33] published results of a subgroup analysis based on the RCT by Chua et al.[34]” Why included this study? It is a duplication publication. Please describe.

-Zhong et al study is included vaginal/cesarean delivery. Please recheck the data with original paper and correct them in your tables.

Discussion:

-This section needs to revise by adding more details and discussion about your results.

Best Regards,

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Solaleh Emamgholipour

Reviewer #2: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PLoS One. 2022 Nov 9;17(11):e0277405. doi: 10.1371/journal.pone.0277405.r002

Author response to Decision Letter 0

18 Sep 2022

Amsterdam, September 2022

PLOS ONE

Dr. Tabatabaei-Malazy

Dear Dr. Tabatabaei-Malazy,

We would like to thank you for the opportunity to revise and resubmit our manuscript “Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: a systematic review” for publication in PLOS ONE.

The thorough feedback of the reviewers is very much appreciated, and we have incorporated their comments to further improve our systematic review. On the following pages, we reply to each comment in chronological order. We hope that the revised manuscript meets the standards for publication in PLOS ONE.

We look forward to hearing from you regarding our submission, and we would be happy to address any further comments.

With kind regards,

on behalf of all authors,

Nora Carpay

First of all, we would like to thank the reviewers for their critical view and constructive remarks. We will reply to their comments in chronological order.

Reviewer #1:

We thank the reviewer for their positive assessment.

Reviewer #2:

We agree that the original search was performed quite some time ago. We repeated the search on August 10 2022 and included one more article by Estorninos et al., which was published in January 2022.

We have clarified our search string by adding that the complete search string including combinations of keywords can be found in the first supplemental table (S1 table), not in the main text of the review. Indeed, we have obtained a high number of articles by using this search string. However, we do not think that this was a lack of accuracy. We did not want to be too specific in our search string to avoid excluding any relevant articles and we constructed this search string in collaboration with a medical librarian. We did use a VOS-viewer to exclude some irrelevant keywords to narrow down the articles we found. Furthermore, we made sure that two independent reviewers carefully screened the titles and abstracts to make sure no relevant articles were missed, even though there was a high number of articles to be screened.

We agree that there are several results presented in the tables which are not discussed in detail in the discussion. We have now elaborated some more on the most important results, especially the observations that were reported in more than one study. We added the following sections, which can also be found in the document with tracked changes: “Furthermore, there were significant increases in Actinobacteria, Proteobacteria and Firmicutes in the probiotic groups compared to the control groups. Moreover, the microbiota composition of the experimental group was significantly different from the control group in two studies, bacterial species diversity was increased in one study after administration of a probiotic or synbiotic.” […] “Moreover, three studies on pro- and synbiotics also found a significantly different microbiota composition or a more diverse microbiota in the intervention groups. In general, the microbiome of healthy newborn infants is characterised by low diversity of bacterial species until solid foods are introduced. Birth following Caesarean section or exposure to antibiotics in the first week of life reduce this diversity to such an extent that makes them susceptible to colonisation by bacteria usually found on the mother’s skin such as Staphylococcus, Corynebacterium and Propionibacterium spp., which is associated with an increased risk of allergies later in life.” […] “Three articles based on two prebiotic studies reported an increase in Bifidobacteria and two of the three also found a significantly different microbiota composition”

We also wanted to include in the tables the changes that were found in only one study to show exactly what is known and which findings need more research to draw clear conclusions on the effects of pre-, pro- and synbiotics.

Other observations are:

Abstract

• Selection criteria should be presented in the abstract.

We added the inclusion criteria to the abstract.

• It is important to state the design of the studies selected for the review.

We added that studies had to be randomised controlled trials to be included in this review.

• Bifidobacterium and Lactobacillus are not species. Please define them or re-write the sentence.

Thank you for this correction. We clarified that the supplemented species were part of the Bifidobacterium and Lactobacillus genus.

• When reporting variations in gut microbial populations, please indicate the group of comparison.

We have now specified in the introduction of the results that the groups of comparisons can be found in Table 1. We chose not to describe each control group in the text of the results to maintain the readability and clarity of this section.

Introduction:

• Why are authors naming “microbiome” to the “collection of microorganisms”? I am aware that many researchers use the term “gut microbiota” and “gut microbiome” indistinctly, but in essence, these terms don´t mean the same. Please explain.

Thank you for your correction, we changed “microbiome” to “microbiota”.

• The lack of vertical mother-to-infant transmission is not only the possible cause of microbial dysbiosis in the newborn. Please complete.

In this section of the introduction, we specifically aimed to explain how Caesarean section causes microbial dysbiosis. We have now elaborated on the hypothesis that the intrapartum antibiotics during a Caesarean section also increases microbial dysbiosis in the introduction: “It has been suggested that the prenatal antibiotic exposure during a Caesarean section also affects the infant’s microbiota development, but a recent randomised controlled trial (RCT) reported that prenatal exposure to antibiotics during caesarean section does not further disrupt the microbiota colonisation.” [reference: Dierikx, T., Berkhout, D., Eck, A., Tims, S., van Limbergen, J., Visser, D., ... & de Meij, T. (2022). Influence of timing of maternal antibiotic administration during caesarean section on infant microbial colonisation: a randomised controlled trial. Gut, 71(9), 1803-1811.]

• When authors write about antibiotic exposure, they seem to present this as an issue independent of caesarean section. However, they should bear in mind that antibiotic administration to the mother also occurs during caesarean section.

Of course, antibiotic exposure also occurs during caesarean section. One of our co-authors, however, investigated the effect of maternal antibiotics before or after caesarean section on the infant’s microbiota and found no significant differences in the colonisation of the developing microbiota (see the article quoted above). We have clarified this topic in the introduction, as quoted above.

• The definitions of pre, pro and synbiotics should be presented.

We provided definitions of pre-, pro- and synbiotics in the second to last paragraph of the introduction: “Probiotics are live microorganisms such as Bifidobacteria and Lactobacilli,[6] while prebiotics are nutrients that promote growth and activity of bacteria that already exist in the gut.[19] Synbiotics are a combination of pre- and probiotics.[19]”

Results

• Authors should indicate the reasons of the elimination of the articles in the first step of the screening (11193).

We added an explanation of how the title/abstract screening process was executed to the methods section. (“Titles and abstracts were screened by determining whether the article could meet the in- and exclusion criteria stated above.”)

• Table 1: The interventions must be given in detail regarding the CFU of the probiotics (alone or in combination with prebiotics in symbiotic preparations) the bacterial strains used in the probiotics and in the synbiotic formulations, the prebiotic amount provided per dose, the dairy dose, and the administration route.

We agree with the reviewer that these data are important. However, given the fact that Table 1 is already very extensive, we decided not to include this specific information. Interested readers can find these data in the full texts of the included articles.

• Footnote of table one present two times “I”, for “Intervention” and for OUT.

Thank you for your correction, we changed the “I” for operational taxonomic units to “OTU”.

• Critical appraisal: authors should indicate what each color means.

The definitions of each colour were stated in the legend of the table. To make this clearer, we put the colour definitions at the top and made them bold to stand out.

• Please check for mistakes in the bacterial nomenclature of bacteria (specially the use of italics) throughout the manuscript, including the tables.

Thank you for bringing this to our attention, we made sure to correct the use of italics in the bacterial nomenclature.

• Authors state that “this is the first systematic review evaluating the effects of pre-, pro- and synbiotics specifically in both Caesarean born and antibiotic-exposed infants”. However only 1 out of the 12 studies are actually dealing with antibiotics.

While we agree that it is a shame that there is only one study investigating the effect of pre-, pro- and synbiotics on infants exposed to antibiotics in early life, we did thoroughly look for any articles dealing with this topic. Furthermore, while we identified one other review on the effects of pre-, pro- and synbiotics on Caesarean-born infants, they also included studies that included vaginally born infants as well without performing subgroup analyses. Therefore we feel justified in saying that this is the first review evaluating the effects of pre-, pro- and synbiotics specifically in Caesarean-born and antibiotic-exposed infants.

Reviewer #3:

Dear Authors,

The manuscript is in interesting filed. However, there are some major concerns.

Overall, whole manuscript is required to English language editing.

We asked a native speaker review and correct the manuscript.

Then, please consider following comments.

Title:

-It is better to brief.

We removed the unnecessary word “supplemented” from the title.

Abstract:

-Methods section: Please insert inclusion/exclusion criteria, main keywords, update the search, and insert grey literature

We inserted the inclusion/exclusion criteria and performed a new search, after which we included one more article by Estorninos et al. Furthermore, we aimed to summarise all relevant published articles but no unpublished papers (grey literature) as it would not be possible to search systematically for such literature. We recently repeated our search, so we believe that any studies described in trial registers for example that have now published their manuscripts would have come up in this second search.

Introduction:

-Nearly, more than half of Ref. are addressed in this section, please reduce Ref.

We removed some unnecessary double citations and reduced the number of references in the introduction from 28 to 18.

-Please address past systematic reviews and then the novelty of the current study.

We address the only other similar review we found in the discussion section and also explain why we think our review is an improvement: “While another systematic review about the effects of pre-, pro- and synbiotics on the microbiota of children born via Caesarean section was published recently,[43] we identified four additional relevant articles that were not included by Martin-Pelaez et al. Furthermore, some of their included articles did not perform a separate subgroup-analysis for children born via Caesarean section.”

Methods:

-It is better to update search, insert grey literature, and confirm the method is based on PRISMA.

We updated our search on August 10 2022 and included one more article. We added that we wrote the review according to the PRISMA statement to the methods section.

-Did you search ref. lists? It is essential to hand search Ref. list of the included studies when conducting a systematic review.

We hand searched the reference lists of the included articles and added this to the methods section.

-In eligibility criteria, clarify characteristics of control group, they should receive which one? prebiotics, placebo, or none of them?

When we composed the in- and exclusion criteria before starting our search, we did not choose to limit our search to specific control groups because we aimed to summarise all available evidence on the effect of pre-, pro- and synbiotics on the microbiota of infants born via Caesarean section or exposed to antibiotics in the first week of life.

-The second inclusion criteria “six weeks after birth” is ambiguous. In table 1 is observed using intervention more than 6w. What is your reason?

We have now clarified in the methods section that administration of the intervention should be started within 6 weeks after birth: “administration of pre-, pro- or synbiotic dietary supplements was started within six weeks after birth,”. We had to decide on a cut-off point before starting the title/abstract screening and we expected that, if interventions were administrated after >6 weeks, there would be too many other factors affecting the infants’ microbiota.

-In critical appraisal; the last sentence “Several studies included…..”should move to discussion.

We changed this sentence to: “If a study included both vaginally and Caesarean-delivered infants and performed a subgroup analysis on the Caesarean-delivered infants, only the methods used for the relevant subgroup analyses were assessed” to make it suitable for the methods section.

-Please delete “the review and protocol were not registrated”.

This sentence cannot be deleted because the PRISMA checklist asks authors to include this sentence in point 24a.

Results:

-First line: correct dictation “deduplication”.

We believe that “deduplication” is the correct term for removing copies of data.

-“ Lay et al.[33] published results of a subgroup analysis based on the RCT by Chua et al.[34]” Why included this study? It is a duplication publication. Please describe.

We included both studies because Lay et al. performed additional analyses on a subgroup of the infants of Chua et al. Therefore, they have some different results from Chua et al. and we did not state in our in- and exclusion criteria that we would exclude such articles. However, we tried to make it very clear throughout the paper that these articles were based on the same study to limit any confusion caused by the inclusion of both papers.

-Zhong et al study is included vaginal/cesarean delivery. Please recheck the data with original paper and correct them in your tables.

Zhong et al. is the only study in our review that investigated infants who were exposed to antibiotics in the first week of life instead of infants born following caesarean section, so in this study vaginally born infants were also included. We clarified this in our inclusion criteria: “(1) study participants were term-born infants who were born following Caesarean section or exposed to antibiotics in the first week of life (born vaginally or following Caesarean section)”. Furthermore, we separated this study from the other studies in tables 1 and 2 by putting a bold line in between the study of Zhong et al. and the other studies focusing on Caesarean born infants.

Discussion:

-This section needs to revise by adding more details and discussion about your results.

We elaborated on the results found in more than one study and also explained the possible clinical relevance: “Furthermore, there were significant increases in Actinobacteria, Proteobacteria and Firmicutes in the probiotic groups compared to the control groups. Moreover, the microbiota composition of the experimental group was significantly different from the control group in two studies, bacterial species diversity was increased in one study after administration of a probiotic or synbiotic.” […] “Moreover, three studies on pro- and synbiotics also found a significantly different microbiota composition or a more diverse microbiota in the intervention groups. In general, the microbiome of healthy newborn infants is characterised by low diversity of bacterial species until solid foods are introduced. Birth following Caesarean section or exposure to antibiotics in the first week of life reduce this diversity to such an extent that makes them susceptible to colonisation by bacteria usually found on the mother’s skin such as Staphylococcus, Corynebacterium and Propionibacterium spp., which is associated with an increased risk of allergies later in life.” […] “Three articles based on two prebiotic studies reported an increase in Bifidobacteria and two of the three also found a significantly different microbiota composition”

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(30.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0277405.r003

Decision Letter 1

Ozra Tabatabaei-Malazy

4 Oct 2022

PONE-D-22-18775R1Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: a systematic reviewPLOS ONE

Dear Dr. Carpay,

==============================

Please submit your revised manuscript by Nov 18 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Ozra Tabatabaei-Malazy

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Partly

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

Reviewer #4: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #3: Dear Authors,

The quality of the manuscript is improved. However, it should be considered following comments.

-Considering clinical trials as one of the inclusion criteria, why is not limited the search strategy to it? It could reduce the initial records, and time of assessment.

-Please insert type of trials in table-1.

-According to following evidence, mode of delivery has influenced on gut microbiota of the infants. I suggest to exclude Zhong study and also revised the title and inclusion criteria.

The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol. 2016 Jul 30;16(1):86. doi: 10.1186/s12876-016-0498-0.

Best Regards,

Reviewer #4: Carpay and colleagues provided a summary of the research on the impact of prebiotics, probiotics, and symbiotics on the makeup of the intestinal microbiota in term infants who were delivered by Caesarean section or who had received antibiotics during the first week of life. The patient, group of patients, or issue being examined; the intervention; comparator interventions; and particular outcomes are the aspects that the authors have addressed that are essential for a systematic review. The rational of the systematic review appears reasonable for me and the authors synthesized the results in a very informative and efficient way. The purpose and backgrounds are appropriately addressed in the introduction and discussion section. Methods section was written at its best. Tables and figures were adequate and inform the readers all the necessary information. Whenever it is questioned, the authors offer the necessary clarification in the discussion area. The review's limitations as well as the ones of the included research have been discussed by the authors. The authors have assessed the potential for bias and taken into account probable RoBs. The manuscript as it is now acceptable for publication in my opinion.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

Reviewer #4: No

**********

PLoS One. 2022 Nov 9;17(11):e0277405. doi: 10.1371/journal.pone.0277405.r004

Author response to Decision Letter 1

23 Oct 2022

Amsterdam, October 2022

PLOS ONE

Dr. Tabatabaei-Malazy

Dear Dr. Tabatabaei-Malazy,

Thank you for the opportunity to revise our manuscript “Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: a systematic review”.

We thank the reviewers for taking the time to critically review and comment upon our manuscript. Our response to the reviewers’ comments can be found below. We hope this clarifies any ambiguities and that the revised manuscript meets the standards for publication in PLOS ONE.

We look forward to hearing from you regarding our submission, and we would be happy to address any further comments.

With kind regards,

on behalf of all authors,

Nora Carpay

Reviewer #3

Dear Authors,

The quality of the manuscript is improved. However, it should be considered following comments.

- Considering clinical trials as one of the inclusion criteria, why is not limited the search strategy to it? It could reduce the initial records, and time of assessment.

In hindsight, this would have been a good option. However, we wanted to make sure that we did not omit important studies of other study designs which we could include in our discussion. In the end, we did not find any relevant studies of other study designs.

- Please insert type of trials in table-1.

Thank you for your suggestion. To maintain the readability of table 1, we changed the title to “General characteristics of the included randomised controlled trials” instead of “General characteristics of the included studies” to clarify.

- According to following evidence, mode of delivery has influenced on gut microbiota of the infants. I suggest to exclude Zhong study and also revised the title and inclusion criteria.

We agree that mode of delivery affects the gut microbiota of infants. However, so does the administration of antibiotics in the first week of life*. In this review we therefore aimed to investigate the effect of pre-, pro- and synbiotics on the gut microbiota of infants born via C-section or after antibiotic exposure. Unfortunately, we only found one study (by Zhong et al.) about the effects of such supplements on infants exposed to antibiotics, but since this was our original question, we do think it is important to include this study to illustrate the need for further research. Furthermore, we do not want to change our initial aim, as this would lead to reporting bias.

*Van Daele E, Kamphorst K, Vlieger AM, Hermes G, Milani C, Ventura M, Belzer C, Smidt H, van Elburg RM, Knol J. Effect of antibiotics in the first week of life on faecal microbiota development. Arch Dis Child Fetal Neonatal Ed. 2022 May 9:fetalneonatal-2021-322861.

Reviewer #4

Carpay and colleagues provided a summary of the research on the impact of prebiotics, probiotics, and symbiotics on the makeup of the intestinal microbiota in term infants who were delivered by Caesarean section or who had received antibiotics during the first week of life. The patient, group of patients, or issue being examined; the intervention; comparator interventions; and particular outcomes are the aspects that the authors have addressed that are essential for a systematic review. The rational of the systematic review appears reasonable for me and the authors synthesized the results in a very informative and efficient way. The purpose and backgrounds are appropriately addressed in the introduction and discussion section. Methods section was written at its best. Tables and figures were adequate and inform the readers all the necessary information. Whenever it is questioned, the authors offer the necessary clarification in the discussion area. The review's limitations as well as the ones of the included research have been discussed by the authors. The authors have assessed the potential for bias and taken into account probable RoBs. The manuscript as it is now acceptable for publication in my opinion.

We thank the reviewer for taking the time to review our manuscript, and for their positive feedback.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(17KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0277405.r005

Decision Letter 2

Ozra Tabatabaei-Malazy

26 Oct 2022

Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: a systematic review

PONE-D-22-18775R2

Dear Dr. Carpay,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ozra Tabatabaei-Malazy

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Full search strategy.

(DOCX)

Click here for additional data file.^{(24KB, docx)}

S2 Table. PRISMA checklist.

(DOCX)

Click here for additional data file.^{(31.6KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(30.8KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(17KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: A systematic review

Nora C Carpay

Kim Kamphorst

Tim G J de Meij

Joost G Daams

Arine M Vlieger

Ruurd M van Elburg

Roles

Abstract

Background and aims

Methods

Results

Discussion

Introduction

Methods

Literature search

Eligibility criteria

Data collection

Critical appraisal

Results

Fig 1. Flowchart showing article selection.

Study characteristics

Table 1. General characteristics of the included randomised controlled trials.

Critical appraisal

Table 2. Risk of bias of the included studies.

The effect of pre-, pro- and synbiotics after antibiotics in the first week of life

Table 3. Effects of pre-, pro- or synbiotic interventions on microbiota composition.

The effect of pre-, pro- and synbiotics after Caesarean section

Fig 2.

Diversity and compositional differences

Phylum level

Family level

Genus level

Species level

Intestinal microenvironment

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Ozra Tabatabaei-Malazy

Roles

Author response to Decision Letter 0

Decision Letter 1

Ozra Tabatabaei-Malazy

Roles

Author response to Decision Letter 1

Decision Letter 2

Ozra Tabatabaei-Malazy

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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