A systematic review of the factors influencing microbial colonization of the preterm infant gut

Figures & data

Figure 1. PRISMA flow diagram of search strategy

Table 1. Characteristics of studies included in the systematic review

Author	Year	Country	Study Design	Sample Size	Sample Characteristics	Intervention or Exposure	Length of Study
Adbulkadir, et al. ^Citation27	2016	USA	Clinical Trial	10	<32 weeks GA	Infloran®	Introduction enteral feeds to 34 weeks cGA
Aly, et al. ^Citation82	2017	Egypt	Clinical Trial	40	≤34 weeks GA	Unprocessed clover honey	d1 to d14 postnatal age
Arboleya, et al. ^Citation65	2015	Spain	Observational	27	24–32 weeks GA		d1 to d90 postnatal age
Armanian, et al ^Citation83	2016	Iran	Clinical Trial	50	<37 weeks GA ≤1500 g BW	GOS and FOS	d3 postnatal age until infants reached 150 ml/kg/day milk
Biagi, et al. ^Citation68	2018	Italy	Observational	16	32–37 weeks GA		d1 to d30 postnatal age
Brooks, et al. ^Citation89	2014	USA	Observational	2*	<37 weeks GA		d1 to d30 postnatal age
Brooks, et al. ^Citation90	2017	USA	Observational	50	<31 weeks GA <1250 g BW		d5 to d28 postnatal age†
Brown, et al. ^Citation56	2018	USA	Observational	35	<37 weeks GA		d1 to d90 postnatal age
Butcher, et al. ^Citation37	2017	Canada	Observational	54	<37 weeks GA <1500 g BW		d1 to d49 postnatal age
Cai, et al. ^Citation46	2019	Canada	Observational	20	<37 weeks GA <1500 g BW		d1 postnatal age to 4 weeks after introduction of enteral feeds
Chernikova, et al. ^Citation32	2016	USA	Observational	9	24–29 weeks GA		d1 to d54 postnatal age†
Chernikova, et al. ^Citation50	2018	USA	Observational	30	<37 weeks GA		Birth until discharge
Cong, et al. ^Citation33	2017	USA	Observational	38	28–32 weeks GA		d1 to d30 postnatal age
Costello, et al. ^Citation62	2013	USA	Observational	6	<37 weeks GA		d8 to d21 postnatal age
Dahl, et al. ^Citation59	2018	Norway	Observational	160	<37 weeks GA		d10 to 1-year postnatal age
Esaiassen, et al. ^Citation53	2018	Norway	Observational	66	<32 weeks GA	Infloran®	d1 to d120 postnatal age
Forsgren, et al. ^Citation17	2016	Finland	Observational	43	32–37 weeks GA		d14 to d180 postnatal age
Gibson, et al. ^Citation60	2016	USA	Observational	84	<33 weeks GA		48 h before and 48 after antibiotic exposure
Gómez, et al. ^Citation61	2017	Spain	Observational	16	≤32 weeks GA ≤1200 g BW		d1 to d21 postnatal age Second screening at 2-years postnatal age
Gregory, et al. ^Citation51	2015	USA	Observational	29	<32 weeks GA		d1 to d42 postnatal age
Gregory, et al. ^Citation57	2016	USA	Observational	30	<32 weeks GA		d1 to d42 postnatal age
Grier, et al. ^Citation64	2017	USA	Observational	95	23–37 weeks GA		Birth until discharge, second screening at 1-month and 1-year adjusted age
Gupta, et al. ^Citation47	2012	USA	Observational	76	≤34 weeks GA ≤1500 g BW	Histamine 2 receptor blockers	One time point at d62 postnatal age
Ho, et al. ^Citation35	2018	USA	Observational	45	<1500 g BW		d1 to d28 postnatal age
Ishizeki, et al. ^Citation84	2013	Japan	Clinical Trial	40	<37 weeks GA	Bifidobacterium breve or combination of B. breve + Bifidobacterium. longum subsp. Infantis + B.longum subsp. longum	Initiation of enteral feeds to 8 weeks after
Korpela, et al. ^Citation38	2018	Norway	Observational	50	<37 weeks GA ≤1500 g BW		d1 to d60 postnatal age
La Rosa, et al. ^Citation48	2014	USA	Observational	58	<37 weeks GA ≤1500 g BW		d1 to d30 postnatal age
Mai, et al. ^Citation63	2013	USA	Observational	28	≤32 weeks GA	PT infants with LOS and Healthy Controls	Birth until discharge
Millar, et al. ^Citation73	2017	UK	Clinical trial	115	<31 weeks GA	B. breve	Birth until 36 weeks cGA
Moles, et al. ^Citation66	2013	Spain	Observational	14	≤32 weeks GA ≤1200 g BW		Birth until discharge
Moles, et al. ^Citation74	2015	Spain	Observational	26	≤32 weeks GA ≤1200 g BW		Birth until discharge, second screening at 2-years postnatal age
Mshvildadze, et al. ^Citation77	2010	USA	Observational	27	<32 weeks GA		Birth until discharge
Normann, et al. ^Citation67	2012	Sweden	Observational	95	<28 weeks GA	PT infants with NEC and Healthy controls	d1 to d49 postnatal age
Parra-Llorca, et al. ^Citation78	2018	Spain	Observational	69	≤32 weeks GA ≤1500 g BW		One time point when full enteral feeds achieved
Pärtty, et al. ^Citation85	2013	Finland	Clinical Trial	34	32–37 weeks GA >1500 g BW	Polydextrose plus GOS or Lactobacillus rhamnosus GG	d30 to d365 postnatal age
Patel, et al. ^Citation43	2016	USA	Observational	12	<35 weeks GA <2000 g		d1 to d30 postnatal age
Poroyko, et al. ^Citation79	2011	USA	Observational	11	<37 weeks GA	Breastmilk or PT formula	One time point at 34–36 weeks cGA
Ravi, et al. ^Citation54	2017	USA	Observational	52	<37 weeks GA	PT infants with NEC and Healthy controls	d1 to d46 postnatal age†
Rougé, et al. ^Citation86	2009	France	Clinical Trial	94	<32 weeks GA <1500 g BW	B. longum BB536 and L. rhamnosus GG	Beginning of enteral feeds until discharge
Rozé, et al. ^Citation88	2017	France	Observational	94	<32 weeks GA		Birth until discharge
Sherman, et al. ^Citation31	2016	USA	Clinical Trial	120	<37 weeks GA ≤1250 g BW	Talactoferrin	d1 to d28 postnatal age
Sim, et al. ^Citation52	2014	UK	Observational	369	<32 weeks GA	PT infants with NEC and Healthy controls	d1 to d30 postnatal age
Soeorg, et al. ^Citation80	2017	Estonia	Observational	49	<37 weeks GA		d1 to d30 postnatal age
Stewart, et al. ^Citation40	2017	UK	Observational	46	<37 weeks GA	Infloran®	d1 to d100 postnatal age
Tauchi, et al. ^Citation55	2019	Japan	Observational	17	<37 weeks GA		From day 5 to 1 month of life
Underwood, et al. ^Citation87	2009	USA	Clinical Trial	90	<35 weeks GA	Culturelle® or ProBioPlus DDS®	d1 to d28 postnatal age or discharge
Underwood, et al. ^Citation30	2013	USA	Clinical Trial	21	<33 weeks GA <1500 g BW	B. longum subsp. infantis or Bifidobacterium animalis subsp. lactis	d1 to d35 postnatal age
Underwood, et al. ^Citation28	2014	USA	Clinical Trial	39	<33 weeks GA <1500 g BW	PT formula + GOS, or PT formula + HMF, or MOM + HMF, or MOM + BMF	For 5 weeks after initiation of enteral feeds
Underwood, et al. ^Citation81	2015	USA	Observational	14	<37 weeks GA	MOM	One time point at 30 weeks cGA
Underwood, et al. ^Citation29	2017	Australia	Clinical Trial	29	<37 weeks GA	B. breve M16-V	Initiation of enteral feeds to 3 weeks after
Wandro, et al. ^Citation41	2018	USA	Observational	32	≤1250 g BW		d1 to d75 postnatal age^Citation1
Westerbeek, et al. ^Citation69	2012	Netherlands	Clinical Trial	113	≤32 weeks GA ≤1500 g BW	GOS + FOS + AOS	d3 to d30 postnatal age
Younge, et al. ^Citation76	2017	USA	Clinical Trial	32	<37 weeks GA	Fish oil + Safflower	Initiation of enteral feeds to 10 weeks after
Younge, et al. ^Citation58	2019	USA	Observational	60	<28 weeks GA		Birth until 40 weeks cGA or discharge
Zeber-Lubecka, et al. ^Citation44	2016	Poland	Clinical Trial	55	25–33 weeks GA	Dierol®	d1 to d42 postnatal age
Zhou, et al. ^Citation42	2015	USA	Observational	38	<32 weeks GA	PT infants with NEC and Healthy controls	d1 to d60 postnatal age or discharge
Zhu, et al. ^Citation70	2017	China	Observational	36	28–37 weeks GA	Postnatal antibiotics	d1 to d7 postnatal age
Zou, et al. ^Citation71	2018	China	Observational	28	<32 weeks GA	Prenatal antibiotics	d1 to d60 postnatal age or discharge
Zwittink, et al. ^Citation45	2017	Netherlands	Observational	10	25–30 weeks GA		d1 to d42 postnatal age
Zwittink, et al. ^Citation34	2018	Netherlands	Observational	15	32–37 weeks GA	Postnatal antibiotics	d1 to d42 postnatal age

* Multiple sampling of the same infants throughout time, a total of 93 stool samples were collected.

† Follow-up varied among participants.

Infloran®: Lactobacillus acidophilus + Bifidobacterium bifidum; ProBioPlus DDS®: Lactobacillus acidophilus + Bifidobacterium longum + Bifidobacterium bifidum + Bifidobacterium infantis + inulin; Culturelle®: Lactobacillus rhamnosus GG + inulin; Dierol®: Saccharomyces. Boulardii.

AOS: acidic oligosaccharides; BMF: bovine milk-based fortifier; BW: birth weight; cGA: corrected gestational age; FOS: fructooligosaccharides; GA: gestational age; GOS: galactooligosaccharides; HMF: human milk-based fortifier; HMOs: human milk oligosaccharides; LOS: late onset sepsis; MOM: mother’s own milk; NEC: necrotizing enterocolitis; PT: preterm.

Table 2. Perinatal factors and gut microbiota composition of PT infants

Factor	Ref	Alpha diversity	Beta diversity	Taxonomy
Pregnancy Complications	^Citation32	↓ diversity across time in PT infants exposed to PPPROM and/or chorioamnionitis		↑ Staphylococcus and Streptococcus across time, faster increase of Enterobacter, and lower increase in Clostridium when exposed to PPPROM ↑ Serratia, Parabacteroides, and Bradyrhizobium when exposed to chorioamnionitis
	^Citation33	No association between PROM and Gini-Simpson diversity index	PROM explained ~2% of the variance from Bray-Curtis dissimilarity index
	^Citation35			↓ Gammaproteobacteria when exposed to chorioamnionitis only in PT infants belonging to Cluster 2* ↑ Gammaproteobacteria associated with antenatal steroids only in PT infants belonging to Cluster 2*
	^Citation34			No association between PROM and gut microbiota composition
Mode of Delivery	^Citation65			↑ Bacteroides in vaginally delivered PT infants at 10 days postnatal age
	^Citation37	Over time, no differences in Shannon diversity index by mode of delivery in PT infants fed MOM	No association in between mode of delivery and Bray-Curtis dissimilarity index Mode of delivery explained ~1% of the variation in PT infants fed MOM	↑ Bacilli in PT infants fed MOM born via C-section during the first 3-weeks of postnatal age
	^Citation46		During late stage of enteral feeds† mode of delivery was associated with Unweighted UniFrac distances
	^Citation32	↑ Simpson diversity index in PT infants born via C-section		↓ Enterobacter, Pantoea, Citrobacter, Kluyvera, Erwinia and Klebsiella in vaginally delivered PT infants
	^Citation50			↑ Bacteroides positively associated with vaginal birth
	^Citation53			At 7 days postnatal age, no differences in microbial composition by mode of delivery
	^Citation51			↑ Bacteroides over time in vaginally delivered PT infants
	^Citation47			↓ Proteobacteria in vaginally delivered PT infants
	^Citation35			↑ Firmicutes in PT infants born by C-section ↑ Gammaproteobacteria in vaginally delivered PT infants at ≤2 weeks postnatal age
	^Citation38	No association between observed OTUs and mode of delivery		↑ Staphylococcus in vaginally delivered PT infants No differences in Enterococcus and Bifidobacterium by mode of delivery
	^Citation48			Infants born <26 weeks GA via C-section: ↑ Bacilli and ↓ Gammaproteobacteria Infants born 26–28 weeks GA via C-section: ↑ Bacilli
	^Citation77	In meconium, and stool of >7 days postnatal age, no difference in Simpson diversity index by mode of delivery
	^Citation43		No association between mode of delivery and Unweighted UniFrac distances
	^Citation54			No association with microbial composition and mode of delivery
	^Citation52			↑ Enterobacteriaceae and ↓ Clostridium in vaginally delivered PT infants
	^Citation40	No differences in Observed OTUs by mode of delivery Vaginally delivered infants kept more OTUs from birth than C-section at 2-months postnatal age and after discharge	No association between mode of delivery and Unweighted UniFrac distances	During first week postnatal age, vaginally delivered PT infants belonged to cluster dominated by Escherichia, and PT infants delivered via C-section belonged to cluster dominated by Klebsiella
	^Citation55			No association with microbial composition and mode of delivery
	^Citation41	No differences in Shannon diversity index by mode of delivery	Mode of delivery explained 12% of the variation of Weighted UniFrac distances	Only vaginally delivered PT infants were colonized with Bacteroides
	^Citation44		No association between mode of delivery and PCA	After supplementation with probiotics‡, Bacteroides and Parabacteroides were only present in vaginally delivered PT infants Mode of delivery significantly predictor of Bacteroides and Parabacteroides abundance
	^Citation42	No differences in Shannon diversity index by mode of delivery
	^Citation45		No association between mode of delivery and mode of delivery in RDA

* Cluster 2 of taxonomic composition that was characterized by higher abundances of Gammaproteobacteria compared to Cluster 1.

† 2–4 weeks after introductions of enteral feeds.

‡ Supplementation with Dierol®.

GA: gestational age; MOM: mother’s own milk; OTU: operational taxonomic unit; PCA: principal component analysis; PPPROM: prolonged preterm premature rupture of membranes; PROM: premature rupture of membranes; PT: preterm; RDA: redundancy analysis.

Table 3. Physiological factors and gut microbiota composition of PT infants

Factor	Ref	Alpha diversity	Beta diversity	Taxonomy
Ethnicity	^Citation35			↑ Firmicutes*, ↑ Gammaproteobacteria in PT infants of Latino ethnicity
Sex	^Citation33	↑ Gini-Simpson diversity index in female PT infants	Sex explained 6% of the variance from Bray-Curtis dissimilarity index
	^Citation34		No association between sex and gut microbiota composition (RDA)
	^Citation42	No association between Shannon diversity index and sex
Weight and Growth	^Citation56		Significant association between community composition and BW
	^Citation57		Significant association between ELBW, VLBW and Bray Curtis distances and Unweight UniFrac distances	↑ Lactobacillales in ELBW infants fed PT formula at 28–30 weeks cGA† ↑ Clostridiales in VLBW infants fed PT formula over time
	^Citation54		Association between birth weight and microbiota composition (PLS-DA)
	^Citation58	↓ Shannon diversity index in PT infants with growth failure‡		↑ Staphylococcaceae, Bacteroideaceae at 0–4 weeks postnatal age in PT infants with growth failure‡ ↑ Enterobacteriaceae and Erysipelotrichaceae at 3–9 weeks postnatal age in PT infants with postnatal growth failure‡ ↑ Bacillaceae, Streptococcaceae, Peptostreptococcaceae, Veillonellaceae, Lachnospiraceae, Micrococcaceae, Tissierellaceae and Clostridiaceae at 1–9 weeks postnatal age in PT infants with appropriate growth
Gestational Age, Postnatal age and Corrected Gestational Age	^Citation65			↑ Comamonadaceae at 2 days postnatal age ↑ Enterobacteriaceae at 10 days postnatal age ↑ Bifidobacterium at 30–90 days postnatal age
	^Citation33		GA explained ~2% of the variance from Bray-Curtis dissimilarity index
	^Citation68			↑ Bifidobacterium positively correlated with postnatal age
	^Citation56		Significant association between community composition and GA, and cGA	Significant association between Propionibacterium sp and cGA
	^Citation37	↑ Shannon diversity index over time in PT infants fed MOM	GA explained 1.28% of the variation Postnatal age explained 7.73% of the variation in PT infants fed MOM	↑ Bacilli during early time points ↓ Bacilli after 21 days postnatal age in PT infants fed MOM ↑ Clostridia over time Gammaproteobacteria remained stable over time in PT infants fed MOM
	^Citation32			↓ Staphylococcus, Escherichia and Shigella over time ↑ Veillonella, Streptococcus and Enterococcus over time
	^Citation50	↑ Simpson diversity index over time ↓ Simpson diversity index in extremely PT infants compared to moderate and very PT infants§ ↑ Simpson diversity index in PT infants born ≥ 32 weeks GA across time No association between cGA and Simpson diversity index		↑ Streptococcus and Bifidobacterium in PT infants born >32 weeks GA ↑ Bacteroides and ↓ Parabacteroides in PT infants born >32 weeks GA at 6 weeks postnatal age ↑ Pantoea in moderate PT infants ↑ Lactobacillus and Streptococcus positively associated with cGA
	^Citation62		Significant association between postnatal age and UniFrac distances	↓ Staphylococcus over time
	^Citation59	↑ Shannon diversity index positively associated with GA at 10 days postnatal age
	^Citation17			Delayed colonization with Bifidobacterium
	^Citation60	↑ Richness over time positively associated with postnatal age
	^Citation61	↑ Shannon diversity index positively associated with postnatal age		↑ Enterobacter aerogenes, Enterococcus spp., Escherichia coli, Granulicatella spp., Klebsiella pneumoniae, Proteus, Serratia and Yersinia at 21 days postnatal age
	^Citation51			↑ Bacteroides positively associated with postnatal age
	^Citation57	↑ Shannon diversity index positively associated with postnatal age and cGA (regardless diet)	Significant association between postnatal age and Bray Curtis distances	↑ Bacillales and Lactobacillales at 28–30 weeks cGA, particularly if formula-fed PT infants ↑ Enterobacteriales and Clostridiales in MOM and formula-fed PT infants
	^Citation64			↑ Bacilli at ≤29 weeks postmenstrual age ↑ Gammaproteobacteria at 28–36 weeks postmenstrual age ↑ Clostridia at 37 weeks postmenstrual age
	^Citation35	↑ Observed OTUs, phylodiversity, Shannon, Chao1 and Simpson diversity indices positively associated with postnatal age		↑ Gammaproteobacteria, Clostridia and Actinobacteria positively associated with postnatal age ↓ Bacilli over time
	^Citation38	↑ Observed OTUs over time		Progression from Staphylococcus-Enterococcus dominated gut microbiota during early points after birth to Enterobacter dominated, and finally Bifidobacterium dominated at later points
	^Citation48			↑ Bacilli in early time points (<28 days postnatal age) ↑ Clostridia in later time points (28 to >56 days postnatal age)
	^Citation63			↓ Proteobacteria over time in healthy PTI
	^Citation66			↑ Staphylococcus in meconium and stool at 1-week postnatal age ↑ Enterococcus at 2- and 3-weeks postnatal age ↑ Prevalence of Serratia in PT infants born <30 weeks GA ↓ Propionibacterium, Lactobacillus plantarum, Streptococcus intermedius, and Streptococcus mitis at 3 weeks postnatal age ↑ Bacteroides splachnicus, Enterococcus, Clostridia, Veillonella, Clostridium difficile, E. coli, K. pneumoniae, Pseudomonas, Serratia and Yersinia at 3 weeks postnatal age
	^Citation67			↑ Enterococcus dominated at <4 weeks postnatal age
	^Citation43		Significant association between postnatal age and Bray-Curtis dissimilarity index	↑ Enterobacteriaceae over time
	^Citation52			↑ Bifidobacterium and Klebsiella over time ↓ Staphylococcus and Streptococcus over time
	^Citation40	↑ Shannon diversity index over time
	^Citation55			Transition over time from Gram-positive cocci dominated to Enterobacteriaceae and/or Bifidobacteriaceae Delayed colonization with Bifidobacterium
	^Citation58			↑ Staphylococcaceae in early time points at <5 weeks postnatal age in PT infants with postnatal growth failure‡ ↑ Enterobacteriaceae at 3–9 weeks postnatal age in PT infants with postnatal growth failure‡
	^Citation42		Significant association between day of life and Bray-Curtis dissimilarity index	Enterobacter: core microbiota in the first 60 days of postnatal age
	^Citation45			Staphylococcus and Enterococcus were part of the core microbiota of PT infants at 2 weeks postnatal age At 3 weeks postnatal age: ↑ Enterococcus, Staphylococcus, and Enterobacter in extremely PT infants ↑ Bifidobacterium in very PT infants

* When PTI belonged to Cluster 1, this was a cluster characterized by lower abundances of Gammaproteobacteria compared to Cluster 2.

† Gestational age at birth + postnatal age.

‡ Growth failure defined as weight below the 3^rd percentile according to the Fenton growth charts.

§ Extremely PT: born <28 weeks of gestation; Very PT: born 28–32 weeks of gestation; Moderate to late PT: born 32–37 weeks of gestation

BW: birth weight; cGA: corrected gestational age; ELBW: extremely low birth weight; GA: gestational age; MOM: mother’s own milk; OTU: operational taxonomic unit; PLS-DA: partial least squares discriminant analysis; PT: preterm; RDA: redundancy analysis; VLBW: very low birth weight.

Table 4. Pharmacological factors and gut microbiota composition of PT infants

Factor	Ref	Alpha diversity	Beta diversity	Taxonomy
Antibiotics	^Citation65			↑ Bifidobacteriaceae, Streptococcaceae Comamonadaceae, Staphylococcaceae and unclassified Bacilli at 30 days postnatal age in PT infants never exposed to antibiotics
	^Citation56	↓ Diversity during or within 5 days of antibiotic use
	^Citation37			↑ Gammaproteobacteria and ↓ Clostridia with higher exposure to antibiotics in PT infants fed MOM
	^Citation32	↓ Simpson diversity index with use of antibiotics
	^Citation50			↓ Bifidobacterium and Bacteroides with antibiotic use after birth
	^Citation33		Antibiotic use in the first 48–72 h explained 2–3% of the Bray-Curtis dissimilarity index
	^Citation53			No differences between short and prolonged* exposure to antibiotic during week 1 postnatal age ↓ Lactobacillus and Veillonella at 4 months postnatal age when exposed to broad-spectrum antibiotic therapy
	^Citation60	↓ Species richness with the use of antibiotics		↑ Staphylococcus epidermis after meroprenem use ↑ Klebsiella pneumoniae after ticarcillin-clavulanate use ↑ Escherichia coli with cefotaxime use
	^Citation51			No association of antibiotic exposure with Bacteroides abundance
	^Citation64			Association between Gammaproteobacteria abundance and antibiotic use
	^Citation38	No significantly difference in bacteria richness after antibiotic use		↓ Enterococcus with aminoglycoside use ↑ Enterococcus with vancomycin use ↓ Bifidobacterium with aminoglycoside or vancomycin use Changes were temporal, microbiota recovered within days after treatment termination
	^Citation48			↓ Clostridia in PT infants born <28 weeks GA with antibiotic use ↑ Gammaproteobacteria in PT infants born >26 weeks GA with antibiotic use
	^Citation73			16–17% less chance of Veillonellaceae colonization with every day increase in use of antibiotics
	^Citation74			Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, E. coli and K. pneumoniae showed resistance to antibiotics At 2-years postnatal age, fecal samples were susceptible to antibiotics
	^Citation43		Significantly association between use of antibiotics and UniFrac distances at week 1 postnatal age
	^Citation41	↓ Shannon diversity index in PT infants with no antibiotic use
	^Citation69	↓ Bacteria count in PT infants on day 30 after receiving antibiotics
	^Citation42	↓ Observed OTUs and Shannon diversity index within 5 days after receiving antibiotics
	^Citation70	↓ Shannon diversity index on day 7 after antibiotic use		↑ Bacteroides and Actinobacteria on day 3 after treatment with penicillin-moxalactam and piperacillin-tazobactam ↑ Sphingomonas, Bacteroides, Lactobacillus on day 3 after treatment with penicillin-moxalactam use and piperacillin-tazobactam ↓ Clostridium on day 3 after treatment with penicillin-moxalactam use ↑ Enterococcus and ↓ Klebsiella on day 7 after treatment with piperacillin-tazobactam use ↑ Escherichia-Shigella with penicillin-moxalactam use
	^Citation71	No differences in Shannon diversity index between PT infants with low or high exposure to antibiotics†		↑ Betaproteobacteria in infants with high† exposure to antibiotics ↓ Bifidobacterium in infants with high† exposure to antibiotics
	^Citation34	No difference between short and long antibiotic treatment‡ ↓ Chao 1 and PD after antibiotic use during week 1 postnatal age Recovery of diversity after secession of treatment	Duration of antibiotic use explained 3.6% of the variation of fecal microbiota composition (RDA)	↓ Enterobacteriaceae with antibiotic use ↓ Bifidobacterium after short antibiotic use during the first 3-weeks postnatal age‡ ↓ Bifidobacterium after long antibiotic use during the first 6-weeks postnatal age‡ ↑ Enterococcus with antibiotic use
	^Citation45		Duration and number of antibiotics administrated explained 25.6% of the variation of fecal microbiota composition (RDA)
Other medications	^Citation64			↑ Bifidobacterium with H2-blockers at >33 weeks postmenstrual age
	^Citation47	↓ Shannon diversity index in PT infants that received H2-blockers		↑ Proteobacteria and ↓ Firmicutes in PT infants that received H2-blockers ↑ Gammaproteobacteria and Enterobacteriaceae in PT infants that received H2-blockers

* Short: ≤ 72 h; prolonged: >72 h.

† Low exposure: ≤ 7 days; High exposure: > 7 days.

‡ Short antibiotic treatment: ≤ 3 days; long antibiotic treatment: ≥ 5 days.

GA: gestational age; H2: histamine-2 receptor; OTU: operational taxonomic unit; PD: phylogenetic diversity; PT: preterm; RDA: redundancy analysis.

Table 5. Dietary factors and gut microbiota composition of PT infants

Factor	Ref	Alpha diversity	Beta diversity	Taxonomy
Macronutrients	^Citation64			↑ Actinobacteria, and Proteobacteria with higher lipid intake* ↑ Firmicutes with higher protein intake† ↑ Actinobacteria, Proteobacteria and Firmicutes with higher carbohydrate intake‡ ↑ Bifidobacterium with lipid intake at >33 weeks postmenstrual age ↓ Bifidobacterium with protein intake at >33 weeks postmenstrual age
	^Citation76	↑ Shannon diversity and Inverse Simpson indices over time in PT infants with HF-PUFA enteral supplementation		↓ Proteobacteria and ↑ Actinobacteria in PT infants with HF-PUFA enteral supplementation ↑ Corynebacterium, Geobacillus, Erwinia in PT infants with HF-PUFA enteral supplementation ↑ Escherichia-Shigella, Salmonella, Serratia, Pantoea, Clostridium, Tatumella, Streptococcus, Cedeceae and Citrobacter in control group
Milk and Fortifiers	^Citation68			↑ Staphylococcus in PT infants consuming MOM with high content of Staphylococcus ↑ Bifidobacterium in PT infants consuming MOM with high content of Rothia, Enterococcus and Streptococcus
	^Citation37			Bacilli, Clostridia and Gammaproteobacteria compromised >90% of bacteria abundance over time in PT infants fed MOM Low levels of Bifidobacterium in PT infants fed MOM No changes in gut microbiota composition after fortification of MOM with BMF
	^Citation46	↑ Chao1 diversity index in PT infants fed MOM + BMF compared to MOM + PT formula or PT formula alone		↑ Proteobacteria in PT infants fed MOM + BMF ↑ Terrisporobacter and Peptoclostridium in formula-fed infants ↓ Veillonella in PT infants fed MOM + BMF
	^Citation50	No association between consumption of MOM and/or DHM with alpha diversity		↓ Lactobacillus in PT infants fed MOM and/or DHM
	^Citation33	↑ Gini-Simpson diversity index in PT infants fed MOM compared to DHM, PF or the combination of two different types of milk. No association between human milk (MOM and/or DHM) fortification with BMF and alpha diversity	Feeding type explained 11% of the variance of Bray-Curtis dissimilarity index	↑ Clostridiales, Lactobacillales and Bacillales in PT infants fed MOM ↑ Enterobacteriales in PT infants fed DHM, PT formula, and DHM + PT formula ↑ Bifidobacteriales in PT infants fed MOM and MOM + PT formula
	^Citation59	↑ Shannon diversity index in early PT formula introduction (<10 days of age)		↓ Firmicutes and ↑ Proteobacteria at 10 days postnatal age in exclusively breastfed PT infants compared to full-term infants
	^Citation60	↑ Species richness in PT infants fed human milk (MOM and/or DHM)
	^Citation57		Association between different types of milk and Bray-Curtis distances	↑ Lactobacillales, Enterobacteriales and Clostridiales in formula-fed PT infants ↑ Clostridiales in VLBW PT infants fed MOM Citrobacter, Clostridium, Ruminococcus and Negativicoccus, best discriminators of PT infants fed MOM Streptococcus, Bacillus and Anaerococcus, best discriminators of PT infants fed PT formula
	^Citation48			↑ Gammaproteobacteria at 28 days postnatal age and at 28 to >56 days postnatal age with higher MOM consumption
	^Citation77	No association between type of milk consumed and Simpson diversity index at >7 days postnatal age
	^Citation78		Association between type of milk consumed and Bray-Curtis dissimilarity index and UniFrac distances	↑ Bifidobacterium, Acitenobacter and Haemophilus in PT infants fed MOM ↑ Staphylococcus, Clostridium, Coprococcus, Aggregatibacter and Lactobacillus, in PT infants fed DHM ↑ Blautia, Streptococcus, Acidaminococcus, Rothia and Dorea in formula-fed PT infants
	^Citation79		Association between type of milk consumed and gut microbiota composition
	^Citation80			↓ Staphylococcus aureus, Staphylococcus hominis, Staphylococcus lugdunensis in PT infants fed MOM compared to full-term infants
	^Citation28			↓ Bifidobacterium in PT infants fed MOM + BMF ↑ Gammaproteobacteria and ↓ Bacillales in PT infants fed MOM + HMF
	^Citation81			↑ Lactobacillaceae and ↓ Gammaproteobacteria when consuming MOM of secretor mothers
	^Citation30	↓ Shannon diversity index in PT infants fed PT formula compared to MOM
	^Citation41	No association between type of milk consumed and Shannon diversity index
	^Citation45		No association between human milk consumption and gut microbiota composition
	^Citation34		No association between human milk consumption and gut microbiota composition
Prebiotics and/or probiotics	^Citation27	↑ Shannon diversity index after Infloran® supplementation		↑ Lactobacillus and Bifidobacterium after supplementation with Infloran®, effect remained after treatment
	^Citation82			↓ Enterobacteriaceae in groups receiving 5, 10, and 15 g/day of honey ↑ Bifidobacterium after 2 weeks of supplementation with honey (regardless of dose) ↑ Lactobacillus only in group receiving 10 g/day of honey
	^Citation83			↑ Lactobacillus with supplementation of GOS + FOS but no difference compared to control group
	^Citation53			↑ Bifidobacterium and Lactobacillus in PT infants supplemented with Infloran® at 7 days postnatal age ↑ Escherichia, ↓ Veillonella and Streptococcus in PT infants supplemented with Infloran® at 28 days postnatal age
	^Citation84			↑ Bifidobacterium in PT infants supplemented with Bifidobacterium breve and combination of B. breve + Bifidobacterium infantis + Bifidobacterium longum ↓ Enterobacteriaceae in PT infants supplemented B. breve + B. infantis +B. longum
	^Citation73	No differences in Simpson diversity index between PT infants supplemented with B. breve strain BBG-001
	^Citation85			↓ Clostridium histolyticum in PT infants receiving Lactobacillus rhamnosus supplementation
	^Citation86			↑ Bifidobacterium and Lactobacillus in PT infants supplemented with B. longum BB536 + L. rhamnosus GG
	^Citation28			↑ Clostridia with increasing doses of GOS or HMOs supplementation
	^Citation29			↑ Enterobacteriaceae and Clostridiceae in non-responders (low Bifidobacterium colonization) to the supplementation with B. breve
	^Citation30	↑ Shannon diversity index in PT infants fed PT formula with Bifidobacterium animals subsp. lactis supplementation		↓ Bifidobacterium in PT infants fed PT formula with Bifidobacterium lactis supplementation (no dose response) ↑ Bifidobacterium in PT infants fed PF with B. infantis, peaking after dose 4 (dose response) ↑↑ Bifidobacterium in PT infants consuming MOM supplemented with B. infantis ↓ Proteobacteria with supplementation of B. infantis
	^Citation87			↑ Bifidobacterium and Lactobacillus over time with ProBioPlus DDS® supplementation ↓ Gram-negative bacteria with Culturelle® supplementation
	^Citation69			No changes in colonization after supplementation of GOS + FOS + AOS
	^Citation44	↓ Simpson diversity index after Dierol® supplementation No differences when comparing with placebo	No association between supplementation with Dierol® (before and after) and gut microbiota composition	↓ Enterococcus, Pseudomonas and ↑ Veillonella, Clostridium and Bifidobacterium with Dierol® supplementation

* Ratio of grams of lipids to total enteral calories (g/kcal)

† Ratio of grams of protein to total enteral calories (g/kcal)

‡ Ratio of grams of carbohydrates to total enteral calories (g/kcal)

¶ Mothers that express 2′-fucosyltransferase and produce milk containing 2′-fucosyllactose and lactodifucotetraose

Infloran®: Lactobacillus acidophilus + Bifidobacterium. bifidum

ProBioPlus DDS: Lactobacillus acidophilus + Bifidobacterium longum + Bifidobacterium bifidum + Bifidobacterium infantis + inulin

Culturelle: Lactobacillus rhamnosus GG + inulin

Dierol®: Saccharomyces. Boulardii

AOS: acidic oligosaccharides; DHM: donor human milk; FOS: fructooligosaccharides; GOS: galactooligosaccharides; HF-PUFA: high-fat polyunsaturated fatty acids; HM: human milk; HMF: human milk fortifier; HMOs: human milk oligosaccharides; MOM: mother’s own milk; PF: preterm formula; PMA: postmenstrual age; PT: preterm.

Table 6. Environmental factors and gut microbiota composition of PT infants

Factor	Ref	Alpha diversity	Beta diversity	Taxonomy
NICU environment	^Citation89			Overlap in colonization with Staphylococcus and Enterococcus faecalis between gut microbiota of PT infant and NICU surfaces
	^Citation90			Overlap in colonization with E. faecalis, Staphylococcus epidermis, Klebsiella pneumoniane, Propionibacterium avidu, Escherichia coli and Pseudomonas aeruginosa between gut microbiota of PT infant and NICU surfaces Clostridia found in PT infant, and rarely found in NICU rooms
	^Citation48			No association between NICU environment (single vs open rooms) and PT infant gut microbiota composition
	^Citation55			Positive association between gut colonization in PT infants with Bifidobacteriaceae and transition from incubator to open bed

NICU: neonatal intensive care unit; PT: preterm.

Figure 2. Multifactorial colonization of the preterm gut

This figure highlights changes in gut microbiota of PT infants associated to perinatal, physiological, pharmacological, dietary, and environmental factors. A. Based on the literature review, ten bacteria with the most evidence of change across all factors were: Bifidobacterium, Staphylococcus, Enterococcus, Gammaproteobacteria, Bacteroides, Streptococcus, Lactobacillus, Enterobacteriaceae, Escherichia, and Clostridia. Green arrows denote increase in abundance, red arrows denote decrease in abundance, and purple arrows denote co-colonization between PT gut and that specific factor. B. Bacterial colonization pattern of the gut microbiota of PT infants by postnatal age. After birth, the main colonizers are bacteria from the genera Enterococcus (red), Staphylococcus (blue), and Bacilli (green). During the first days of life, the abundance of Enterococcus and Staphylococcus decreases abruptly. With an increase in postnatal age, Enterobacteriaceae (teal), Clostridia (orange), and Bifidobacterium (pink) become more abundant, although the colonization with the latter is delayed in PT infants. Dashed lines represent decrease in abundance. Continuous lines represent increase in abundance. C. Factors affecting alpha diversity. Evidence showed that PROM, chorioamnionitis, growth failure, the exposure to antibiotics and consumption of PT formula decrease alpha diversity. In contrast, gestational age, postnatal age, HF-PUFA enteral supplementation, and human milk (particularly MOM) consumption increase alpha diversity in the gut microbiota of PT infants.¹ Ratio of grams of lipids to total enteral calories (g/kcal).² Ratio of grams of protein to total enteral calories (g/kcal).³ Enteral supplementation.⁴ Growth failure: defined as weight below the 3^rd percentile on the Fenton growth charts. BW: birth weight; HF-PUFA: high fat polyunsaturated; MOM: mother’s own milk; NICU: neonatal intensive care unit; PMA: postmenstrual age; PROM: premature rupture of membranes; PT: preterm. Created with BioRender.com with images by MAL.

Abdulkadir B, Nelson A, Skeath T, Marrs ECL, Perry JD, Cummings SP, Embleton ND, Berrington JE, Stewart CJ. Routine use of probiotics in preterm infants: longitudinal impact on the microbiome and metabolome. Neonatology [Internet]. 2016; accessed 2019 May 6]; 109(4):239–247. doi:10.1159/000442936

 Google Scholar

Aly H, Said RN, Wali IE, Elwakkad A, Soliman Y, Awad AR, Shawky MA, Alam MSA, Mohamed MA. Medically Graded Honey Supplementation Formula to Preterm Infants as a Prebiotic. J Pediatr Gastroenterol Nutr. [Internet] 2017; accessed 2019 May 6]; 64(6):966–970. doi:10.1097/MPG.0000000000001597

 Google Scholar

Arboleya S, Sánchez B, Milani C, Duranti S, Solís G, Fernández N, de Los Reyes-gavilán CG, Ventura M, Margolles A, Gueimonde M. Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. J Pediatr. [Internet] 2015;166(3):538–544. doi:10.1016/j.jpeds.2014.09.041.

 Google Scholar

Armanian A-M, Sadeghnia A, Hoseinzadeh M, Mirlohi M, Feizi A, Salehimehr N, Torkan M, Shirani Z. The effect of neutral oligosaccharides on fecal microbiota in premature infants fed exclusively with breast milk: A randomized clinical trial. J Res Pharm Pract. [Internet] 2016;5(1):27. doi:10.4103/2279-042X.176558.

 Google Scholar

Biagi E, Aceti A, Quercia S, Beghetti I, Rampelli S, Turroni S, Soverini M, Zambrini AV, Faldella G, Candela M, et al. Microbial community dynamics in mother’s milk and infant’s mouth and gut in moderately preterm infants. Front Microbiol. [Internet] 2018;9:2512. doi:10.3389/fmicb.2018.02512.

 Google Scholar

Brooks B, Firek BA, Miller CS, Sharon I, Thomas BC, Baker R, Morowitz MJ, Banfield JF. Microbes in the neonatal intensive care unit resemble those found in the gut of premature infants. Microbiome. 2014 [Internet];2(1):1. doi:10.1186/2049-2618-2-1.

 Google Scholar

Brooks B, Olm MR, Firek BA, Baker R, Thomas BC, Morowitz MJ, Banfield JF. Strain-resolved analysis of hospital rooms and infants reveals overlap between the human and room microbiome. Nat Commun. [Internet] 2017; accessed 2019 May 6]; 8(1):1814. doi:10.1038/s41467-017-02018-w

 Google Scholar

Brown CT, Xiong W, Olm MR, Thomas BC, Baker R, Firek B, Morowitz MJ, Hettich RL, Banfield JF.Hospitalized premature infants are colonized by related bacterial strains with distinct proteomic profiles. MBio. [Internet] 2018;9(2). doi:10.1128/mBio.00441-18.

 Google Scholar

Butcher J, Unger S, Li J, Bando N, Romain G, Francis J, Mottawea W, Mack D, Stintzi A, O’Connor DL. Independent of birth mode or gestational age, very-low-birth-weight infants fed their mothers’ milk rapidly develop personalized microbiotas low in bifidobacterium. J Nutr [Internet]. 2018; accessed 2019 May 6]; 148(3):326–335. doi:10.1093/jn/nxx071

 Google Scholar

Cai C, Zhang Z, Morales M, Wang Y, Khafipour E, Friel J. Feeding practice influences gut microbiome composition in very low birth weight preterm infants and the association with oxidative stress: A prospective cohort study. Free Radic Biol Med [Internet]. 2019;142:146–154. doi:10.1016/j.freeradbiomed.2019.02.032.

 Google Scholar

Chernikova DA, Koestler DC, Hoen AG, Housman ML, Hibberd PL, Moore JH, Morrison HG, Sogin ML, Zain-ul-abideen M, Madan JC. Fetal exposures and perinatal influences on the stool microbiota of premature infants. J Matern Neonatal Med [Internet]. 2016; accessed 2019 May 6]; 29(1):99–105. doi:10.3109/14767058.2014.987748

 Google Scholar

Chernikova DA, Madan JC, Housman ML, Zain-ul-abideen M, Lundgren SN, Morrison HG, Sogin ML, Williams SM, Moore JH, Karagas MR, et al. The premature infant gut microbiome during the first 6 weeks of life differs based on gestational maturity at birth. Pediatr Res [Internet]. 2018;84(1):71–79. doi:10.1038/s41390-018-0022-z.

 Google Scholar

Cong X, Judge M, Xu W, Diallo A, Janton S, Brownell EA, Maas K, Graf J. Influence of feeding type on gut microbiome development in hospitalized preterm infants. Nurs Res [Internet]. 2017;66(2):123–133. doi:10.1097/NNR.0000000000000208.

 Google Scholar

Costello EK, Carlisle EM, Bik EM, Morowitz MJ, Relman DA Microbiome assembly across multiple body sites in low-birthweight infants. MBio [Internet] 2013 [ accessed 2019 May 6]; 4(6). doi:10.1128/mBio.00782-13

 Google Scholar

Dahl C, Stigum H, Valeur J, Iszatt N, Lenters V, Peddada S, Bjørnholt JV, Midtvedt T, Mandal S, Eggesbø M. Preterm infants have distinct microbiomes not explained by mode of delivery, breastfeeding duration or antibiotic exposure. Int J Epidemiol. [Internet] 2018;47(5):1658–1669. doi:10.1093/ije/dyy064.

 Google Scholar

Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Støen R, Nakstad B, Willassen NP, Klingenberg C Effects of probiotic supplementation on the gut microbiota and antibiotic resistome development in preterm infants. Front Pediatr [Internet] 2018 [ accessed 2019 May 6]; 6. doi:10.3389/fped.2018.00347

 Google Scholar

Forsgren M, Isolauri E, Salminen S, Rautava S. Late preterm birth has direct and indirect effects on infant gut microbiota development during the first six months of life. Acta Paediatr [Internet]. 2017;[ accesssed 2019 May 6]. 106(7):1103–1109. doi:10.1111/apa.13837

 Google Scholar

Gibson MK, Wang B, Ahmadi S, Burnham C-AD, Tarr PI, Warner BB, Dantas G. Developmental dynamics of the preterm infant gut microbiota and antibiotic resistome. Nat Microbiol. [Internet] 2016; accessed 2019 May 6]; 1(4):16024. doi:10.1038/nmicrobiol.2016.24

 Google Scholar

Gómez M, Moles L, Espinosa-Martos I, Bustos G, de Vos W, Fernández L, Rodríguez J, Fuentes S, Jiménez E. Bacteriological and immunological profiling of meconium and fecal samples from preterm infants: a two-year follow-up study. Nutrients. [Internet] 2017; accessed 2019 May 6]; 9(12):1293. doi:10.3390/nu9121293

 Google Scholar

Gregory KE, LaPlante RD, Shan G, Kumar DV, Gregas M. Mode of birth influences preterm infant intestinal colonization with bacteroides over the early neonatal period. Adv Neonatal Care [Internet]. 2015; accessed 2019 May 6]; 15(6):386–393. doi:10.1097/ANC.0000000000000237

 Google Scholar

Gregory KE, Samuel BS, Houghteling P, Shan G, Ausubel FM, Sadreyev RI, Walker WA. Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome. [Internet] 2016; accessed 2019 May 6]; 4(1):68. doi:10.1186/s40168-016-0214-x

 Google Scholar

Grier A, Qiu X, Bandyopadhyay S, Holden-Wiltse J, Kessler HA, Gill AL, Hamilton B, Huyck H, Misra S, Mariani TJ, et al. Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. Microbiome [ Internet] 2017 [ accessed 2019 May 6]; 5(1):158. doi:10.1186/s40168-017-0377-0

 Google Scholar

Gupta RW, Tran L, Norori J, Ferris MJ, Eren AM, Taylor CM, Dowd SE, Penn D. Histamine-2 receptor blockers alter the fecal microbiota in premature infants. J Pediatr Gastroenterol Nutr. [Internet] 2013;56(4):397–400. doi:10.1097/MPG.0b013e318282a8c2.

 Google Scholar

Ho TTB, Groer MW, Kane B, Yee AL, Torres BA, Gilbert JA, Maheshwari A. Dichotomous development of the gut microbiome in preterm infants. Microbiome [Internet]. 2018; accessed 2019 May 6]; 6(1):157. doi:10.1186/s40168-018-0547-8

 Google Scholar

Ishizeki S, Sugita M, Takata M, Yaeshima T. Effect of administration of bifidobacteria on intestinal microbiota in low-birth-weight infants and transition of administered bifidobacteria: A comparison between one-species and three-species administration. Anaerobe. [Internet] 2013;23:38–44. doi:10.1016/j.anaerobe.2013.08.002.

 Google Scholar

Korpela K, Blakstad EW, Moltu SJ, Strømmen K, Nakstad B, Rønnestad AE, Brække K, Iversen PO, Drevon CA, de Vos W. Intestinal microbiota development and gestational age in preterm neonates. Sci Rep [Internet] 2018; accessed 2019 May 6]; 8(1):2453. doi:10.1038/s41598-018-20827-x

 Google Scholar

La Rosa PS, Warner BB, Zhou Y, Weinstock GM, Sodergren E, Hall-Moore CM, Stevens HJ, Bennett WE, Shaikh N, Linneman LA, et al. Patterned progression of bacterial populations in the premature infant gut. Proc Natl Acad Sci [Internet] 2014 [ accessed 2019 May 6]; 111(34):12522–12527. doi:10.1073/pnas.1409497111

 Google Scholar

Mai V, Torrazza RM, Ukhanova M, Wang X, Sun Y, Li N, Shuster J, Sharma R, Hudak ML, Neu J. Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants. PLoS One. [Internet] 2013;8(1):e52876. doi:10.1371/journal.pone.0052876.

 Google Scholar

Millar M, Seale J, Greenland M, Hardy P, Juszczak E, Wilks M, Panton N, Costeloe K, Wade WG The microbiome of infants recruited to a randomised placebo-controlled probiotic trial (PiPS Trial). EBioMedicine [Internet] 2017 [ accessed 2019 May 6]; 20:255–262. doi:10.1016/j.ebiom.2017.05.019

 Google Scholar

Moles L, Gómez M, Heilig H, Bustos G, Fuentes S, de Vos W, Fernández L, Rodríguez JM, Jiménez E. Bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life. PLoS One. [Internet] 2013;8(6):e66986. doi:10.1371/journal.pone.0066986.

 Google Scholar

Moles L, Gómez M, Jiménez E, Fernández L, Bustos G, Chaves F, Cantón R, Rodríguez JM, Del Campo R Preterm infant gut colonization in the neonatal ICU and complete restoration 2 years later. Clin Microbiol Infect [Internet] 2015 [ accessed 2019 May 6]; 21(10):936.e1-936.e10. doi:10.1016/j.cmi.2015.06.003

 Google Scholar

Mshvildadze M, Neu J, Shuster J, Theriaque D, Li N, Mai V. Intestinal microbial ecology in premature infants assessed with non–culture-based techniques. J Pediatr. [Internet] 2010;156(1):20–25. doi:10.1016/j.jpeds.2009.06.063.

 Google Scholar

Normann E, Fahlén A, Engstrand L, Lilja HE. Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis. Acta Paediatr. [Internet] 2013;102(2):129–136. doi:10.1111/apa.12059.

 Google Scholar

Parra-Llorca A, Gormaz M, Alcántara C, Cernada M, Nuñez-Ramiro A, Vento M, Collado MC. Preterm gut microbiome depending on feeding type: significance of donor human milk. Front Microbiol. [Internet] 2018;9:1376. doi:10.3389/fmicb.2018.01376.

 Google Scholar

Pärtty A, Luoto R, Kalliomäki M, Salminen S, Isolauri E. Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. [Internet] 2013;163(5):1272–1277.e2. doi:10.1016/j.jpeds.2013.05.035.

 Google Scholar

Patel AL, Mutlu EA, Sun Y, Koenig L, Green S, Jakubowicz A, Mryan J, Engen P, Fogg L, Chen AL, et al. Longitudinal survey of microbiota in hospitalized preterm very-low-birth-weight infants. J Pediatr Gastroenterol Nutr [Internet] 2016 [ accessed 2019 May 6]; 62(2):292–303. doi:10.1097/MPG.0000000000000913

 Google Scholar

Poroyko V, Morowitz M, Bell T, Ulanov A, Wang M, Donovan S, Bao N, Gu S, Hong L, Alverdy JC, et al. Diet creates metabolic niches in the “immature gut” that shape microbial communities. Nutr Hosp. 2011;26(6):1283–1295. doi:10.1590/S0212-16112011000600015.

 Google Scholar

Ravi A, Estensmo ELF, Abée-Lund TML, Foley SL, Allgaier B, Martin CR, Claud EC, Rudi K. Association of the gut microbiota mobilome with hospital location and birth weight in preterm infants. Pediatr Res. [Internet] 2017; accessed 2019 May 6]; 82(5):829–838. doi:10.1038/pr.2017.146

 Google Scholar

Rougé C, Piloquet H, Butel M-J, Berger B, Rochat F, Ferraris L, Des Robert C, Legrand A, de la Cochetière M-F, N’Guyen J-M, et al. Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr [Internet] 2009 [ accessed 2019 May 6]; 89(6):1828–1835. doi:10.3945/ajcn.2008.26919

 Google Scholar

Rozé J-C, Ancel P-Y, Lepage P, Martin-Marchand L, Al Nabhani Z, Delannoy J, Picaud J-C, Lapillonne A, Aires J, Durox M, et al. Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants. Am J Clin Nutr [Internet] 2017 [ accessed 2019 May 6]; 106(3):821–830. doi:10.3945/ajcn.117.152967

 Google Scholar

Sherman MP, Sherman J, Arcinue R, Niklas V Randomized control trial of human recombinant lactoferrin: a substudy reveals effects on the fecal microbiome of very low birth weight infants. J Pediatr [Internet]. 2016 [ accessed 2019 May 6]:173:S37–42. doi:10.1016/j.jpeds.2016.02.074

 Google Scholar

Sim K, Shaw AG, Randell P, Cox MJ, McClure ZE, Li M-S, Haddad M, Langford PR, Cookson WOCM, Moffatt MF, et al. Dysbiosis Anticipating Necrotizing Enterocolitis in Very Premature Infants. Clin Infect Dis. [Internet] 2015;60(3):389–397. doi:10.1093/cid/ciu822.

 Google Scholar

Soeorg H, Metsvaht T, Eelmäe I, Merila M, Treumuth S, Huik K, Jürna-Ellam M, Ilmoja M-L, Lutsar I. The role of breast milk in the colonization of neonatal gut and skin with coagulase-negative staphylococci. Pediatr Res. [Internet] 2017; accessed 2019 May 6]; 82(5):759–767. doi:10.1038/pr.2017.150

 Google Scholar

Stewart CJ, Embleton ND, Clements E, Luna PN, Smith DP, Fofanova TY, Nelson A, Taylor G, Orr CH, Petrosino JF, et al. Cesarean or vaginal birth does not impact the longitudinal development of the gut microbiome in a cohort of exclusively preterm infants. Front Microbiol [Internet] 2017;8:1008. doi:10.3389/fmicb.2017.01008.

 Google Scholar

Tauchi H, Yahagi K, Yamauchi T, Hara T, Yamaoka R, Tsukuda N, Watanabe Y, Tajima S, Ochi F, Iwata H, et al. Gut microbiota development of preterm infants hospitalised in intensive care units. Benef Microbes. [Internet] 2019;10(6):641–651. doi:10.3920/BM2019.0003.

 Google Scholar

Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA, Marcobal A, Tancredi DJ, Bevins CL, Sherman MP. A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids. J Pediatr Gastroenterol Nutr. [Internet] 2009;48(2):216–225. doi:10.1097/MPG.0b013e31818de195.

 Google Scholar

Underwood MA, Kalanetra KM, Bokulich NA, Lewis ZT, Mirmiran M, Tancredi DJ, Mills DAA. Comparison of two probiotic strains of bifidobacteria in premature infants. J Pediatr [Internet]. 2013;163(6):1585–1591.e9. doi:10.1016/j.jpeds.2013.07.017.

 Google Scholar

Underwood MA, Kalanetra KM, Bokulich NA, Mirmiran M, Barile D, Tancredi DJ, German JB, Lebrilla CB, Mills DA. Prebiotic oligosaccharides in premature infants. J Pediatr Gastroenterol Nutr [Internet]. 2014;58(3):352–360. doi:10.1097/MPG.0000000000000211.

 Google Scholar

Underwood MA, Gaerlan S, De Leoz MLA, Dimapasoc L, Kalanetra KM, Lemay DG, German JB, Mills DA, Lebrilla CB. Human milk oligosaccharides in premature infants: absorption, excretion, and influence on the intestinal microbiota. Pediatr Res. [Internet] 2015; accessed 2019 May 6]; 78(6):670–677. doi:10.1038/pr.2015.162

 Google Scholar

Underwood MA, Davis JCC, Kalanetra KM, Gehlot S, Patole S, Tancredi DJ, Mills DA, Lebrilla CB, Simmer K. Digestion of human milk oligosaccharides by bifidobacterium breve in the premature infant. J Pediatr Gastroenterol Nutr [Internet]. 2017; accessed 2019 May 6]; 65(4): 449–455. doi:10.1097/MPG.0000000000001590

 Google Scholar

Wandro S, Osborne S, Enriquez C, Bixby C, Arrieta A, Whiteson K The microbiome and metabolome of preterm infant stool are personalized and not driven by health outcomes, including necrotizing enterocolitis and late-onset sepsis. mSphere [Internet]. 2018; 3(3) doi:10.1128/mSphere.00104-18

 Google Scholar

Hasan N, Yang H. Factors affecting the composition of the gut microbiota, and its modulation. PeerJ [Internet]. 2019;7:e7502. https://pubmed.ncbi.nlm.nih.gov/31440436

 Google Scholar

Westerbeek EAM, Slump RA, Lafeber HN, Knol J, Georgi G, Fetter WPF, Elburg RM. The effect of enteral supplementation of specific neutral and acidic oligosaccharides on the faecal microbiota and intestinal microenvironment in preterm infants. Eur J Clin Microbiol Infect Dis. [Internet] 2013;32(2):269–276. doi:10.1007/s10096-012-1739-y.

 Google Scholar

Younge N, Yang Q, Seed PC Enteral high fat-polyunsaturated fatty acid blend alters the pathogen composition of the intestinal microbiome in premature infants with an enterostomy. J Pediatr [Internet] 2017 [ accessed 2019 May 6]; 181:93–101.e6. doi:10.1016/j.jpeds.2016.10.053

 Google Scholar

Younge NE, Newgard CB, Cotten CM, Goldberg RN, Muehlbauer MJ, Bain JR, Stevens RD, O’Connell TM, Rawls JF, Seed PC, et al. Disrupted maturation of the microbiota and metabolome among extremely preterm infants with postnatal growth failure. Sci Rep. [Internet] 2019;9(1):8167. doi:10.1038/s41598-019-44547-y.

 Google Scholar

Zeber-Lubecka N, Kulecka M, Ambrozkiewicz F, Paziewska A, Lechowicz M, Konopka E, Majewska U, Borszewska-Kornacka M, Mikula M, Cukrowska B, et al. Effect of Saccharomyces boulardii and mode of delivery on the early development of the gut microbial community in preterm infants. PLoS One [Internet] 2016 [ accessed 2019 May 6]; 11(2):e0150306. doi:10.1371/journal.pone.0150306

 Google Scholar

Zhou Y, Shan G, Sodergren E, Weinstock G, Walker WA, Gregory KE. Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. PLoS One [Internet]. 2015;10(3):e0118632. doi:10.1371/journal.pone.0118632.

 Google Scholar

Zhu D, Xiao S, Yu J, Ai Q, He Y, Cheng C, Zhang Y, Pan Y. Effects of one-week empirical antibiotic therapy on the early development of gut microbiota and metabolites in preterm infants. Sci Rep. [Internet] 2017; accessed 2019 May 6]; 7(1):8025 doi:10.1038/s41598-017-08530-9

 Google Scholar

Zou Z-H, Liu D, Li H-D, Zhu D-P, He Y, Hou T, Yu J-L. Prenatal and postnatal antibiotic exposure influences the gut microbiota of preterm infants in neonatal intensive care units. Ann Clin Microbiol Antimicrob. [Internet] 2018; accessed 2019 May 6]; 17(1):9. doi:10.1186/s12941-018-0264-y

 Google Scholar

Zwittink RD, van Zoeren-grobben D, Martin R, van Lingen RA, Groot Jebbink LJ, Boeren S, Renes IB, van Elburg RM, Belzer C, Knol J. Metaproteomics reveals functional differences in intestinal microbiota development of preterm infants. Mol Cell Proteomics [Internet]. 2017; accessed 2019 May 6]; 16(9):1610–1620. doi:10.1074/mcp.RA117.000102

 Google Scholar

Zwittink RD, Renes IB, van Lingen RA, van Zoeren-grobben D, Konstanti P, Norbruis OF, Martin R, Groot Jebbink LJM, Knol J, Belzer C. Association between duration of intravenous antibiotic administration and early-life microbiota development in late-preterm infants. Eur J Clin Microbiol Infect Dis [Internet]. 2018; accessed 2019 May 6]; 37(3):475–483. doi:10.1007/s10096-018-3193-y

 Google Scholar

Deschasaux M, Bouter KE, Prodan A, Levin E, Groen AK, Herrema H, Tremaroli V, Bakker GJ, Attaye I, Pinto-Sietsma S-J, et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat Med [Internet]. 2018;24(10):1526–33. doi:10.1038/s41591-018-0160-1.

 Google Scholar

Stinson LF, Payne MS, Keelan JA, Critical A. Review of the bacterial baptism hypothesis and the impact of cesarean delivery on the infant microbiome. Front Med [Internet]. 2018;5:135. doi:10.3389/fmed.2018.00135.

 Google Scholar

Stewart CJ, Ajami NJ, O’Brien JL, Hutchinson DS, Smith DP, Wong MC, Ross MC, Lloyd RE, Doddapaneni H, Metcalf GA, et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature [Internet]. 2018;562(7728):583–588. doi:10.1038/s41586-018-0617-x.

 Google Scholar