1 

Dynamics of the Preterm Gut Microbiome in Health and Disease

2  Authors: Alain Cuna1,2, Michael J. Morowitz3, Ishfaq Ahmed 4, Shahid Umar5,

3  Venkatesh Sampath1,2

4  Affiliations: 1Children’s Mercy Kansas City, Kansas City MO; 2University of Missouri

5  Kansas City, Kansas City MO; 3University of Pittsburgh, Pittsburgh PA; 4Kansas City

6  Kansas Community College, Kansas City KS; 5University of Kansas Medical Center,

7  Kansas City KS

8 

9  Corresponding author: Venkatesh Sampath, MD, Department of Pediatrics, Division of

10  Neonatology, Children’s Mercy Kansas City, 2401 Gillham Rd, Kansas City, MO 64108,

11  Tel: (816) 234-3591, Fax: (816) 234-3590, Email: vsampath@cmh.edu

12 

13  Disclosure statement: The authors have no potential or perceived conflicts of interest
14  to disclose.
15 

16  Statement of financial support: This study was supported by institutional funds at

17  Children’s Mercy Hospital (VS, AC), R01DK117296 (VS) and K08DK125735 (AC).

18 

19 
20  ABSTRACT

21  Advances in metagenomics have allowed a detailed study of the gut microbiome, and

22  its role in human health and disease. Infants born prematurely possess a fragile gut

23  microbial ecosystem that is vulnerable to perturbation. Alterations in the developing gut

24  microbiome in preterm infants are linked to life-threatening diseases such as necrotizing

25  enterocolitis (NEC) and late onset sepsis; and may impact future risk of asthma, atopy,

26  obesity, and psychosocial disease. In this mini review, we summarize recent literature

27  on the origins and patterns of development of the preterm gut microbiome in the

28  perinatal period. The host-microbiome-environmental factors that portend development

29  of dysbiotic intestinal microbial patterns associated with NEC and sepsis are reviewed.

30  Strategies to manipulate the microbiome and mitigate dysbiosis, including the use of

31  probiotics and prebiotics will also be discussed. Finally, we explore the challenges and

32  future directions of gut microbiome research in preterm infants.

33 
34  Introduction

35  The human gastrointestinal (GI) tract harbors a complex and diverse microbial

36  community which is dominated by bacteria, but also includes viruses, archaea, fungi,

37  and other eukaryotes. This complex ecosystem with 1012-14 cells from 100-1000

38  species, is considered to be the most dense microbial habitat on earth (74). Compared

39  to approximately 23,000 genes of human genome, the gut microbiome has been

40  referred to as a ‘hidden’ metabolic organ and encodes over 3 million genes producing

41  thousands of metabolites (78). 90% of the GI microbiota is composed of bacteria from

42  two major phyla namely Bacteroidetes and Firmicutes. Other phyla consistently found in

43  human gut include Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia

44  (4). At lower taxonomic levels however, individuals differ considerably in composition of

45  fecal microbiota and each individual may have his or her own distinctive pattern of

46  microbial profile (25).

47  Studies suggest that the early pattern of infant gut microbial colonization is

48  critical for proper development of the human GI tract. The neonatal gut microbiota plays

49  an essential role in the acquisition of postnatal intestinal endotoxin tolerance (45) and

50  specifically regulates maturation of regulatory T cells (CD4+, Foxp3+), natural killer cell

51  and gamma delta T cells (69). Dysbiosis or imbalance in gut microbial communities

52  during this critical period is linked to several diseases including inflammatory, metabolic,

53  neurologic, cardiovascular, and GI illnesses (73). Compared to term neonates, infants

54  born prematurely are at greater risk for disruptions to the gut microbiota. Herein, we

55  briefly review commonly used metagenomic methods for microbiome analysis, compare

56  the challenges of preterm versus term gut microbiome, delineate antecedents and
57  consequences of preterm gut dysbiosis, and discuss advances in microbiome

58  modulation therapy in preterm infants. We focus predominantly on the bacterial

59  communities as most research has been done in this area.

60  Methods of microbial profiling with 16S and shotgun sequencing

61  Currently available high-throughput sequencing technologies used to profile the

62  genomic composition of a microbial community in a culture-independent manner can be

63  sub-divided into two different approaches, namely 16S rRNA gene sequencing and

64  shotgun metagenomics. In 16S rRNA sequencing, the 16S rRNA gene is used as a

65  genetic fingerprint to decipher bacterial phylogeny and taxonomy. A component of the

66  30S subunit of prokaryotic ribosome, the 16S rRNA gene is 1500 base pair long and is

67  comprised of nine variable regions (V1 – V9) interspersed among the conserved regions

68  of its sequence. These hypervariable regions are unique to each bacterial taxon while

69  the conserved regions allow for the development of universal primers that bind to known

70  sequences shared among most bacteria. During data analysis, amplified 16S rRNA

71  sequences are assigned to Operational Taxonomic Units (OTUs) and OTU clustering

72  methods using a moderately stringent sequence identity threshold allowing for basic

73  taxonomic assignments (family level or higher) (26). Amplicon sequencing targeting the

74  16S rRNA gene is limited by differences arising from the different variable region

75  chosen for PCR amplification, sequencing errors, poor discriminatory power for some

76  genera, and severely limited resolution at the species level due to short-read amplicon

77  sequencing, potential for contamination, and sequencing platform used (64, 76, 87).

78  Unlike 16S sequencing which only targets 16S rRNA sequences, shotgun

79  metagenomics generates whole genome sequencing data that can be compared to
 80  existing reference databases for accurate taxonomic identification. By sequencing all

81  genetic information within a sample, shotgun metagenomic studies can extract both

82  taxonomic and functional information from complex microbial communities and therefore

83  guide phenotypic studies to understand their potential roles in health and disease. While

84  shotgun metagenomics can be used to extract species- and even strain-level

85  information through computational approaches, it can still be challenging to differentiate

86  between closely related or co-existing bacterial taxa (65). This has mandated the need

87  for extensive and well-characterized collections of reference genomes including those

88  from the Human Microbiome Project and the Human Gastrointestinal Bacteria Genome

89  Collection (28, 63).

90  Challenges of the preterm infant that shapes the gut microbiome in comparison

91  with the term infant

92  Preterm infants face several unique environmental and host conditions that negatively

93  impact development of their gut microbiome. Even before birth, about 25% to 30% of

94  preterm infants are exposed to microbes in the context of preterm premature rupture of

95  membranes and intra-amniotic infection (32). Cesarean section, with subsequent gut

96  colonization by skin microbiota rather than vaginal and rectal microbiota from vaginal

97  delivery, is also more common in preterm than term infants (67). After delivery, most

98  preterm infants need stabilization and subsequent care in the neonatal intensive care

99  unit which, while necessary, is also invasive and results in exposure to the hospital

100  microbial environment. Consequently, as risk of serious nosocomial infection is high,

101  preterm infants are often exposed to powerful broad-spectrum antibiotics throughout

102  their hospital stay. Preterm nutrition and feeding practices – such as delayed
103  introduction of enteral feedings, frequent withholding of feeds, use of acid-suppressive

104  medications, and provision of exclusive human milk diet or formula – are also major

105  modifiers of gut microbiota composition (13). Together, these environmental factors

106  interact with the intrinsically immature GI tract and immune system of the preterm infant

107  in a highly complex but poorly defined process that significantly impact the developing

108  preterm gut microbiome (36, 85).

109  In general, the intestinal microbiota in the preterm infant differs from the term

110  infant in having delayed colonization, fewer bacterial species, and less diversity and

111  abundance (2, 36, 59). There is also a predilection to being colonized by potentially

112  pathogenic facultative anaerobes (e.g. Enterobacter, Escherichia, and Klebsiella) and

113  decreased levels of commensal strictly anaerobic organisms (e.g. Bifidobacterium,

114  Bacteroides, and Clostridium) (Table 1) (34). A shared patterned progression of

115  microbial communities from Bacilli to Gammaproteobacteria to Clostridia has also been

116  described in preterm infants (41). The pace of this patterned progression is

117  predominantly influenced by gestational age, while mode of delivery, antibiotic

118  exposure, and type of feeding appear to have less impact (41).

119  Whether the differences in gut microbiota of preterm versus term infant

120  constitutes true dysbiosis or merely represents the common gut microbiome signature in

121  very low birth weight infants is debatable. Current studies do not clarify whether a

122  distinct pattern of dysbiosis that portends disease susceptibility exists, apart from a

123  modest increase in Enterobacteriaceae in infants who develop necrotizing enterocolitis

124  (NEC), as further discussed below.

125  Antecedents of dysbiosis in preterm infants

126  Prenatal factors. The development of intestinal microbiome in the preterm neonate and

127  the proclivity to a dysbiotic signature is influenced by several prenatal factors (Fig 1).

128  Maternal gestational diet appears to alter the composition of the first stool after birth

129  (meconium), with depletion of Bacteroides observed with high-fat diet (9). Other studies

130  have described an interactive effect between maternal diet and mode of delivery on the

131  neonatal gut microbiome, with fruit intake increasing intestinal Streptococcus/

132  Clostridium in infants delivered vaginally, while increased dairy intake was associated

133  with higher abundance of Clostridium among infants by Cesarean section (46). In

134  pregnancies complicated by intrauterine amniotic infection or chorioamnionitis, a higher

135  relative abundance of Mycoplasmataceae and phylum Bacteroidetes has been identified

136  in stool of infants postnatally (62). While previous studies had suggested the presence

137  of microbial communities in the placenta and amniotic fluid of healthy pregnancies

138  potentially colonizing the gut prenatally, more vigorous recent studies have disproved

139  the existence of a distinct placental microbiome (14, 20).

140  Intrapartum antibiotics (IAP) administered to prevent Group B streptococcal

141  transmission has also been shown to have significant early effects on the composition

142  of gut microbiome in neonates that persist through the first year of life (12, 15, 56).

143  Nogacka et al. (56) showed a persistent increase in Proteobacteria and Firmicutes with

144  decreases in Acinetobacter and Bacteroides in association with higher occurrence of

145  some bacterial genes that code for β-lactamase resistance. Others have shown that the

146  use of IAP was associated with decreases in Bifidobacteria spp at 7 days of life, while

147  Lactobacillus spp remains unchanged (15). Further, the effects of IAP on the infant

148  microbiome may be selective with penicillin suppressing Bacteroides spp., and
149  cephalosporin delaying the increase in Bifidobacteria (12). These studies suggest that

150  maternal gestational diet, chorioamnionitis and IAP influence the composition of the

151  neonatal microbiome and these effects can last well beyond the neonatal period.

152  Postnatal factors. Several postnatal factors influence the development of gut

153  microbiome and can program intestinal dysbiosis (Fig 1). The mode of birth, i.e., vaginal

154  vs. cesarean, has been shown to influence the neonatal microbiome (10, 23, 67).

155  Infants born by cesarean section have less intestinal microbial diversity, decreased

156  colonization with Bifidobacteria, Bacteroides and Lactobacilli, and tended to have

157  increased skin microbiota such as Streptococcus and Staphylococcus in the first weeks

158  after birth (23, 67). Interestingly, differences related to mode of delivery are less evident

159  with maturity, likely because other factors like postnatal diet impact the gut microbiota

160  (10).

161  Early exposure to parenteral antibiotics is also a risk factor for gut dysbiosis (27,

162  72). Fouhy et al. (29) demonstrated that early (<48hr) antibiotic treatment with ampicillin

163  and gentamicin was associated with increases in Proteobacteria and decreased

164  abundance of Actinobacteria, Bifidobacteria and Lactobacillus. Gibson et al. (31)

165  demonstrated that broad spectrum antibiotics such as meropenem, cephalosporins and

166  ticarcillin-clavulanate decreased species richness whereas vancomycin and gentamicin

167  had non-uniform results. They also noted emergence of antibiotics resistant genes that

168  was antibiotic- and species-specific. Zwittink et al. (90) noted that the use of short- or

169  long-term amoxicillin/ceftazidime treatment was associated with significant higher

170  abundance of Enterococcus during the first two postnatal weeks at the expense of

171  Bifidobacterium and Streptococcus.

172  Nutrition is also a strong modifier of the of the gut microbiome. Preterm infants

173  fed with formula milk exhibit a less diverse gut microbiome with less enrichment of

174  Clostridiales and Bifidobacteria compared to preterm infants fed mothers’ own milk (84).

175  In summary, major postnatal factors linked to a dysbiotic gut signature in preterm infants

176  include mode of delivery, exposure to antibiotics and other medications, and type of milk

177  feeding.

178  Consequences of dysbiosis in preterm infants

179  Necrotizing enterocolitis (NEC). NEC is the most widely recognized consequence of

180  gut dysbiosis in preterm infants (Fig 1). The role of gut bacteria in NEC is demonstrated

181  from mouse models showing absence of disease in a germfree environment, direct

182  studies of human stools showing dysbiotic signatures, and demonstration of bacterial

183  invasion by fluorescent techniques in surgically resected human tissues (39, 66, 79).

184  Clusters of NEC outbreaks related to specific organisms that have varied by institution

185  have also been reported, providing additional evidence of the role of microbes in NEC

186  pathogenesis. With advances in metagenomics, several studies have demonstrated that

187  preterm infants who develop NEC have altered gut microbiota signatures compared to

188  preterm infants who do not develop NEC, though these signatures have varied between

189  studies (50).

190  In a small study, Heida et al. (37) identified enrichment of Clostridrium

191  perfringens in meconium of preterm infants who subsequently developed NEC,

192  suggesting that a pathogenic microbial signature for NEC may be present in the very

193  first days of life. However, meconial or very early stool signatures for NEC have not

194  been demonstrated in subsequent studies (59, 82). In one of largest longitudinal studies
195  in preterm infants, Warner et al. (82) studied >2400 stool samples from 122 infants born

196  with a birthweight <1500g to demonstrate that NEC was associated with

197  Gammaproteobacteria abundance, and relative depletion of Negativicutes, an

198  anaerobe. Interestingly, these patterns emerged typically after the first 4 weeks of life.

199  Other interesting observations were that antibiotic use increased proportions of Bacilli

200  while vaginal birth was associated with decreased proportions of Bacilli, and the volume

201  of human milk feeds did not impact bacterial community architecture.

202  Similar to the landmark study by Warner et al. (82), several investigators have

203  reported an enrichment of potentially pathogenic Gram-negative bacteria in the intestine

204  in addition to a relative decrease in the abundance of Firmicutes and Bacteroides prior

205  to the onset of NEC (51, 57, 59, 81, 82). Furthermore, while preterm infants in general

206  have low gut microbial diversity compared to term infants, several studies have noted

207  further reduced levels of diversity in preterm infants who develop NEC compared to

208  preterm infants without NEC (22, 50, 59, 70). A meta-analysis of published studies

209  confirmed a relative abundance of Gammaproteobacteria, with decreased relative

210  proportions of Firmicutes and Bacteroides preceding NEC, but did not confirm reduced

211  microbial diversity prior to NEC onset (59). Gammaproteobacteria, which include

212  several well-known pathogenic species that have the endotoxin lipopolysaccharide, can

213  induce excessive intestinal and systemic inflammation through stimulation of Toll-like

214  receptors (39); while Firmicutes and Bacteroides can enhance gut development by

215  facilitating intestinal epithelial cell differentiation and preserving mucin and tight junction

216  integrity (88).

217  While these studies have primarily focused on bacterial signatures, a potential

218  role for viruses such as norovirus, rotavirus, and cytomegalovirus (CMV) in NEC

219  causation is also recognized (11, 50). For example, case reports (75) have described

220  infants with CMV-associated NEC, and retrospective studies using surgical specimens

221  (58, 60) have detected CMV in intestinal tissue of preterm infants with NEC or

222  spontaneous intestinal perforation. Infants with CMV-associated NEC tend to have

223  lower gestational age and thrombocytopenia than non-CMV associated cases. The

224  relative impact of viruses on NEC remains poorly characterized as reported rates of

225  detection of CMV and other viruses can vary depending on the sample (blood, stool,

226  intestinal tissue), technique (immunohistochemistry, polymerase chain reaction,

227  enzyme-linked immunosorbent assay), and sample size of NEC cohort (7, 71, 77). The

228  potential role of fungi and the mycobiome in NEC also remain largely unexplored (38).

229  While metagenomic studies provide a snapshot of microbial patterns associated

230  with NEC, more rigorous studies are needed to elucidate their mechanistic role and

231  establish their contribution in NEC. More recently, multi-omic studies combining

232  metagenomics, metatranscriptomics, and metabolomics are beginning to shed new light

233  on bacterial replication rates, quorum sensing patterns, and metabolic profiles

234  associated with intestinal dysbiosis preceding NEC (57, 59, 70). For example, Morrow

235  et al. (51) evaluated the urinary metabolome and gut microbiome of 11 preterm infants

236  with NEC and 21 matched controls. Using this two complementary “-omic” approaches,

237  the authors found that the urinary metabolite alanine was directly correlated with

238  Firmicutes and indirectly correlated with Proteobacteria in the gut, suggesting that

239  specific intestinal bacteria can influence production and utilization of specific
240  metabolites which may be useful as surrogate biomarkers for early diagnosis of NEC.

241  While still at its infancy, these novel multi-omic approaches are anticipated to further

242  advance our understanding and provide a full mechanistic picture of NEC pathogenesis

243  (54).

244  Sepsis and other diseases. The consequences of dysbiosis in the preterm infants

245  extend beyond the predisposition to develop NEC (Fig 1). Stewart et al. (72) noted that

246  the bacteria isolated from a blood culture during sepsis corresponded to the dominant

247  bacterial genera in the gut microbiome, and that Bifidobacteria abundance was

248  observed in infants who did not develop sepsis or NEC. Other studies have also noted

249  decreased diversity and lower abundance of Bifidobacteria among infants who

250  developed sepsis (47). Potential mechanisms by which Bifidobacteria can protect

251  against sepsis include reduced bacterial translocation through enhanced intestinal

252  barrier function and increased production of beneficial short-chain fatty acids like

253  acetate (30, 43). Sepsis related to antibiotic-resistant strains of bacteria originating from

254  the gut are also increased in preterm infants treated with broad spectrum antibiotics that

255  increase dysbiosis (31, 72, 82). While not the focus here, dysbiosis in preterm infants

256  has also been linked to bronchopulmonary dysplasia (a chronic debilitating lung

257  condition of infants) and growth failure (68, 86).

258  Potential long-term consequences. Epidemiological studies suggest a link between

259  early disturbances to the gut microbiome from antibiotics or cesarean delivery with later

260  childhood diseases including allergy (3, 48, 55), obesity (1, 42), and attention deficit

261  hyperactivity disorder (6). A recent population-based cohort study using the Rochester

262  Epidemiological Project found similar associations between early life antibiotic exposure
263  and increased risk for several childhood immunological, metabolic, and neurobehavioral

264  health conditions (5). While these studies did not differentiate term from preterm infants,

265  the aforementioned stressors that preterm infants experience in the hospital

266  environment puts them at greatest risk for early gut microbial dysbiosis (35). Additional

267  studies in mice provide supporting evidence for the hypothesis that early life

268  perturbations during key developmental periods can have long-term consequences. For

269  example, in a mouse model of early gut microbial disruption with low-dose penicillin,

270  long-lasting metabolic effects of increased fat mass were observed even with limited

271  antibiotic administration where microbial communities recovered after cessation of

272  antibiotics (16).

273  Microbiome modulation therapy

274  With accumulating evidence of how gut microbiome perturbations contribute to preterm

275  diseases, novel strategies that reverse or alleviate dysbiosis are being explored.

276  Probiotics. Probiotics are defined as living microorganisms that confer health benefits

277  when administered in adequate amounts. In addition to favorable alteration of gut

278  microbiome, probiotics are now recognized to confer benefit through other mechanisms

279  such as colonization resistance against pathogenic bacteria, enhanced gut barrier

280  function, and immunomodulation (18). Numerous clinical trials have demonstrated the

281  safety and efficacy of prophylactic administration of probiotics in preterm infants for the

282  prevention of NEC. A recent network meta-analysis (63 trials, 15,712 preterm infants)

283  identified that a multi-species combination that contains Lactobacillus and

284  Bifidobacterium provided superior benefits for NEC prevention compared to single
285  species or other multi-species probiotic combinations for reducing mortality and

286  necrotizing enterocolitis in preterm infants (49).

287  Prebiotics. Prebiotics are nutrient substrates that selectively enrich beneficial

288  microbiota in the gut. The most important source of prebiotics for preterm infants is

289  human milk oligosaccharides (HMO) - complex sugars not otherwise digestible by the

290  human gut but utilized by specific microbes such as Bifidobacteria and Bacteroides to

291  promote their growth and activity. In addition to stimulating probiotic growth, prebiotics

292  also help improve intestinal mobility and gut barrier function. Artificial or non-human milk

293  oligosaccharides designed to function in a similar manner to HMOs have also been

294  tested in small clinical trials with promising results (8). Other active areas of

295  investigation include synbiotics which are combination products that contain both

296  prebiotics and probiotics (53).

297  Postbiotics. Postbiotics are metabolic byproducts of probiotic bacteria that can exert

298  positive biologic activity in the host. In a recent study, Zheng et al. (89) demonstrated

299  that short chain fatty acids, such as butyrate and acetate produced by Bifidobacterium

300  infantis from metabolism of complex carbohydrates expressed in breastmilk, have anti-

301  inflammatory effects in immature enterocytes. Other studies have shown how butyrate,

302  can also enhance intestinal barrier function and regulate mucosal immunity (44). By

303  using metabolites instead of bacteria, postbiotics potentially provide an effective,

304  simpler, and safer alternative to ingestion of live microorganisms. A related strategy is

305  the use of para-probiotics, which are inactivated microbial cells or cell fractions typically

306  produced by heat-killing probiotics (21).

307  Fecal microbiota transplantation (FMT). In FMT, fecal material from a healthy donor

308  is transplanted to the recipient’s GI tract to restore microbial homeostasis. Compared to

309  probiotics, FMT allows more robust and longer-lasting community of diverse microbes

310  with a single-dose. Safety concerns include inadvertent introduction or promotion of

311  pathogenic species and transference of antibiotic resistance. FMT in preterm infants

312  remains largely unexplored except in experimental animal research (61). A similar

313  thematic approach is vaginal seeding, wherein bacteria from the mother’s vaginal tract

314  is transferred to the infants face and body when infants are born via cesarean section

315  (52).

316  Conclusion

317  The concept of the holobiont, consisting of the human host and the resident microbial

318  communities, is important in considering perturbations of intestinal microbial assembly

319  in preterm infants (24, 73). The development of a symbiotic intestinal ecosystem is a

320  central event for successful adaptation to postnatal life. Maternal disease, intrauterine

321  infection, and perinatal use of antibiotics can disrupt establishment of co-evolved

322  microbial communities, which are integral for the optimal function and development of

323  the intestine, the immune system, the brain, and other physiological processes (24, 73).

324  Restoration to a normal microbial assembly is further impeded in the preterm neonate

325  fed formula milk, exposed to long term antibiotics and deviant microbial dispersal

326  patterns in a pathogen-rich milieu, and microbial community priority effects. These

327  adverse influences result in the establishment of a dysbiotic microbial signature

328  characterized by a relative abundance in Gammaproteobacteria, decreased diversity,

329  and a modest decrease in Bifidobacteria. Several studies link these dysbiotic signatures
330  to increased vulnerability to life-threatening neonatal illness such as NEC and sepsis,

331  and increasingly to childhood asthma, allergic disease, disorders of mood and obesity

332  (24, 73). Efforts at restoring microbial community structure using probiotics have shown

333  promise in alleviating NEC and sepsis risk. Other approaches based on prebiotics or

334  enteral immune therapy, however, warrant careful trials. Understanding the role of host

335  genetics in programming the neonatal gut microbial assembly, combining metabolomic

336  and transcriptomic signatures concurrent with dysbiotic microbiota signatures, and

337  personalized approaches in reconstituting the deviant microbial assembly in preterm

338  neonates to prevent disease and ensure healthy outcomes remain highly significant

339  areas for translational research (17, 40, 70).

340 
341  ACKNOWLEDGMENTS

342  Fig 1 created using www.biorender.com.

343 

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347 
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671 

672 
673  FIGURE LEGENDS

674  Fig 1. Summary of antecedents and consequences of gut dysbiosis in preterm

675  infants. Several prenatal, birth, and postnatal factors negatively impact the developing

676  gut microbiome of the preterm infant. The resulting dysbiotic gut microbial communities

677  during this critical period of development has been linked to both short-term and long-

678  term morbidities. * highlights factors considered to have relatively greater impact than

679  others.

680 
 Antecedents Consequences
Birth Short-term
NEC
Mode of delivery
Sepsis
GBS status Long-term
BPD
Antibiotics * Postnatal Asthma
Allergies
NICU environment
Obesity
Formula vs Breastmilk *
Psychiatric illness
Antibiotics *
Anti-acid therapy

Prenatal
Maternal diet
Chorioamnionitis
Antibiotics *
Table 1. Major differences in bacterial gut colonization of preterm infants compared to

term infants.

Bacterial groups Important characteristics and function

Decreased in preterm infants

Bacteroidetes Anti-inflammatory function through surface

(eg Bacteroides fragilis) component polysaccharide A (33)

Actinobacteria Anti-inflammatory function through secretion of

(eg Bifidobacterium infantis, short chain fatty acids (89), and acceleration of

Bifidobacterium breve) maturation of intestinal innate immune response

genes (83)

Increased in preterm infants

Firmicutes Gram positive cocci that can act as opportunistic

(eg Enterococcus faecalis, pathogens, especially in patients with prolonged

Staphylococcus) hospitalization or has received multiple antibiotic

therapy (19)

Proteobacteria Gram negative bacteria commonly associated with

(eg Escherichia coli, Klebsiella opportunistic nosocomial infections; have an outer

pneumoniae) membrane that contains the endotoxin

lipopolysaccharide (80)
 Antecedents Consequences
Birth Short-term
NEC
Mode of delivery
Sepsis
GBS status Long-term
BPD
Antibiotics * Postnatal Asthma
Allergies
NICU environment
Obesity
Formula vs Breastmilk *
Psychiatric illness
Antibiotics *
Anti-acid therapy

Prenatal
Maternal diet
Chorioamnionitis
Antibiotics *