Background
The survival rate of preterm infants has increased substantially in recent years. Preterm infants, due to their immature development, are characterized by underdeveloped gastrointestinal tracts, delayed colonization of intestinal flora, and low immune function. Therefore, preterm infants are prone to feeding intolerance, infection, and even neonatal necrotizing enterocolitis (NEC), all of which affect growth and quality of life [
1].
Probiotics are living microorganisms, which, when administered in adequate amounts, can confer a health benefit to the host [
2]. As a microecological preparation, probiotics seem to be useful in nourishing the intestines, adjusting the microbiota, ameliorating immunity and reducing inflammation. In 2017, the World Gastroenterology Organization updated global guidelines about the use of probiotics and prebiotics. A large amount of clinical trials confirmed that probiotics have a beneficial effect on the prevention and treatment of digestive diseases [
3]. The clinical application of probiotics in neonates is increasingly widespread for many indications, including the prevention and treatment of feeding intolerance, diarrhea, NEC, neonatal jaundice, and allergic diseases [
4].
Lactobacillus reuteri (
L. reuteri) DSM 17938 is a progeny strain of
L. reuteri ATCC 55730, which was originally extracted from the breast milk of Peruvian women living in the Andes. In 2007, 2 plasmids with antibiotic resistance (tetracycline and lincomycin) were removed in order to enhance safety, and the modified strain was stored at The German Center for the Conservation of Microbial Species, also called the DSMZ, and named
L. reuteri DSM 17938. This strain can live throughout the gastrointestinal tract and colonize in normal human gastric bodies, including the gastric antrum, duodenum, and ileum [
5]. In one study, its colonization required continuous supplementation for 7 days, and the highest colonization rate was reached at 21 days; after discontinuing supplementation, the colonization rate decreased significantly at 1 week and was undetectable at 2 months [
6]. The role of
L. reuteri in the effective treatment of infantile colic is clearly illustrated [
7,
8], and it has been widely used in the prevention and treatment of infantile reflux, functional constipation, and acute gastroenteritis. However, research of the effects of
L. reuteri on the clinical course in preterm infants is limited.
The aim of the study was to investigate the efficacy of L. reuteri in early feeding tolerance, growth, infection prevention, and other aspects of preterm infant development.
Discussion
Preterm infants have poor sucking and swallowing abilities, immature digestive systems, insufficient gastrointestinal motility, and low gastrointestinal mucosal barrier function, and they are prone to feeding intolerance such as regurgitation, vomiting, abdominal distension, and gastric retention during feeding [
13]. Studies have shown that probiotics could stimulate the secretion of gastrin and motilin, promote gastrointestinal motility, reduce the incidence of feeding intolerance, and shorten the time to achieve total enteral nutrition [
14]. Reflux refers to the reverse movement of gastric contents, usually referred to gastroesophageal reflux (GOR). GOR is a prominent condition among preterm infants. Symptoms such as apnoea, bradycardia, vomiting, poor weight gain and irritability have been attributable to GOR, which is called gastroesophageal reflux disease (GORD), when symptoms are severe [
15]. Experimental data showed that
L. reuteri can promote gastric motility, accelerate gastric emptying, promote colonic peristalsis, and reduce the incidence of dyspepsia and reflux [
16,
17]. Indrio et al. [
18] conducted a randomized, double-blind, controlled study of 30 preterm infants: 10 preterm infants were exclusively breastfed and the remaining 20 were fed formula; the formula-fed infants were randomly assigned to receive
L. reuteri or a placebo for 30 days. The results showed that the number of reflux episodes in the
L. reuteri group was significantly lower than that in the placebo group (
P < 0.01). Moreover, the incidence of reflux episodes in the supplemented group resulted similar to that of the breastfed group. It demonstrated that oral supplementation with
L. reuteri improved feeding tolerance in preterm infants. This is consistent with our findings. Our study demonstrated that
L. reuteri was able to reduce severity and number of reflux episodes (GORD incidence was 8.88% in the intervention vs. 12.5% in the control group). We may speculate that this lead to a shorter TFF, thus improving the rapidity of the growth of formula-fed preterm infants. Our study also found that oral administration of
L. reuteri may increase the daily defecation frequency of formula-fed preterm infants and shorten their hospital stays. Our study showed that no adverse effects occurred while formula-fed preterm infants were receiving
L. reuteri, which was consistent with the results of Oncel et al. [
19].
In the neonatal period, infections are common and are a major risk factor for neonatal death, especially septicemia, which has an insidious onset and rapid progression [
20]. The digestive tract of preterm infants is hypoplasic, bacterial flora is less diverse, and colonization is delayed compared to full-term infants. Most digestive bacteria, including
Klebsiella,
Enterobacter, and
Clostridium, are potentially pathogenic and can trigger digestive tract injury. Digestive tract injury combined with the deficiency of the innate immune system increases the probability that pathogens will spread throughout the entire body and cause a systemic infection [
21]. Probiotics influence the functions of various immune cells, such as lymphocytes and dendritic cells, by direct or indirect regulation and they play a role in immune regulation and control of inflammation progression.
L. reuteri DSM 17938 can ferment in vivo to produce acetic acid and reuterin. Acetic acid can lower the pH in vivo and it has a strong antibacterial effect on many pathogens; reuterin can cause oxidative stress in pathogens and effectively resist bacteria [
22,
23]. Valeur [
5] reported that
L. reuteri activated CD4+ Th-cells and coordinated other immune cells to regulate the immune response. Preidis et al. [
24] showed that
L. reuteri could significantly induce the production of immunoglobulin A, inhibit the adhesion of bacteria and viruses to epithelial cells, and neutralize toxins. A randomized controlled trial showed that
L. reuteri significantly reduced the incidence of diarrhea and respiratory infections in preschoolers, as well as shortened the course of disease [
25]. Oncel et al. [
26] reported that
L. reuteri could significantly reduce the incidence of septicemia in extremely low birthweight (ELBW) infants with a gestational age of less than 32 weeks (6.5% vs. 12.5%,
P = 0.041). On the contrary, in our study, there were no statistical differences in the incidence of sepsis (4.44% vs. 8.33%,
P > 0.05) or localized infection (6.67% vs. 8.33%,
P > 0.05) between the two groups. These two different results may be related to different sub-population, gestational age, birth weight or feeding patterns. Whether
L. reuteri can prevent infection should be verified with larger sample sizes in future research.
The main pathogenesis of NEC include immature intestinal development, imperfect intestinal flora, formula feeding, and circulation disorders. The establishment of the microecological environment in the gastrointestinal tract is significant for maintaining the stability of the body environment and inhibiting intestinal inflammation. Breastfeeding is currently the only recognized protective factor against NEC. Research has confirmed that probiotics could effectively prevent and reduce the incidence of NEC in preterm infants [
27,
28].
L. reuteri can improve the intestinal microecological environment, maintain the integrity of the gastrointestinal mucosal barrier, directly or indirectly regulate a variety of immune cell functions, and control the progression of intestinal inflammation [
29]. Liu et al. [
30,
31] found that
L. reuteri could significantly down-regulate the level of tumor necrosis factor alpha by regulating TLR2, TLR4, and NF-кB signaling pathways in the intestine and reduce the incidence and severity of experimental NEC in rats. Hunter et al. [
32] retrospectively analyzed 311 ELBW infants (79 cases with oral
L. reuteri administration) and found that the incidence of NEC was significantly reduced in neonates receiving
L. reuteri (15.1% vs. 2.5%,
P = 0.0475). Our study showed that the incidence of NEC in the intervention group was 2.22% (1 case, stage IIA), while the incidence of NEC in the control group was 10.42% (5 cases in total: 3 cases in stage IIB, 2 cases in stage IIIA), which showed no statistically significant difference between the 2 groups (
P > 0.05). More research is needed to confirm if oral administration of
L. reuteri can reduce the incidence and severity of NEC in formula-fed preterm infants.
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