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Review

Therapeutic Potential of Gut Microbiota and Its Metabolite Short-Chain Fatty Acids in Neonatal Necrotizing Enterocolitis

by
Naser A. Alsharairi
Heart, Mind and Body Research Group, Griffith University, Gold Coast, QLD 4222, Australia
Life 2023, 13(2), 561; https://doi.org/10.3390/life13020561
Submission received: 19 December 2022 / Revised: 31 January 2023 / Accepted: 15 February 2023 / Published: 16 February 2023
(This article belongs to the Special Issue Pediatric Nutrition for a Healthy Life)
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Abstract

:
Short chain fatty acids (SCFAs), the principle end-products produced by the anaerobic gut microbial fermentation of complex carbohydrates (CHO) in the colon perform beneficial roles in metabolic health. Butyrate, acetate and propionate are the main SCFA metabolites, which maintain gut homeostasis and host immune responses, enhance gut barrier integrity and reduce gut inflammation via a range of epigenetic modifications in DNA/histone methylation underlying these effects. The infant gut microbiota composition is characterized by higher abundances of SCFA-producing bacteria. A large number of in vitro/vivo studies have demonstrated the therapeutic implications of SCFA-producing bacteria in infant inflammatory diseases, such as obesity and asthma, but the application of gut microbiota and its metabolite SCFAs to necrotizing enterocolitis (NEC), an acute inflammatory necrosis of the distal small intestine/colon affecting premature newborns, is scarce. Indeed, the beneficial health effects attributed to SCFAs and SCFA-producing bacteria in neonatal NEC are still to be understood. Thus, this literature review aims to summarize the available evidence on the therapeutic potential of gut microbiota and its metabolite SCFAs in neonatal NEC using the PubMed/MEDLINE database.

1. Introduction

The gut microbiota composition and function undergo drastic changes during the first years of life [1] that are characterized by early microbial colonization with Escherichia and Bifidobacterium, which are gradually decreased following weaning and replaced by species of obligate anaerobic bacteria within the Firmicutes phylum, such as Coprococcus, Enterococcus, Roseburia and Clostridium [2,3,4]. The short-chain fatty acids (SCFAs), butyrate, propionate and acetate, are the main metabolic products of gut microbial Firmicutes phyla fermentation of complex non-digestible dietary substrates, such as fiber and resistant starch [5]. Bifidobacterium and lactic acid bacteria (LAB) produce lactate, which acts as an intermediate fermentation product for butyrate production [6]. In general, Bifidobacterium spp. are considered the primary colonizers of the breastfed infant gut, mainly due to the presence of human milk oligosaccharides (HMOs) [7,8,9,10]. The degradation of HMOs and complex carbohydrates (CHO) could result in high SCFA production (mainly butyrate and acetate), which can be used by other butyrogenic bacteria, such as Faecalibacterium prausnitzi (F. prausnitzi), Bacteroides and Roseburia, for growth by cross-feeding [7,8]. SCFAs produced by the infant-type Bifidobacterium spp. can enhance immunomodulatory responses by reducing inflammatory cytokines through the microbiota-gut-brain axis [10].
Necrotizing enterocolitis (NEC) is a severe inflammatory necrosis of the distal small intestine/colon that primarily affects preterm (less than 32 weeks’ gestation) or very low birth weight (VLBW: <1500 g) infants after the introduction of enteral feeds. NEC is characterized by hyperosmolar injury and intestinal ischemia, which reduce the integrity of the epithelial barrier that is evident by peritonitis, hemodynamic instability, abdominal tenderness/cellulitis, acute feeding intolerance, bacteremia and abdominal distension [11,12]. The aetiology of NEC is not clear, but it is thought to be related to several factors, including pre-eclampsia, aberrant bacterial colonization (e.g., infection), premature rupture of the membranes, placental abruption, intrauterine growth restriction, LBW, patent ductus arteriosus, sepsis and anemia [13]. Early gut microbial dysbiosis is also implicated in disease pathogenesis, in which the gut microbiota composition of preterm infants with NEC is characterized by reduced abundances of Bifidobacterium, Firmicutes and Bacteroidetes and increased abundances of Prevotella, Clostridioides, Staphylococcaceae, Proteobacteria, Enterobacteriaceae, Rothia, Streptococcus and Blautia [14,15,16,17,18,19,20].
Pregnancy and lactation perform a crucial role in shaping the composition of infant gut microbiota, which is influenced by a range of pre-and post-natal factors, such as antibiotic exposure, lactation stage, gestational age, mode of feeding/delivery, diet and body mass index (BMI) [3,17,21]. Maternal diet during pregnancy and lactation has been linked to an increased risk of developing obesity and asthma in the infant’s early years of life [22,23] and the mechanisms underlying such effects are postulated to be the alterations in maternal/infant gut microbiota and/or milk microbiota [21]. A high-fiber diet during pregnancy and lactation increases SCFAs production [21,22,23,24,25,26]. SCFAs are essential for differentiation of helper T cells (Th1, Th2) by their binding to G-protein coupled receptors (GPCRs), including free the fatty acid 2/3 receptor (FFAR2, FFAR3) present in the colon, thereby maintaining gut homeostasis and regulating inflammation by reducing the expression of pro-inflammatory cytokines [24,25]. Higher levels of SCFAs detected in breastmilk may enhance the neonatal anti-inflammatory immune responses by inducing factor fork head box protein 3 (FOXP3+) regulatory T (Treg) cell differentiation in the gut [27]. Breastmilk is a source of secretory IgA immunoglobulin A (SIgA) and IgA-producing antibody-secreting cells (ASCs), which regulate early gut microbiota maturation and immunity by binding to SCFA-producing Bifidobacterium and Lactobacillus, resulting in reduced NEC-related inflammation in preterm infants [28]. It has been suggested that infant feeding with probiotics-supplemented formulas and solid/complementary foods alter gut microbiota composition during the first years of life [9,29,30,31]. Evidence from randomised controlled trials (RCTs) has shown that NEC-specific treatments, such as oral lactoferrin combined with probiotics and parenteral/oral supplementation with arginine, reduce the disease risk [13,32,33,34,35]. Probiotic supplementation with Bifidobacterium and Lactobacillus strains, prebiotics (e.g., HMOs), synbiotics (mixtures of probiotics and prebiotics), long chain polyunsaturated fatty acid (PUFA) and bovine colostrum were also demonstrated by a large number of human RCTs, to be effective preventive strategies for NEC, which are thought to modulate the immune response and increase the abundance of beneficial gut microbes [36,37,38,39]. Breastfeeding has been demonstrated to have a protective role against NEC due to its potential to promote the colonization of commensal bacteria and decrease the susceptibility to gut dysbiosis in premature infants [40,41].
SCFAs contribute as mechanisms linking diet, gut microbiota and human health [5], resulting in induced epigenetic changes in the gene patterns of offspring, thereby being a potential epigenetic target in the treatment of gastrointestinal diseases during the first years of life. SCFAs could alter DNA and histone methylation patterns in several genes, resulting in reduced cytokines and chemokines with pro-inflammatory effects in the infant’s gut [22,23]. Findings from recent reviews in infants/children have demonstrated the potential efficacy of SCFA-producing bacteria in reducing inflammation-related disease risk, including obesity, asthma and inflammatory bowel diseases (IBD) [22,23,42]. However, no reviews yet discuss the role of SCFAs and SCFA-producing bacteria as therapeutic agents against neonatal NEC. Thus, this review aims to explore the therapeutic role of gut microbiota and its metabolite SCFAs in neonatal NEC. It is hypothesized that gut microbial-derived SCFA metabolites can be regarded as having health benefits in neonatal NEC. Preterm infants with NEC who are fed breastmilk/formula and/or supplemented with probiotics/prebiotics are postulated to have higher SCFA levels and abundance of SCFA-producing bacteria, which may perform a significant role in modulating the inflammatory immune responses of immature intestinal cells.

2. Methods

A literature search of PubMed/MEDLINE database was performed up to December 2022 to identify studies exploring the potential role of gut microbiota and its metabolite SCFAs in NEC treatment using the following keywords “NEC”, “preterm/premature infants”, “immature intestinal cells”, “intestinal inflammation”, “inflammatory biomarkers”, “gut microbiota”, “epigenetic”, “SCFAs”, “probiotics/prebiotics” and “feeding types”. The search was limited to retrieve human studies published in English irrespective of design.

3. Epigenetics and Inflammatory Biomarkers in NEC

Epigenetic alternation in the immature intestine, such as changes in DNA methylation and long non-coding RNA (lncRNA) patterns, may contribute to increased risk of NEC. Epigenetic changes are attributed to prenatal and postnatal factors (e.g., microbiome, intrauterine infection and enteral feeding) that may affect intestinal function/structure and cause upregulation of pro-inflammatory cytokines [43,44]. DNA methylation changes in cytosine-phosphate-guanine dinucleotides (CpG) regions of NEC-related genes are related to disease risk. For example, high levels of CpG methylation in the DNMT3A, TNT2/3, TNIP1, GALNT6 and HNF4 genes have been identified in stools and colons of premature infants with NEC [45,46,47]. An association of CpG methylation in the cytokine Oncostatin M (OSM) with NEC has also been observed, which can induce intestinal inflammation [47]. The hypermethylation of four genes (MPL, KDM6A, ZNF335 and RASAL3) has been reported in the intestine of neonatal NEC, which is associated with lymphocyte proliferation and intestinal epithelial permeability [48]. Analyses of CpG methylation positions in the intestinal epithelial cells of neonatal NEC revealed a significant hypermethylation in five genes (toll-like receptor 4; TLR4, ENOS, EPO, DEFA5 and VEGFA) at three sites [49]. Overexpression of micro-431 (miR-431) in the intestinal tissues of neonatal NEC results in significantly inhibited FOXA1 and HNF4A and increased pro-inflammatory (e.g., interleukins IL-6, IL-8, IL-10, LGR5, tumor necrosis factor-α; TNF-α and PRKCZ) gene expression in response to lipopolysaccharide (LPS) stimulation [50]. lncRNA influences the expression of mRNAs in the intestine tissues of neonatal NEC by upregulating expression levels of IL-6, IL-1β and TLR4 after LPS exposure, which induces activation of peroxisome proliferator-activated receptors (PPARs) and phosphatidylinositol-3 kinase/serine-threonine kinase (PI3K-AkT) signaling pathways, suggesting that lncRNA contributes to NEC pathogenesis [51].
NEC is characterized by decreased FOXP3+ Treg cell levels and gut expression of transforming growth factor β (TGF-β). Infants with NEC displayed elevated levels of nitric oxide (NO) and high cytokine expression levels with pro-inflammatory effects (e.g., Nuclear factor-κB; NF-κB, tumor necrosis factor-α; TNF-α, interferon; IFN-γ, IL-6, IL-8, IL-10, IL-1β) induced by LPS and produced by the cells of the adaptive immune system in response to colonization by pathogenic bacteria (e.g., Staphylococcus spp., and Clostridium spp.), thereby disturbing the integrity of epithelial tight junctions [52,53,54,55,56,57,58]. An experimental study has shown overexpression of TLR2 and TLR4 receptor-mediated IL-8 mRNA expression in the immature intestine of neonatal NEC [59]. Data from a human NEC experiment showed that pro-inflammatory cytokine expression of IL-1β, IL-1A, IL-6, TNF-α and IL-36 isoforms IL36A were increased in epithelial cells, whereas cytokines IL-37 and IL-22, which are considered protective, were decreased [60]. Evidence from an experimental study showed that IL-17F expression and its related pro-inflammatory C-X-C motif chemokines ligand 8 and 10 (CXCL8, CXCL10) are upregulated in the intestine of neonatal NEC [61]. A case–control study demonstrated higher levels of TNF-α, IL-8, IL-1β and lower levels of TGF-β, FOXP3+ Treg and IL-10 in the ileum of surgical NEC patients compared with matched controls (patients with spontaneous intestinal perforation/congenital intestinal atresia) [18]. Another case–control study showed that the levels of serum TNF-α, IL-6 and intestinal fatty acid-binding protein (I-FABP) were higher in NEC patients than non-NEC counterparts [62]. In a recent experimental study, preterm newborns displayed increased mRNA expression of fecal cytokines IL-1α/β, IL-7 and IL-12p40 [20]. This suggests that preterm infants with NEC display intestinal inflammation with markedly increased pro-inflammatory cytokines and chemokines, in which DNA methylation and lncRNA as epigenetic mechanisms are involved.

4. Insights into the SCFA-Producing Bacteria in Preterm Infants

SCFAs produced by gut microbiota act as epigenetic mechanisms in reducing intestinal inflammation by inducing DNA/histone methylation changes in the gene patterns of infants [22,23,42]. On this basis, it is important to provide an overview of SCFA-producing bacteria, such as Bifidobacterium, Lactobacillus, Enterococcus and Bacteroides, that may perform a crucial role in protecting from NEC-related inflammation.
The role of SCFAs in neonatal NEC treatment remains controversial. High luminal SCFAs production (e.g., butyric acid) by bacterial colonization in preterm infants is due to poor gastrointestinal motility and carbohydrates malabsorption [63]. Enteric bacterial pathogens, including Clostridium perfringens (C. perfringens), C. difficile, C. paraputrificum, C. butyricum and Klebsiella pneumoniae (K. pneumoniae) have shown to be implicated in NEC via increasing butyric acid production as result of lactose fermentation [64]. A high production of butyric acid by C. butyricum increases inducible nitric oxide synthase (iNOS) gene expression responsible for mucosal injury in NEC [65]. These findings suggest that excessive SCFAs produced by pathogenic bacteria may reduce the intestinal epithelial barrier integrity and increase metabolic inflammation in neonatal NEC. Thus, it is proposed that SCFA-producing commensal microbes (e.g., Bifidobacterium, Lactobacillus) may contribute to the regulation of gut immune homeostasis.
Preterm infants demonstrated a significantly less diverse microbiome, including Bifidobacterium spp. [14,15,16,17,18,19,20]. Bifidobacterium spp. within the Actinobacteria phylum are Gram-positive non-motile/spore forming bacteria [66,67] dominated in the gut of breastfed infants [10]. Several strains belonging to Bifidobacterium spp., including B. breve, B. longum subsp. longum, B. longum subsp. infantis and B. bifidum, are among the prevalent members of breastmilk [68,69,70,71,72,73]. The genomes of Bifidobacterium strains include a large set of enzymes belonging to the glycosyl hydrolase family (β-N-acetylhexosaminidase, α-L-fucosidases) essential for HMO degradation in the breastfed infant gut via the intracellular galacto-N-biose/lacto-N-biose (GNB/LNB) pathway [70,74,75]. HMOs, such as galacto-oligosaccharide (GOS) and fructo-oligosaccharide (FOS), may act as prebiotics, which perform a key role in the development of the infant gut microbiota [76]. FOS promotes the growth of B. breve and B. bifidum in preterm fecal microbiota, which produce high levels of butyric, propionic and acetic acids [77]. Fermentation of resistant starch by Bifidobacterium spp. has been shown to increase production of acetate, propionate and butyrate in pre-weaning and weaning infant feces [78].
Lactobacillus is a genus of Gram-positive facultative LAB that is typically classified in the class Bacilli, phylum Firmicutes [66,79]. Lactobacillus spp. were detected at a relatively high percentage in the meconium of preterm infants [80,81]. Breastmilk and the breast-fed infant gut are dominated by several Lactobacillus spp. mainly L. rhamnosus, L. gasseri, L. reuteri, L. acidophilus, L. fermentum, L. crispatus, L. paracasei and L. salivarius [68,69,82,83,84,85]. Lactobacillus spp. produce high D(−), L(+) and DL-Lactic acid levels [86], which have the ability to generate SCFAs, bacteriocins and FOS [87,88].
Analysis of the fecal and meconium microbiota of preterm infants revealed a high abundance of Enterococcus [80,89,90]. E. faecalis and E. faecium constitute the most dominant Enterococcus of fecal microbiota in preterm infants [80]. The genus Enterococcus belongs to a large group of LAB in the class Bacilli that is typically identified as facultative anaerobic bacteria within the Firmicutes phylum [66,79,91]. Enterococcus spp. produce L(+)-Lactic acid as the main end metabolic product yielded from sugar fermentation [86]. Enterococcus increases the production of acetate, propionate and butyrate in pre-weaned and weaning infants’ feces upon fermentation of resistant starch [78]. The E. faecalis strain ATCC19433 exhibits growth in response to fucosylated HMOs (2′-FL or 3-FL) and produces lactate [92]. The E. faecalis strain AG5 has been found to assimilate cholesterol and produce propionate in vitro [93].
Multiple Streptococcus spp. (S. thermophilus, S. mitis, S. anginosus and S. sanguinis) dominated the meconium microbiome of preterm infants during the first 21 days of early life [80]. The genus Streptococcus is a facultative anaerobe Gram-positive bacteria within the Firmicutes phylum [94]. S. thermophilus has been shown to produce L(+)-Lactic acid as the major fermentative end-product [86]. Such species can use the acetyl-CoA “Wood-Ljungdahl” pathway of carbon dioxide (CO2) fixation as the main mechanism for transforming pyruvate to acetate [95]. Fucosylated HMOs (2-FL or 3-FL) are found to be metabolized into lactate by the S. thermophilus strain ATCC19258 [92].
The genus Bacteroides that belongs to the phylum Bacteroidetes, is the most abundant Gram-negative anaerobic bacteria in the fecal microbiota of preterm infants [96]. B. fragilis was the species that predominated in the fecal microbiota of preterm infants in the first weeks of life [97,98]. Bacteroides spp. have large genomes with extremely high numbers of carbohydrate cleaving enzymes [99,100,101], which degraded complex oligosaccharides, such as mucin glycans [102] and HMOs [103,104,105]. Butyrate, acetate and propionate were the major end-products of resistant starch fermentation generated by Bacteroides spp. in weaned infants’ feces [78]. The acetyl-CoA and succinate pathways are the major routes for the production of acetate and propionate, which exist mainly in Bacteroides spp. [95,106,107,108].

5. Effects of Feeding Types on Gut Microbiota and Its Metabolite SCFAs in Preterm Infants

Evidence from several prospective cohort studies and RCTs suggests that breastmilk and/or formula with probiotics/prebiotics may have the potential to enhance the growth of SCFA-producing bacteria and increase SCFAs levels in preterm infants.

5.1. Prospective Cohort Studies

A cohort study over 1-year period has demonstrated the potential of breastmilk and formula to influence fecal SCFA profiles in LBW preterm infants. The concentrations of fecal acetate and propionate were found to be higher in infants who were fed breastmilk, whereas the concentrations of fecal butyrate were higher in those fed Similac special care formula [109]. It has been has shown that premature infants fed formula have higher concentrations of butyrate and acetate, while those fed breastmilk have higher concentrations of propionate in their feces over 1-year follow-up. This may be due to the colonization of SCFA-producing Bifidobacterium and Lactobacillus influenced by breastmilk and formula [110]. A study evaluated the beneficial effects of probiotics supplementation in preterm infants over 100-day period and found that a combination of B. bifidum with L. acidophilus (Bif/Lacto) increases fecal lactate levels and the abundance of Bifidobacterium spp. consistent with their ability to metablize HMOs into acetate [111].
Over a 10-year longitudinal study, preterm infants who were fed breastmilk or supplemented with two different probiotics (Infloran and Labinic) showed a significant increase in the relative abundance of Bifidobacterium spp. and a significant decrease in the relative abundance of pathogenic bacteria in their feces. The study suggests that long-term colonization of Bifidobacterium depends on the type of probiotics used [112]. In a recent study, with follow-up over 1 year, aimed to identify variation in fecal microbiota from admission to discharge, preterm infants who were fed breastmilk demonstrated a higher abundance of Bifidobacterium spp. and lower abundance of Veillonella. However, infants who were fed probiotic formula demonstrated a lower abundance of Lactobacillus [113]. A cohort study showed that the gut microbiota colonization varied among preterm infants as a result of probiotic formula-feeding. Bifidobacterium and Lactobacillus were found in higher abundance in the fecal microbiota of preterm infants fed with formula supplemented with probiotic B. lactis over 3-month period [114]. Use of the probiotic B. longum subsp. infantis EVC001 in conjunction with breastmilk has been shown to increase the gut microbiome abundance of Bifidobacteriaceae and decrease the abundance of Staphylococcaceae and Enterobacteriaceae associated with gut dysbiosis and antibiotic-resistance in preterm infants in longitudinal 5 months of follow-up [115]. The relative abundances of Bifidobacterium spp. have been found to increase the fecal microbiota of preterm infants fed with breastmilk and human donor milk during the first three months of life [116]. In a study conducted to examine the effect of breastmilk, donor human milk or formula on shaping the fecal microbiota of preterm infants during the first month of life, infants fed with mother’s own milk have higher fecal SCFA-producing bacteria compared with those fed donor human milk or formula [117]. A previous study found that breastmilk influences the microbial colonization of preterm infants over the first 30 days of life. Breastmilk fed infants have higher abundance in Lactobacillus and Granulicatella than non-breast milk fed infants [118].
A study found that oral administration of B. breve M-16V to LBW infants resulted in increased fecal abundance of Bifidobacterium and Enterococcus 10 weeks post-administration. This is attributed to acetic acid, which may inhibit the growth of Proteobacteria, thus providing a suitable environment for SCFA-producing bacteria growth [119]. Evidence from a cohort study supports supplementation with multiple-strain probiotics including bifidobacteria in preterm infants. Three Bifidobacterium strains have been administrated in infants showing lower detection rates of Enterobacteriaceae and higher rates of bifidobacteria in the feces over 6-month follow-up [120]. A longitudinal multi-center study has shown that the fecal microbiota of preterm infants after supplementation with probiotic Infloran have a high relative abundance of Bifidobacterium and Lactobacillus up to 4 months of age [121]. Another multi-center cohort study showed that administering a combination probiotics mixture to preterm infants resulted in influenced the fecal microbiota profile with Lactobacillus and Bifidobacterium predominating over 5-month period [122]. In a cohort study over a 5-month follow-up, suspected bacterial signatures from Bifidobacterium and Lactobacillus were identified in the fecal microbiota of preterm infants after discontinuation of a probiotic mixture containing Bifidobacterium and Lactobacillus spp. [123].
In one cohort study, the administrated strain, B. bifidum ATCC15696 and L. acidophilus NCIMB701748, showed significant alterations in the fecal microbiota of preterm infants as demonstrated by high Lactobacillus and Bifidobacterium abundances over 1-month period [124]. A cohort study on human milk-fed preterm infants has indicated probiotic supplementation with B. longum subsp. infantis influences the fecal colonization by Bifidobacterium [125]. Probiotic supplementation with L. rhamnosus GG and B. animalis ssp. lactis BB-12 increases the relative abundance of Firmicutes and Actinobacteria and decreases the abundance of Weissella, Veillonella and Klebsiella in preterm infants during the first month of life [126]. A recent study showed that supplementation of probiotics rich in L. acidophilus and B. bifidum alters the fecal microbiota of preterm infants during the first 30 days of life by increasing Lactobacillus spp. and E. faecium abundances [127].

5.2. RCTs

A previous study resulted in increased fecal colonization with bifidobacteria and acetic acid levels in premature infants after receiving formula supplemented with prebiotic/probiotic combinations compared to those in the placebo group [128]. In a recent study, multi-strain probiotics are found to be effective in increasing fecal butyric and propionic acid levels, whereas single-strain probiotic increases fecal butyric acid levels only in preterm infants. Infants who were supplemented with probiotics showed higher fecal abundance of Bifidobacterium spp. and lower fecal abundance of Clostridium [129]. An RCT showed that preterm infants receiving probiotic supplementation with the B. breve (BBG-01) strain in conjunction with breastmilk and feeding with maternal colostrum have higher fecal Bifidobacterium abundance compared with those in placebo groups [130]. In one previous study, supplementation of a bovine milk formula with galacto and fructo-oligosaccharide mixtures has been shown to increase the relative abundance of fecal bifidobacteria in preterm infants [131]. Preterm infants supplemented with a probiotic mixture containing S. thermophilus TH-4, B. longum subsp. infantis BB-02 and B. animalis subsp. lactis BB-12 showed a significant increase in the relative abundance of Bifidobacterium spp. in the gut microbiota compared to those in the placebo group [132]. Supplementation of preterm infants with the B. lactis Bb12 probiotic strain compared with placebo modulates the gut microbiota by lowering the cell counts of clostridia and enterobacteria and increasing the cell count of bifidobacteria [133]. Probiotic supplementation with L. reuteri DSM 17938 modulates the gut microbiota composition in preterm infants by increasing the relative abundance of Lactobacillus and decreasing the abundance of Clostridium, Enterobacteriaceae and Staphylococcaceae [134]. A supplementation with a mixture of S. thermophilus TH-4, B. animalis subsp. lactis BB-12 and B. longum subsp. infantis BB-02 increases the bacterial abundance of probiotic species in the preterm infant’s gut [135].
The effects of feeding types on fecal SCFAs and SCFA-producing bacteria in preterm infants are summarized in Table 1.

6. Role of Gut Microbiota and Its Metabolite SCFAs as Therapeutic Potential Agents in NEC

Gene expression including cytokines and chemokines result from histone and long non-coding RNA (lncRNA) modifications have been linked to immune cell function and inflammation in NEC [45,46,47,48,49,50,51]. Given that SCFAs have been identified as epigenetic modifier exert anti-inflammatory effects in inflammatory diseases [22,23,42], it is likely that SCFA-producing bacteria and SCFAs could perform an epigenetic role in modulating immune responses in the inflamed gut of neonatal NEC by reducing pro-inflammatory cytokines and chemokines. Thus, this section presents the therapeutic role of gut microbiota and its metabolite SCFAs in regulating NEC-related inflammation in which epigenetic changes are implicated.
Evidence from a few studies has revealed a significant decrease in the levels of butyric, propionic and acetic acids in NEC patients [18,19]. It has been shown that colonization of fecal microbiota of NEC patients with Firmicutes and Bacteroidetes increases butyric acid synthesis, resulting in increased Treg/Thelper cell ratio [18]. An in vitro study showed that butyrate inhibits IL-1β-induced IL-6, CX3XL1 and CXCL5 gene expression in human immature enterocytes (H4 cells) and regulates tight junction and mucin-related gene expression via increasing the mRNA expression of Mucin (MUC20), Claudins (CLDN4, CLDN11 and CLDN15) and Occludin (OCLN) [136]. In fetal small intestinal epithelial FHs 74 Int cells, butyrate, acetate and propionate were found to decrease IL-1β-induced IL-6 and IL-8 mRNA levels through inhibiting the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-JUN NH2-terminal kinase 1/2 (JNK1/2) and NF-κB p65 signaling pathways [137]. Treatment of fetal immature enterocytes (H4 cells) with butyrate, acetate and propionate results in a significant inhibition of IL-1β-induced histone deacetylase 3 and 5 (HDAC3, HDAC5) and IL-8 mRNA expression and activation of G-protein coupled receptor 109A (GPR109A) mRNA expression [24]. Butyrate and propionate have been shown to reduce inflammation in vitro by inhibiting several chemokines (e.g., CCL3, CCL4, CCL5, CCL9) and LPS-induced IL-6 and IL-12p40 mRNA expression in both mature and immature human monocyte-derived dendritic cells (DCs) [138]. In vitro treatment of amnion epithelial and mesenchymal cells in preterm infants with butyrate and propionate inhibit several inflammation-induced cytokines and chemokines (TNF-α, IL-6, IL-1β, CCL2, CCL8, CXCL5, CXCL8 and CXCL10) and prostaglandin (PTGS2) mRNA expression through suppressing activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways [139].
In one experimental study, supplementation with B. infantis EVC001 strain resulted in decreased IL-1β and TNFα production in preterm infants [115]. An in vitro human model showed that probiotic L. rhamnosus GG attenuates fetal intestinal epithelial cell line H4 inflammatory responses by inhibiting TLR3 and TLR4 mRNA expression and Salmonella Typhimurium (S. Typhimurium)-induced TNF-α mRNA expression [140]. Another in vitro study demonstrated a potential inhibitory effect of B. infantis and L. acidophilus on TLR2/TLR4 mRNA expression and IL-1β/LPS-induced IL-6 and IL-8 mRNA expression in fetal immature enterocytes FHs74 [141]. Pretreatment of immature enterocyte H4 cells with B. longum supp infantis resulted in suppression of interleukin-1 receptor-associated kinase 2 (IRAK-2) and IL-1β-induced IL-6 and activator-protein 1 (AP-1) transcription factors c-Jun and c-Fos mRNA expression in a TLR-4-dependent manner [142]. It has also been shown that IL-1β-induced IL-8 mRNA expression is inhibited via downregulating the signal transducer and activator of the transcription 1 (STAT1) signaling pathway in immature enterocyte H4 cells pretreated with indole-3-lactic acid (ILA), a predominant breastmilk tryptophan metabolite, produced by B. longum supp infantis [143]. Treatment with the probiotic strains B. infantis and L. acidophilus modulates the inflammatory response of immature enterocyte H4 cells by inhibiting IL-1β-induced IL-6 and IL-8 mRNA expression and NF-κB p65 levels [144]. Two studies have shown that Polysaccharide (PSA) pretreatment produced by B. fragilis reduces inflammation in immature enterocyte H4 cells by reducing IL-1β-induced IL-8, CXCL5, CXCL10, matrix metalloproteinase-1 (MMPI), P-c-Jun and zona pellucida protein 4 (ZP4) mRNA expression in both TLR2 and TLR4 dependent-manner [145,146].
Taken together, these findings suggest that SCFAs and SCFA-producing bacteria may have a potential anti-inflammatory role in neonatal NEC by protecting fetal intestinal epithelial cells against pro-inflammatory cytokines and chemokines via inhibition of different cellular signaling pathways.
Figure 1 summarizes the therapeutic role of SCFAs and SCFA-producing bacteria in neonatal NEC.

7. Conclusions

SCFAs as epigenetic substrates perform a significant role in mediating microbe-host immune interactions, which could be a potential treatment for NEC-induced inflammation. During the colonization process in preterm infants, the gut is exposed to microbes that are more pathogenic but less commensal, which may contribute to NEC by increasing TLR4 signaling, leading to release of pro-inflammatory cytokines and chemokines. Breastmilk and/or formula with probiotics/prebiotics could modulate preterm infants’ gut microbiota colonization by decreasing the growth of pathogenic microbes, while increasing microbial species belonging to phyla Actinobacteria (Bifidobacterium spp.), Firmicutes (Lactobacillus spp., Enterococcus spp., Streptococcus spp.) and Bacteroidetes (B. fragilis), which produce different amounts of SCFAs.
SCFAs and SCFA-producing bacteria exert anti-inflammatory effects on cytokine and chemokine production in immature enterocyte H4 cells through inhibiting different signaling pathways. Breastmilk and feeding with probiotic/prebiotic formula increase SCFA production and the abundance of SCFA-producing bacteria in preterm infants. However, how these feeding types epigenetically determine NEC phenotype by exerting anti-inflammatory effects are still being unraveled. In conclusion, SCFAs and SCFA-producing bacteria could be potential targets in the treatment of NEC. Further studies are needed to examine whether breastmilk or feeding with probiotic/prebiotic formula could increase SCFA levels and influence the growth of SCFA-producing bacteria and the protective effects thereof on reducing NEC-related inflammatory markers through the epigenetic mechanisms.

Funding

This review received no financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

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Life 13 00561 g001 550
Figure 1. Role of SCFAs and its producing bacteria in neonatal NEC therapy. (↓) decrease; (↑) increase.
Figure 1. Role of SCFAs and its producing bacteria in neonatal NEC therapy. (↓) decrease; (↑) increase.
Life 13 00561 g001
Table
Table 1. Effects of feeding types on gut microbiota and its metabolite SCFAs bacteria in preterm infants.
Table 1. Effects of feeding types on gut microbiota and its metabolite SCFAs bacteria in preterm infants.
Study DesignSample CharacteristicsFeeding TypesSCFAs/MicroorganismsReferences
Prospective cohort study32 preterm infants delivered at <32 weeks of gestation over 1-year periodbreastmilk with bovine milk-based fortifier OR Similac advanced special care formulaBreastmilk = acetate, propionate ↑
Formula = butyrate ↑		[109]
Prospective cohort study60 preterm infants delivered at ≤36 weeks of gestation/birth weight (<1500 g) over 1-year periodBreastmilk OR formulaBreastmilk = propionate ↑
Formula = butyrate, acetate ↑		[110]
Prospective cohort study234 preterm infants = 101 infants orally supplemented with probiotics over 100 day-period
and 133 infants not supplemented 		Probiotics Bifidobacterium and Lactobacillus (Bif/Lacto)Bif/Lacto group = lactate, acetate, B. bifidum, B. breve ↑[111]
Prospective cohort study95 preterm infants delivered at <32 weeks of gestation who did not develop a disease over a study period of 10 years received probiotics and 28 infants not supplemented Breastmilk, probiotic Infloran (B. bifidum, L. acidophilus), probiotic Labinic (B. bifidum, B. longum subsp. infantis, L. acidophilus) Breastmilk = Bifidobacterium spp. ↑, Staphylococci ↓
Infloran probiotic= B. breve, B. bifidum, E. faecium ↑, Veillonella parvula, Propionibacterium acnes ↓
Labinic probiotic = B. animalis ↑
No probiotic = Klebsiella spp. ↑		[112]
Prospective cohort study134 preterm infants delivered at <32 weeks of gestation/birth weight (<1500 g) over 1-year periodBreastmilk, OR probiotic formula (L. acidophilus, L. bifidus, B. bifidum)Breastmilk = Bifidobacterium spp. ↑, Veillonella ↓
Probiotic formula = Lactobacillus ↓		[113]
Prospective cohort study90 preterm infants delivered at <37 weeks of gestation/birth weight (<2500 g) fed with breastmilk or probiotic formula over 3 months and 48 infants received no probioticBreastmilk OR probiotic formula (B. lactis) Probiotic = Bifidobacterium, Lactobacillus ↑
No probiotic = Enterococcus, Streptococcus, Klebsiella ↑		[114]
Prospective cohort study31 preterm infants delivered at <32 weeks of gestation/birth weight (<1500 g) received probiotics over 5 month-period and 46 infants non-supplemented Probiotic B. infantis EVC001Probiotic group = Bifidobacteriaceae ↑, Staphylococcaceae, Enterobacteriaceae ↓[115]
Prospective cohort study42 preterm infants
over 3 month-period		Breastmilk OR donor human milk Breastmilk = B. longum, B. breve, B. pseudolongum spp. globosum, B. longum spp. infantis, B. animalis spp. lactis, B. adolescentis, B. bifidum, B. dentium ↑
Human donor milk = B. bifidum, B. longum spp. longum, B. reuteri, B. vansinderenii, B. pseudolongum spp. pseudolongum, B. animalis spp. lactis, B. longum spp. suis ↑ 		[116]
Prospective cohort study117 preterm infants delivered at ≤32 weeks of gestation over 26-day periodBreastmilk, donor human milk OR formula Breastmilk = Bifidobacterium, Lactobacillus, Bacteroides, Bacteroidetes, Enterococcus ↑[117]
Prospective cohort study29 preterm infants over 30-day periodBreastmilkClostridiales, Lactobacillales ↑[118]
Prospective cohort study12 preterm infants supplemented with a probiotic over 10 weeks-period
and 10 infants not supplemented		Probiotic B.breve M-16VProbiotic group = Bifidobacterium, Enterococcus ↑, Lactococcus, Klebsiella, Rothia ↓ [119]
Prospective cohort study28 preterm infants supplemented with single or mixture probiotics over 6 month-period
and 16 infants not supplemented		Single-strain probiotic B.breve M-16V
Multiple-strain probiotics (B. longum subsp. infantis M-63, B. breve M-16V and B. longum subsp. longum BB536)		Single-strain probiotic = Clostridium ↓
Multiple-strain probiotics = bifidobacteria ↑, Enterobacteriaceae ↓		[120]
Prospective cohort study31 preterm infants delivered at <32 weeks of gestation received probiotics over 4-month period, 35 preterm infants not received probiotics and 10 healthy full-term infants Probiotic Infloran (L. acidophilus ATCC 4356, B. longum subspecies infantis ATCC 15697Probiotic = Bifidobacterium, Lactobacillus ↑ [121]
Prospective cohort study36 preterm infants delivered at birth weight (<1500 g) received two different probiotics over 5-month period, and 18 infants did not received probiotics Probiotic L. rhamnosus
Probiotics B. infantis and L. acidophilus 		Probiotic groups = Bifidobacterium, Lactobacillus ↑ [122]
Prospective cohort study8 preterm infants received a probiotic formula over 5-month period, and 14 infants not received a probiotic Probiotic formula (B. breve HA-129, B. bifidum HA-132, B. longum subsp. longum HA-135, B. longum subsp. infantis HA-116, L. rhamnosus HA-111) Probiotic group = Bifidobacterium, Lactobacillus ↑ [123]
Prospective cohort study7 preterm infants delivered at <32 weeks of gestation received a probiotic formula over 1-month period and 3 preterm infants not received a probiotic Probiotic Infloran (B. bifidum ATCC15696 and L. acidophilus NCIMB701748)Probiotic group = Bifidobacterium, Lactobacillus ↑ [124]
Prospective cohort study10 Preterm infants at delivered at <32 weeks of gestation received two different probiotics over 1-month period Probiotics B. longum subsp. infantis OR L. reuteriProbiotic B. longum subsp. Infantis = Bifidobacterium ↑
Probiotic L. reuteri = HMO ↑ 		[125]
Prospective cohort study87 preterm infants at delivered at <30 weeks of gestation received a probiotic formula over 1-month period, and 165 infants did not receive a probiotic Probiotic formula (L. rhamnosus GG and B. animalis ssp. lactis BB-12)Probiotic group = Firmicutes, Actinobacteria ↑, Weissella, Veillonella, Klebsiella ↓ [126]
Prospective cohort study70 preterm infants at delivered at ≤28 weeks of gestation received a probiotic formula over 1-month period, and 50 infants did not receive a probiotic Probiotic Infloran (L. acidophilus and B. bifidum)Probiotic group = Lactobacillus spp., E. faecium ↑, Yersiniaceae, Staphylococcus, Klebsiella spp. ↓[127]
RCT90 preterm infants delivered at <35 weeks of gestation supplemented with either probiotic species (CUL) or prebiotic/probiotic combinations (PBP)
29 preterm infants received Pregestamil formula (placebo) 		CUL probiotics = Two lactobacillus spp.
PBP probiotics = Several lactobacillus and Bifidobacterium spp. plus fructo-oligosaccharides		PBP group = acetate, bifidobacteria ↑
Placebo = bifidobacteria ↓		[128]
RCT173 preterm infants delivered at <28 weeks of gestation supplemented with either single (SS) or triple-strain (TS) probiotics
29 preterm infants (no probiotics, placebo) 		SS probiotic = B. breve M-16V
TS probiotics = B. breve M-16V, B. longum subsp. infantis M-63 and B. longum subsp. longum BB536		SS group = propionate, B.breve, B.bifidum ↑, Clostridium ↓
TS group = butyrate, propionate, B. longum, B. reuteri, B. longum subsp. infantis, B. longum subsp. longum ↑, Clostridium ↓
Placebo = Clostridium butyricum, Streptococcus salivarius, S. thermophilus ↑ 		[129]
RCT17 preterm infants delivered at <31 weeks of gestation/birth weight (<1500 g) supplemented with probiotic (Bifid)
18 preterm infants received vehicle supplement only (placebo)		Probiotic B. breve BBG-01 Bifid group = Bifidobacterium ↑[130]
RCT15 preterm infants delivered at <32 weeks of gestation supplemented with prebiotic formula
15 preterm infants supplemented with maltodextrin (placebo)		Prebiotic formula (mixture of fructo-oligosaccharides and galacto-oligosaccharides) Prebiotic group = bifidobacteria ↑[131]
RCT38 preterm infants delivered at <32 weeks of gestation/birth weight (<1500 g) supplemented with probiotics mixture
28 preterm infants supplemented with maltodextrin (placebo)		Probiotics mixture (S. thermophilus TH-4, B. longum subsp. infantis BB-02 and B. animalis subsp. lactis BB-12)Probiotics group = Bifidobacterium ↑[132]
RCT37 preterm infants delivered at <37 weeks of gestation received a probiotic
32 preterm infants received Nestle ’ FM 2000B formula (placebo)		Probiotic B. lactis Bb12Probiotic group = bifidobacteria ↑, Clostridia, Enterobacteria spp. ↓[133]
RCT54 preterm infants received a probiotic, and 54 infants no received any probiotic (placebo)Probiotic L. reuteri DSM 17938Probiotic group = Lactobacillus ↑, Clostridium, Enterobacteriaceae, Staphylococcaceae ↓[134]
RCT229 preterm infants delivered at <32 weeks of gestation received a probiotic formula, and
230 infants did not receive a probiotic (placebo)		Probiotic formula (S. thermophilus TH-4, B. animalis subsp. lactis BB-12 and B. longum subsp. infantis BB-02)Probiotic group = B. longum subsp. infantis, B. animalis subsp. lactis, S. thermophilus ↑[135]
(↓) decrease, (↑) increase.
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Alsharairi, N.A. Therapeutic Potential of Gut Microbiota and Its Metabolite Short-Chain Fatty Acids in Neonatal Necrotizing Enterocolitis. Life 2023, 13, 561. https://doi.org/10.3390/life13020561

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Alsharairi NA. Therapeutic Potential of Gut Microbiota and Its Metabolite Short-Chain Fatty Acids in Neonatal Necrotizing Enterocolitis. Life. 2023; 13(2):561. https://doi.org/10.3390/life13020561

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Alsharairi, Naser A. 2023. "Therapeutic Potential of Gut Microbiota and Its Metabolite Short-Chain Fatty Acids in Neonatal Necrotizing Enterocolitis" Life 13, no. 2: 561. https://doi.org/10.3390/life13020561

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