Maternal imprinting of the neonatal microbiota colonization in intrauterine growth restricted piglets: a review
Journal of Animal Science and Biotechnology volume 10, Article number: 88 (2019)
Early colonization of intestinal microbiota during the neonatal stage plays an important role on the development of intestinal immune system and nutrients absorption of the host. Compared to the normal birth weight (NBW) piglets, intrauterine growth restricted (IUGR) piglets have a different intestinal microbiota during their early life, which is related to maternal imprinting on intestinal microbial succession during gestation, at birth and via suckling. Imbalanced allocation of limited nutrients among fetuses during gestation could be one of the main causes for impaired intestinal development and microbiota colonization in neonatal IUGR piglets. In this review, we summarized the potential impact of maternal imprinting on the colonization of the intestinal microbiota in IUGR piglets, including maternal undernutrition, imbalanced allocation of nutrients among fetuses, as well as vertical microbial transmission from mother to offspring during gestation and lactation. At the same time, we give information about the current maternal nutritional strategies (mainly breastfeeding, probiotics and prebiotics) to help colonization of the advantageous intestinal microbiota for IUGR piglets.
The gastrointestinal tract (GIT) of mammalian animals contains a large microbial community . Early colonization of the intestinal microbiota is believed to be paramount for maturation of the intestinal innate immune system and barrier function, as well as health of the host [2, 3]. At the same time, the intestinal microbiota in neonates is extremely turbulent and can be shaped by the different physiological status of their host , the dietary changes , and the feeding environments [6, 7]. A recent study has indicated that the intestinal microbiota of IUGR piglets was significantly different from that of the NBW piglets during their neonatal stages . Considering the delivery transition from relative sterile environment in uterus to the complex bacterial environment in farrowing house, the impaired small intestine of newborn IUGR piglets could be a starting point for the postnatal dysbiosis of intestinal microbial community. Therefore, the microbiota colonization in IUGR piglets could be maternally imprinted, due to malnutrition of sows or imbalanced allocation of limited nutrients among fetuses during gestation.
Given these developmental deficits of the intestine and their microbiota in IUGR piglets, the purpose of this review article is to review the potential ways from the perspective of maternal imprinting. As well, the nutritional strategies for improving colonization of the advantageous intestinal microbiota in neonatal IUGR piglets are also summarized, with a perspective of maternal intervention.
Maternal malnutrition as a reason for occurrence of the IUGR piglets
During the mid and late gestation, the utero-placental circulation and umbilical cord vein are mainly responsible for delivering the nutrients from the mother to the fetuses . It has been reported that the transportation of nutrients from mother to IUGR porcine fetuses was altered during gestation due to the decreased blood flow in placenta [10, 11]. Expression of several proteins related to energy metabolism was decreased in placenta and endometrium of the IUGR fetuses (d 60, 90, and 110 of gestation), which could contribute to the inadequate energy provision and insufficient nutrient transport and thus the occurrence of IUGR . One important feature was the insufficient amino acid transmission from the sow to the IUGR fetuses . Specifically, IUGR fetus had a decreased supply of amino acids in the arginine family such as arginine and glutamine, and also the branched chain amino acids (valine, leucine, and isoleucine), as well as glucose, while increased levels of ammonia in the umbilical cord vein . In an obese sow model, maternal malnutrition (50% standard grain-based diet) during the last two-thirds of gestation induced asymmetryical growth retardation and metabolic alterations in the newborn piglets . In addition, Mickiewicz et al.  and Metges et al.  found that low protein diets (6.5% protein) administrated to gilts led to IUGR, and even the delayed catch-up growth in IUGR piglets, it was possibly a lack of indispensable amino acids that led to injured lipoprotein metabolism. Likewise, feeding a low-protein diet (50% of standard-protein) to the sows during late-gestation resulted in notable decrease in birth weight of newborn piglets, as well as the reduced expression and activity of 11β-hydroxysteroid dehydrogenase 2 in placenta with a sex-dependent way .
Oocyte maturity might be a crucial factor of embryonic uniformity and subsequent within-litter variation in birth weight , therefore, nutritional supplies during pre-mating or peri-implantation period may have significant effects on within-litter uniformity of the birth weight. Large numbers of evidences have suggested that the maternal malnutrition before breeding and the peri-implantation period posed a threat on the oocyte quality and embryonic development [20, 21]. Feeding low-energy diets to sows during the weaning-to-estrus interval lowered ovulation rate, follicle size and litter homogeneity . While appropriate increasing energy intake (3.5 kg/d) for pre-mating sows can decrease the within-litter variability in blastocyst size at d 12 of pregnancy, compared with that from sows fed a maintenance diet (1.15 kg/d) . Moreover, the uniformity of birth weight in the litter was decreased in sows on dextrose-supplemented diets (150 g/d) compared to the sows fed basal-diet during the weaning-to-estrus interval . Therefore, modest energy requirements for sows prior to mating have a crucial impact on within-litter uniformity.
The developmental defects in the intestine of IUGR piglets
Recent studies identified an impairment of intestinal development in IUGR piglets at birth [25, 26], and this injury persisted during the whole suckling period [27, 28]. One of the causes of this damage was the abnormally regulated DNA methylation [29, 30]. As well, the intestinal barrier integrity were injured in the IUGR newborn piglets, demonstrated as damaged villi, shorter microvilli, reduced villus surface areas, fewer number of epithelial goblet cells or lymphocyte, and the decreased levels of the cytokines such as tumor necrosis factor-α and interferon-γ as well as their gene expressions . Additionally, the decreased intestinal immunity function in IUGR piglets was connected with overexpression of the heat shock protein 70, which impairs the nuclear factor-kappa B signaling and upregulates forkhead box O3a expression in the intestine . One of the possible mechanisms was targeted degradation of the proteins in tight junction pathways and extracellular matrix by the miRNA-29a, which then results in the impairment of intestinal epithelial integrity . Taken all together, the developmental defects in the intestine and intestinal immune system of IUGR piglets are mainly mediated by changes in the key cytokines, immune-related proteins and inflammation-related cell signaling pathways, thus resulting in poor nutritional absorption and high risk of intestinal infection, as well as the higher morbidity and mortality in their early postnatal life.
The altered intestinal microbiota in neonatal IUGR piglets
Accompanying the injured intestinal barriers in IUGR piglets, the establishment and succession of their intestinal microbiota is also changed. A previous study found that the permeability of macromolecules through the intestinal barrier of IUGR piglets was increased , leading to higher counts of adherent bacteria to the intestinal mucosa [35, 36]. Recent research has suggested that IUGR piglets had lower diversity of Bacteroidetes and Bacteroides in the jeunum at d 7, 21, and 28, Oscillibacter in the jejunum at d 21, and there was a positive correction between the Bacteroides and Oscillibacter abundances and the body weight of IUGR piglets . A previous study also has indicated that the commensal bacteria such as Lactobacillus and Streptococcus were significantly decreased and the potential pathogens including Fusobacterium and Campylobacter were increased in the feces of IUGR piglets from d 7 to 21 of age, along with the altered concentrations of metabolites (e.g., fatty acid metabolism, bile acid biosynthesis and amino acid metabolism) . Specially, qPCR outcomes revealed that the copy number of predominant Lactobacillus species like L. salivarius on d 7 and L. amylovorus on d 21 were significantly reduced in the colon of IUGR piglets . Similarly, two trials conducted on rats and mice also reported that the cecocolic and fecal microbial composition were changed in IUGR infancy [39, 40], compared to their normal counterparts. In preterm infants, facultative anaerobes like Enterococcus, Enterobacter, and Lactobacillus spp., were prevalent, while amounts of strict anaerobes and advantageous intestinal microbiota such as Bifidobacterium and Bacteroides were uncommon [41, 42]. In addition, low diversity of intestinal microbiota and prevalence of pathogenic bacteria were usually present in the intestine of preterm infants, which embodies a typical example of dysbiosis [43, 44]. More remarkably, recent experiments identified an increased abundance of Escherichia-Shigella and a decreased abundance of Clostridium_sensu_stricto_1 in IUGR piglets, which was closely associated with the alterations of cytokines (tumor necrosis factor-α, interleukin-6, interleukin-1β and interferon-γ,) and plasma metabolites in the first 12 h of life (unpublished data), suggesting early-life interactions between intestinal microbiota and the intestinal immune function in IUGR piglets.
The above results indicate that the IUGR piglets have an intestinal dysbiosis, which is associated with the alteration in intestinal adaptation and microbial composition during the neonatal period.
Maternal imprinting on intestinal microbiota of the IUGR piglets by vertical microbial transition during gestation
It is widely accepted that the microbiota in neonates was firstly established at birth, along with the exposure to microbes existing in the maternal vaginal canal during natural labor or the maternal skin during a cesarean. However, the conventional idea of ‘sterile womb’ has been questioned with an increasing attention of vertical microbial transition from mother to offspring . Increased number of scientific studies from healthy full-term women have shown that there was bacterial DNA in placenta , amniotic fluid , umbilical cord blood , and meconium [49, 50]. Also, a recent experiment by meta-genomic analysis revealed that the human utero including cervical canal and peritoneal fluid contains microbiota . However, some opposite arguments have been put forward, mainly because the research results above could not exclude the contamination . Correspondingly, some suggestions to reduce the impact of contaminations in low biomass microbial studies have been made [52, 53]. All these results remind us that the effects of maternal imprinting on intestinal microbiota of the neonates might start from the intrauterine environments, but whether the colonization of intestinal microbiota happened in fetal stage requires more work to get verification.
It is clear that the fetuses absorb the nutrients from the umbilical cord vein during their fetal stage. Consequently, the early microbial colonization in neonatal intestine is possibly influenced by the microbial metabolites in uterus. A study in sows found that the microbiota community in umbilical cord vein, ultimately, impacted the microbiota and fermentative end-products profile including short-chain fatty acids and branched-chain fatty acids of the neonatal piglets . In humans, the relative richness of dominant phylum such as Firmicutes in placenta was significantly lower in the IUGR neonates . Similarly, another study reported that the reduced microbial richness of placenta was accompanied with spontaneous preterm neonates . Above two outcomes in human revealed that the close associations of the decreased placental microbiome with IUGR neonates. However, the effects of microbiota from the intrauterine environment on IUGR progeny are scant. More clinical trials and experimental animal studies are required to explore it further.
Maternal imprinting on intestinal microbiota of the IUGR piglets during the perinatal and lactation period
Besides intrauterine environment during gestation, some other factors including delivery mode, gestational ages at delivery, as well as the feeding patterns and environmental factors during lactating period could also affect the microbiota colonization of the neonatal IUGR piglets .
The delivery mode could be one of the important drivers for establishment of the intestinal microbiota in neonates . Compared to the caesarean-delivered piglets, vaginally-delivered piglets had higher bacterial densities including Bacteroides, Prevotella at d 7 and Clostridium XIVa at d 14, which was consistent with the relatively abundant Bacteroides in vaginal microflora of the healthy sows . At the same time, the vaginally-delivered piglets had higher propionate in ileum and butyrate in the ascending colon , which could be used as energy sources and believed to be health-enhancing for host [60, 61]. Therefore, maternal delivery mode might be regarded as a possible factor for affecting early-life microbial structure of neonatal IUGR piglets.
Maternal gestational age at delivery is also an important variable contribution to the preterm births. By comparing the preterm and full-term piglets, Kamal et al.  found that colonization of the dominant bacteria, Enterobacteriaceae, at d 5 was delayed in preterm piglets. Similar reports for fecal microbial differences between human preterm and full-term neonates also suggested that the preterm neonates had delayed gut colonization of commensal anaerobe microbes and increased levels of pathogenic microorganisms [42, 63, 64].
The maternal impacts on the neonatal intestinal microbiota continue with lactation. The different effects between nursing and other feeding patterns such as milk replacer or compound feed on the intestinal microbiota of neonatal piglets have been reported [65, 66]. Compared to the sow-reared piglets, relative abundance of the Lactobacillus and Escherichia in colon of the neonatal piglets with commercial milk-replacer was notably decreased . Feeding formula could predispose the piglets to necrotizing enterocolitis (NEC), and to be prone to Clostridium perfringens infection [68, 69]. Likewise, the changed microbial composition and enhanced concentrations of short-chain fatty acids in response to early milk-feeding in neonatal piglets have also been revealed by others [70, 71]. So, we can see the important role of sow’s milk in colonization of the neonatal intestinal microbiota. One of the studies has showed that the bacteria populations in milk might be a source of intestinal bacteria .
In addition, environmental factors during lactation also show clear links with the intestinal microbiota of neonates. Lactating sows contain large amounts of bacteria and can be easily obtained by the nursing piglets. A study has demonstrated that the fecal microbial composition and function in neonatal piglets on d 1 were inclined to be analogous with those in sow’s milk and nipple surface . Also, when the neonatal piglets were transferred from one sow to another, their intestinal microbial communities would be closer to the subsequent nursing sow’s [74, 75]. Since the variations in rearing environment could be complex, more trials are required to determine the corresponding variables and their contributions to the colonization of intestinal microbiota during suckling piglets.
Maternal nutritional intervention during lactation to improve colonization of the advantageous intestinal microbiota in neonatal IUGR piglets
It is obvious that the lactating sows require a diet that could supply enough energy and nutrients to support their individual maintainence and also the growth of their offspring through milk production. As an important nutritional source, colostrum and milk could influence the establishment and succession of intestinal microbiota in neonates . Thus, an enhanced maternal microbiota might provide advantageous microbes for either direct colonization or for indirect influence on the succession of indigenous intestinal microbiota in neonates. There were many studies showing the supplementation of probiotics and prebiotics for sows that could improve the colonization of beneficial intestinal microbiota in neonatal piglets [77, 78]. Here we mainly focused on discussing the effects and advancements of breastfeeding, probiotics and prebiotics supplementation for improving the intestinal health and colonization of intestinal microbiota in IUGR piglets.
Milk is the first diet source of neonates. It has a variety of biological functions, including supply of nutrients, protective Ig, antimicrobial and anti-inflammatory factors, which could enhance the early GIT development [79, 80]. It is worth noting that pigs have a very restricted transference of maternal Ig through the placenta, and thus, colostrum is the only source of Ig for neonatal piglets [81, 82]. Previous data confirmed that the multiple bioactivities (mainly Ig) of colostrum could regulate the innate immune reaction of intestinal epithelial cells . Of note, IUGR piglets had delayed and lower amounts of colostrum intake than the NBW piglets [84, 85], which might be an important reason for intestinal immune deficiency and impairment. A recent research has evidenced that colostrum feeding partially ameliorated the inferior status of jejunal mucosa in IUGR piglets , thus probably leading to the change of establishment and composition of their intestinal microbiota. Moreover, 16S rRNA sequencing outcomes noted that the diversity of sow milk microbiota altered markedly in colostrum but remains relatively stable in transitional milk and mature milk , these results are line with the results of Liu et al. . Cross-fostering could be a helpful practice to promote the quantity of colostrum received by the IUGR piglets. Maradiaga et al. has proposed that cross-fostering did not influence microbial composition present in the piglets GIT, but there was a notably correction between microbial communities of maternal colostrum and feces of piglets .
In addition, there is growing data suggesting that breastfeeding is one of the most key determinants of neonatal intestinal colonization. Not only because of the abundant bacterial communities in milk , but because a rich and natural source of oligosaccharide (OS) that regarded as a prebiotic activity, although the origin composition of milk microbita and OS are relatively complex and not completely illuminated . Results in preterm infants have pointed out human milk OS could enhance the initial bacterial diversity and decrease the occurrence of NEC [92, 93]. By comparing the characterization of porcine milk OS and their relation to the fecal microbiota, Salcedo et al. investigated that fucose-consuming bacterial taxa in the intestinal microbiota of piglets were qualitatively but not quantitatively different between suckling and weaning stages , indicating that the composition and structure of milk OS may be important in shaping the intestinal microbiota of piglets. Besides, from the aspects of vertical transfer of sow’s microbiota, recent data suggested that the microbes from teats or the milk canal and feces are primarily responsible for the initial colonization of neonatal intestinal microbiota . So, Further studies detecting the composition and function of milk-associated OS, might be useful to the development of intestinal health of IUGR piglets.
Most often, probiotics with the highest positive effects on human and animal GIT health are believed to be Lactobacillus species, Bifidobacterium species, Enterococcus faecium strains (commonly habitat in gastrointestinal tract), Bacillus genus spores (commonly habitat in soil), Saccharomyces cerevisiae yeast strains, etc. . In the model of preterm/very low birth weight infants, a growing number of data has revealed that maternal supplementation with probiotic bacteria could reduce the occurrence of NEC and improve the infant weight [96, 97]. A meta-analysis even evidenced that combination of probiotics seems to be more effective than a single probiotics in preventing NEC and mortality of preterm/very LBW infants . For example, supplementing combined probiotic milk (Lactobacillus rhamnosus GG, Lacidophilus La-5, and Bifidobacterium animalis subsp. Lactis Bb-12) from 36 weeks of gestation up to 3 months postnatally, can notably elevate the relative abundance of administrated probiotics in mothers, but only the Lactobacillus rhamnosus GG bacteria colonized the infant at 10 days and at 3 months of age , which indicates that different probiotic bacteria appear to have different ability to transfer from the mother to their offspring, thereby having different effects on their progeny. Either administrating the Bacillus or Enterococcus faecium probiotic strain to sows significantly increased the counts and quantity of Lactobacillus species [100, 101], and decreased the Clostridium spp. in the feces of neonatal piglets [101, 102]. Also, oral supplementation of nine microbial species supplements to lactating sows made the Clostridium cluster IV and subcluster XIVa particularly increased in their weaned piglets . Above information suggests that probiotics or their combination during lactation period might be a potential intervention for reshaping the intestinal microbiota in IUGR piglets, but attention should be paid to the type of probiotics.
Prebiotics can selectively provoke the beneficial growth or activity of advantageous bacteria . Previous results have proposed that inulin addition during the gestation and lactation can enhance the numbers of enterococci in sows. Also, a higher level of enterococci were detected in the cecal content of the suckling piglets . Feeding diets with high-resistant starch (amylose corn) to sows from gestation to lactation increased milk nutrients probably via changing maternal intestinal microbiota composition, thus improving growth trait of offspring . These emphasized that maternal prebiotics supplementation might be a useful method to modulate the intestinal microbiota and health in IUGR piglets. On the contrary, supplementation of resistant starch (pea starch) during gestation and lactation affected the fecal microbiota of the sows, but not that of their progeny, and neither the body weight or frequency of diarrhea of the piglets . This attributes to the characteristics of the different types of fibers. On the whole, because of the complexity and diversity of fiber types, little understanding on corresponding metabolic condition of sows and the microbial imprinting on next generation exist nowadays. Therefore, relevant work needs to be pushed forward.
In conclusion, intestinal development and microbiota colonization in the piglets were negatively affected by IUGR, due to imbalanced allocation of limited nutrients among fetuses during gestation. This is connected with the maternal microbial influences during gestation, at delivery or during lactation, and even at the pre-gestational stage through imprinting of the oocyte maturation. Maternal nutritional interventions with breastfeeding, probiotics or prebiotics could also help the colonization of advantageous intestinal microbiota in IUGR piglets.
Availability of data and materials
Intrauterine growth restriction
Normal birth weight
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16:341.
Matamoros S, Gras-leguen C, Le Vacon F, Potel G, de la Cochetiere MF. Development of intestinal microbiota in infants and its impact on health. Trends Microbiol. 2013;21:167–73.
Kabat AM, Srinivasan N, Maloy KJ. Modulation of immune development and function by intestinal microbiota. Trends Immunol. 2014;35:507–17.
Goodrich J, Waters J, Poole A, Sutter J, Koren O, Ran B, et al. Human genetics shape the gut microbiome. Cell. 2014;159:789–99.
Min L, Bauer LL, Xin C, Mei W, Kuhlenschmidt TB, Kuhlenschmidt MS, et al. Microbial composition and in vitro fermentation patterns of human milk oligosaccharides and prebiotics differ between formula-fed and sow-reared piglets. J Nutr. 2012;142:681.
Inman CF, Haverson K, ., Konstantinov SR, Jones PH, Harris C, ., Smidt H, ., et al. Rearing environment affects development of the immune system in neonates. Clin Exp Immunol 2010;160:431–439.
Schokker D, Zhang J, Zhang LL, Vastenhouw SA, Heilig HG, Smidt H, et al. Early-life environmental variation affects intestinal microbiota and immune development in new-born piglets. PLoS One. 2014;9:e100040.
Li N, Huang S, Jiang L, Wang W, Li T, Zuo B, et al. Differences in the gut microbiota establishment and metabolome characteristics between low-and normal-birth-weight piglets during early-life. Front Microbiol. 2018;9:1798.
Kiserud T, Acharya G. The fetal circulation. Prenat Diagn. 2004;24:1049.
Kim SW, Weaver AC, Yan BS, Yan Z. Improving efficiency of sow productivity: nutrition and health. J Anim Sci Biotechno. 2013;4:26.
Reynolds LP, Caton JS, Redmer DA, Grazul-Bilska AT, Vonnahme KA, Borowicz PP, et al. Evidence for altered placental blood flow and vascularity in compromised pregnancies. J Physiol. 2006;572:51–8.
Chen F, Wang T, Feng C, Lin G, Zhu Y, Wu G, et al. Proteome differences in placenta and endometrium between Normal and intrauterine growth restricted pig fetuses. PLoS One. 2015;10:e0142396.
Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW, Li XL, et al. Impacts of amino acid nutrition on pregnancy outcome in pigs:mechanisms and implications for swine production. J Anim Sci. 2010;88:195–204.
Lin G, Liu C, Feng C, Fan Z, Dai Z, Lai C, et al. Metabolomic analysis reveals differences in umbilical vein plasma metabolites between normal and growth-restricted fetal pigs during late gestation. J Nutr. 2012;142:990–8.
Cristina Ó, Antonio GB, Rita B, Miriam A, Alicia B, Pérez-Solana ML, et al. Prenatal programming in an obese swine model: sex-related effects of maternal energy restriction on morphology, metabolism and hypothalamic gene expression. Br J Nutr. 2014;111:735–46.
Mickiewicz M, Zabielski R, Grenier B, Le Normand L, Savary G, Holst JJ, et al. Structural and functional development of small intestine in intrauterine growth retarded porcine offspring born to gilts fed diets with differing protein ratios throughout pregnancy. J Physiol Pharmacol. 2012;63:225–39.
Metges CC, Lang IS, Hennig U, Brussow KP, Kanitz E, Tuchscherer M, et al. Intrauterine growth retarded progeny of pregnant sows fed high protein:low carbohydrate diet is related to metabolic energy deficit. PLoS One. 2012;7:e31390.
Shang Y, Jia Y, Sun Q, Shi W, Li R, Wang S, et al. Sexually dimorphic effects of maternal dietary protein restriction on fetal growth and placental expression of 11β-HSD2 in the pig. Anim Reprod Sci. 2015;160:40–8.
Lende TVD, Hazeleger W, Jager DD. Weight distribution within litters at the early foetal stage and at birth in relation to embryonic mortality in the pig. Livest Prod Sci. 1990;26:53–65.
Ashworth CJ, Toma LM, Hunter MG. Nutritional effects on oocyte and embryo development in mammals: implications for reproductive efficiency and environmental sustainability. Philos Trans R Soc Lond Ser B Biol Sci. 2009;364:3351–61.
Johnston L, Shurson J, Whitney M. Nutritional effects on fetal imprinting in swine. Owatonna: Proceeding of 2008 Minnesota Nutrition Conference; 2008. p. 207–22.
Brand H, Van Den DSJ, Soede NM, Kemp B. Dietary energy source at two feeding levels during lactation of primiparous sows: I. Effects on glucose, insulin, and luteinizing hormone and on follicle development, weaning-to-estrus interval, and ovulation rate. J Anim Sci. 2000;78:396–404.
Ashworth CJ, Beattie L, Antipatis C, Vallet JL. Effects of pre- and post-mating feed intake on blastocyst size, secretory function and glucose metabolism in Meishan gilts. Reprod Fert Develop. 1999;11:323–7.
Van den Brand H, Soede NM, Kemp B. Supplementation of dextrose to the diet during the weaning to estrus interval affects subsequent variation in within-litter piglet birth weight. Anim Reprod Sci. 2006;91:353–8.
Wang J, Chen L, Li D, Yin Y, Wang X, Li P, Dangott L, et al. Intrauterine growth restriction affects the proteomes of the small intestine, liver, and skeletal muscle in newborn pigs. J Nutr. 2008;138:60–6.
Bauer R, Walter B, Brust P, Füchtner F, Zwiener U. Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets. Eur J Obstet Gynecol Reprod Biol. 2003;110:S40–9.
Wiyaporn M, Thongsong B, Kalandakanondthongsong S. Growth and small intestine histomorphology of low and normal birth weight piglets during the early suckling period. Livest Sci. 2013;158:215–22.
Wang X, Wu W, Lin G, Li D, Wu G, Wang J. Temporal proteomic analysis reveals continuous impairment of intestinal development in neonatal piglets with intrauterine growth restriction. J Proteome Res. 2010;9:924–35.
Hu Y, Hu L, Gong D, Lu H, Xuan Y, Wang R, et al. Genome-wide DNA methylation analysis in jejunum of Sus scrofa with intrauterine growth restriction. Mol Genet Genomics. 2018;293(4):807.
Tao S, Zhou T, Saelao P, Wang Y, Zhu Y, Li T, et al. Intrauterine growth restriction alters the genome-wide DNA methylation profiles in small intestine, liver and longissimus dorsi muscle of newborn piglets. Curr Protein Pept Sci. 2019;20(7):713.
Dong L, Zhong X, Ahmad H, Li W, Wang Y, Zhang L, et al. Intrauterine growth restriction impairs small intestinal mucosal immunity in neonatal piglets. J Histochem Cytochem. 2014;62:510–8.
Zhong X, Li W, Huang X, Zhang L, Yimamu M, Raiput N, et al. Impairment of cellular immunity is associated with overexpression of heat shock protein 70 in neonatal pigs with intrauterine growth retardation. Cell Stress Chaperon. 2012;17:495–505.
Zhu Y, Wang W, Yuan T, Fu L, Zhou L, Lin G, et al. MicroRNA-29a mediates the impairment of intestinal epithelial integrity induced by intrauterine growth restriction in pig. Am J Physiol Gastrointest Liver Physiol. 2017;312:G434–42.
Wang W, Degroote J, Van Ginneken C, Van Poucke M, Vergauwen H, Dam TM, et al. Intrauterine growth restriction in neonatal piglets affects small intestinal mucosal permeability and mRNA expression of redox-sensitive genes. FASEB J. 2015;30:863.
D'Inca R, Gras-Le Guen C, Che L, Sangild PT, Le Huërou-Luron I. Intrauterine growth restriction delays feeding-induced gut adaptation in term newborn pigs. Neonatology. 2011;99:208–16.
Romain DI, Maela K, Christèle GLG, Isabelle HRL. Intrauterine growth restriction modifies the developmental pattern of intestinal structure, transcriptomic profile, and bacterial colonization in neonatal pigs. J Nutr. 2010;140:925–31.
Zhang W, Ma C, Xie P, Zhu Q, Wang X, Yin Y, et al. Gut microbiota of newborn piglets with intrauterine growth restriction have lower diversity and different taxonomic abundances. J Appl Microbiol. 2019;127:354–69.
Li N, Huang S, Jiang L, Dai Z, Li T, Han D, et al. Characterization of the early life microbiota development and predominant Lactobacillus species at distinct gut segments of low- and normal-birth-weight piglets. Front Microbiol. 2019;10:797.
Wang J, Tang H, Wang X, Zhang X, Zhang C, Zhang M, et al. The structural alteration of gut microbiota in low-birth-weight mice undergoing accelerated postnatal growth. Sci Rep. 2016;6:27780.
Fanca-Berthon P, Hoebler C, Mouzet E, David A, Michel C. Intrauterine growth restriction not only modifies the cecocolonic microbiota in neonatal rats but also affects its activity in young adult rats. J Pediatr Gastroenterol Nutr. 2010;51:402–13.
Arboleya S, Solís G. Facultative to strict anaerobes ratio in the preterm infant microbiota. Gut Microbes. 2012;3:583–8.
Arboleya S, Binetti A, Salazar N, Fernández N, Solís G, Hernándezbarranco A, et al. Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol Ecol. 2012;79:763–72.
Mai V, Torrazza RM, Ukhanova M, Wang X, Sun Y, Li N, et al. Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants. PLoS One. 2013;8:e52876.
Madan JC, Farzan SF, Hibberd PL, Karagas MR. Normal neonatal microbiome variation in relation to environmental factors, infection and allergy. Curr Opin Pediatr. 2012;24:753–9.
Perez-Muñoz ME, Arrieta MC, Ramer-Tait AE, Walter J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome. 2017;5:48.
Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014;6:237ra65.
Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016;6:23129.
Hornef M, Penders J. Does a prenatal bacterial microbiota exist? Mucosal Immunol. 2017;10:598–601.
Nagpal R, Tsuji H, Takahashi T, Kawashima K, Nagata S, Nomoto K, et al. Sensitive quantitative analysis of the meconium bacterial microbiota in healthy term infants born vaginally or by cesarean section. Front Microbiol. 2016;7:1997.
Hansen R, Scott KP, Khan S, Martin JC, Berry SH, Stevenson M, et al. First-pass meconium samples from healthy term vaginally-delivered neonates: an analysis of the microbiota. PLoS One. 2015;10:e0133320.
Li F, Chen C, Wei W, Wang Z, Dai J, Hao L, et al. The metagenome of the female upper reproductive tract. Gigascience. 2018;7:giy107.
Lauder AP, Roche AM, Sherrill-Mix S, Bailey A, Laughlin AL, Bittinger K, et al. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota. Microbiome. 2016;4:29.
Salter SJ, Cox MJ, Turek EM, Calus ST, Cookson WO, Moffatt MF, et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 2014;12:87.
Leblois J, Massart S, Li B, Wavreille J, Bindelle J, Everaert N. Modulation of piglets’ microbiota: differential effects by a high wheat bran maternal diet during gestation and lactation. Sci Rep. 2017;7:7426.
Zheng J, Xiao X, Zhang Q, Mao L, Yu M, Xu J. The placental microbiome varies in association with low birth weight in full-term neonates. Nutrients. 2015;7:6924–37.
Foxcroft GR, Dixon WT, Dyck MK, Novak S, Harding JC, Almeida FC. Prenatal programming of postnatal development in the pig. Soc Reprod Fertil Suppl. 2009;66:213–31.
Stinson LF, Payne MS, Keelan JA. A critical review of the bacterial baptism hypothesis and the impact of cesarean delivery on the infant microbiome. Front Med. 2018;5:135.
Wang J, Li C, Nesengani LT, Gong Y, Zhang S, Lu W. Characterization of vaginal microbiota of endometritis and healthy sows using high-throughput pyrosequencing of 16S rRNA gene. Microb Pathog. 2017;111:S0882401017305144.
Wang M, Radlowski EC, Monaco MH, Fahey GC Jr, Gaskins HR, Donovan SM. Mode of delivery and early nutrition modulate microbial colonization and fermentation products in neonatal piglets. J Nutr. 2013;143:795.
Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I. Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation. Nutrients. 2015;7:2839–49.
Guilloteau P, Martin L, Eeckhaut V, Ducatelle R, Zabielski R, Immerseel F. Van. From the gut to the peripheral tissues: the multiple effects of butyrate. Nutr Res Rev. 2010;23:366–84.
Kamal SS, Andersen AD, Krych L, Lauridsen C, Sangild PT, Thymann T, et al. Preterm birth has effects on gut colonization in piglets within the first 4 weeks of life. J Pediatr Gastroenterol Nutr. 2019;68(5):727.
Cong X, Xu W, Janton S, Henderson WA, Matson A, Mcgrath JM, et al. Gut microbiome developmental patterns in early life of preterm infants: impacts of feeding and gender. PLoS One. 2016;11:e0152751.
Hill CJ, Lynch DB, Murphy K, Ulaszewska M, Jeffery IB, O’Shea CA, et al. Erratum to: evolution of gut microbiota composition from birth to 24 weeks in the infantmet cohort. Microbiome. 2017;5:4.
Poulsen AR, De JN, Sugiharto S, Nielsen JL, Lauridsen C, Canibe N. The microbial community of the gut differs between piglets fed sow milk, milk replacer or bovine colostrum. Br J Nutr. 2017;117:1.
Saraf MK, Piccolo BD, Bowlin AK, Mercer KE, LeRoith T, Chintapalli SV, et al. Formula diet driven microbiota shifts tryptophan metabolism from serotonin to tryptamine in neonatal porcine colon. Microbiome. 2017;5:77.
Shi C, Zhu Y, Niu Q, Wang J, Wang J, Zhu W. The changes of colonic bacterial composition and bacterial metabolism induced by an early food introduction in a neonatal porcine model. Curr Microbiol. 2018;75:1–7.
Grzeskowiak L, MartãNez-VallespãN B, Dadi TH, Radloff J, Amasheh S, Heinsen FA, et al. Formula-feeding predisposes neonatal piglets to clostridium difficile gut infection. J Infect Dis. 2018;217:1442.
Sangild PT. Diet- and colonization-dependent intestinal dysfunction predisposes to necrotizing enterocolitis in preterm pigs. Gastroenterology. 2006;130:1776–92.
Le Huërou-Luron I, Blat S, Boudry G. Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects. Nutr Res Rev. 2010;23:23–36.
Valeriy P, James Robert W, Mei W, Sharon D, John A, Liu DC, et al. Gut microbial gene expression in mother-fed and formula-fed piglets. PLoS One. 2010;5:e12459.
Rodríguez JM. The origin of human milk bacteria: is there a bacterial entero-mammary pathway during late pregnancy and lactation? Adv Nutr. 2014;5:779.
Chen X, Xu J, Ren E, Su Y, Zhu W. Co-occurrence of early gut colonization in neonatal piglets with microbiota in the maternal and surrounding delivery environments. Anaerobe. 2017;49:30–40.
Bian G, Ma S, Zhu Z, Su Y, Zoetendal EG, Mackie R, et al. Age, introduction of solid feed and weaning are more important determinants of gut bacterial succession in piglets than breed and nursing mother as revealed by a reciprocal cross-fostering model. Environ Microbiol. 2016;18:1566–77.
Daft JG, Ptacek T, Kumar R, Morrow C, Lorenz RG. Cross-fostering immediately after birth induces a permanent microbiota shift that is shaped by the nursing mother. Microbiome. 2015;3:17.
Ojofeitimi EO, Elegbe IA. The effect of early initiation of colostrum feeding on proliferation of intestinal bacteria in neonates. Clin Pediatr. 1982;21:39–42.
Herfel TM, Jacobi SK, Lin X, Jouni ZE, Chichlowski M, Stahl CH, et al. Dietary supplementation of Bifidobacterium longum strain AH1206 increases its cecal abundance and elevates intestinal interleukin-10 expression in the neonatal piglet. Food Chem Toxicol. 2013;60:116–22.
Yan H, Lu H, Almeida VV, Ward MG, Adeola O, Nakatsu CH, et al. Effects of dietary resistant starch content on metabolic status, milk composition, and microbial profiling in lactating sows and on offspring performance. J Anim Physiol Anim Nutr. 2017;101:n/a-n/a.
Danielsen M, Pedersen LJ, Bendixen E. An in vivo characterization of colostrum protein uptake in porcine gut during early lactation. J Proteome. 2011;74:101–9.
Stelwagen K, Carpenter E, Haigh B, Hodgkinson A, Wheeler TT. Immune components of bovine colostrum and milk. J Anim Sci. 2009;87:3–9.
Sangild PT. Uptake of colostral immunoglobulins by the compromised newborn farm animal. Acta Vet Scand Suppl. 2003;44:105–22.
Tuo W, Zhu D, Bazer FW. Transfer of heterologous immunoglobulin into the uterine lumen of pigs. J Reprod Immunol. 1996;32:145.
Jørgensen AL, Juul-Madsen HR, Stagsted J. Colostrum and bioactive, colostral peptides differentially modulate the innate immune response of intestinal epithelial cells. J Pept Sci. 2010;16:21–30.
Amdi C, Krogh U, Flummer C, Oksbjerg N, Hansen CF, Theil PK. Intrauterine growth restricted piglets defined by their head shape ingest insufficient amounts of colostrum1. J Anim Sci. 2013;91:5605–13.
Quesnel H, Farmer C, Devillers N. Colostrum intake: influence on piglet performance and factors of variation. Livest Sci. 2012;146:105–14.
Wang X, Zhu Y, Feng C, Lin G, Wu G, Li D, et al. Innate differences and colostrum-induced alterations of jejunal mucosal proteins in piglets with intra-uterine growth restriction. Br J Nutr. 2018;119:734–47.
Chen W, Mi J, Lv N, Gao J, Cheng J, Wu R, et al. Lactation stage-dependency of the sow Milk microbiota. Front Microbiol. 2018;9:945.
Liu H, Hou C, Li N, Zhang X, Zhang G, Yang F, et al. Microbial and metabolic alterations in gut microbiota of sows during pregnancy and lactation. FASEB J. 2019;33(3):4490 fj201801221RR.
Maradiaga N, Aldridge B, Zeineldin M, Lowe J. Gastrointestinal microbiota and mucosal immune gene expression in neonatal pigs reared in a cross-fostering model. Microb Pathog. 2018;121:27–39.
Zhang F, Wang Z, Lei F, Wang B, Jiang S, Peng Q, et al. Bacterial diversity in goat milk from the Guanzhong area of China. J Dairy Sci. 2017;100:7812–24.
McGuire MK, McGuire MA. Got bacteria? The astounding, yet not-so-surprising, microbiome of human milk. Curr Opin Biotechnol. 2017;44:63–8.
Gregory KE, Samuel BS, Houghteling P, Shan G, Ausubel FM, Sadreyev RI, et al. Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome. 2016;4:68.
Vongbhavit K, Underwood MA. Prevention of necrotizing enterocolitis through manipulation of the intestinal microbiota of the premature infant. Clin Ther. 2016;38:716–32.
Salcedo J, Frese SA, Mills DA, Barile D. Characterization of porcine milk oligosaccharides during early lactation and their relation to the fecal microbiome. J Dairy Sci. 2016;99:7733–43.
Simon O. Micro-organisms as feed additives–probiotics. Adv Pork Prod. 2005;16:161–7.
Mantaring J, Benyacoub J, Destura R, Pecquet S, Vidal K, Volger S, et al. Effect of maternal supplement beverage with and without probiotics during pregnancy and lactation on maternal and infant health: a randomized controlled trial in the Philippines. Bmc Pregnancy Childb. 2018;18:193.
Alfaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Evidence-Based Child Health: A Cochrane Rev J. 2010;5:339–68.
Chang HY, Chen JH, Chang JH, Lin HC, Lin CY, Peng CC. Multiple strains probiotics appear to be the most effective probiotics in the prevention of necrotizing enterocolitis and mortality: an updated meta-analysis. PLoS One. 2017;12:e0171579.
Dotterud CK, Avershina E, Sekelja M, Simpson MR, Rudi K, Storrø O, et al. Does maternal perinatal probiotic supplementation alter the intestinal microbiota of mother and child? J Pediatr Gastr Nutr. 2015;61:200–7.
Starke IC, Pieper R, Neumann K, Zentek J, Vahjen W. Individual responses of mother sows to a probiotic Enterococcus faecium strain lead to different microbiota composition in their offspring. Benef Microbes. 2013;4:345–56.
Baker AA, Davis E, Spencer JD, Moser R, Rehberger T. The effect of a Bacillus-based direct-fed microbial supplemented to sows on the gastrointestinal microbiota of their neonatal piglets. J Anim Sci. 2013;91:3390–9.
Kritas SK, Marubashi T, Filioussis G, Petridou E, Christodoulopoulos G, Burriel AR, et al. Reproductive performance of sows was improved by administration of a sporing bacillary probiotic (Bacillus subtilis C-3102). J Anim Sci. 2015;93:405–13.
Mori K, Ito T, Miyamoto H, Ozawa M, Wada S, Kumagai Y, et al. Oral administration of multispecies microbial supplements to sows influences the composition of gut microbiota and fecal organic acids in their post-weaned piglets. J Biosci Bioeng. 2011;112:145–50.
Hutkins RW, Krumbeck JA, Bindels LB, Cani PD, Fahey G Jr, Goh YJ, et al. Prebiotics: why definitions matter. Curr Opin Biotechnol. 2016;37:1–7.
Paßlack N, Vahjen W, Zentek J. Dietary inulin affects the intestinal microbiota in sows and their suckling piglets. BMC Vet Res. 2015;11:51.
Leblois J, Massart S, Soyeurt H, Grelet C, Dehareng F, Schroyen M, et al. Feeding sows resistant starch during gestation and lactation impacts their faecal microbiota and milk composition but shows limited effects on their progeny. PLoS One. 2018;13:e0199568.
This work was supported by the Beijing Municipal Natural Science Foundation (S170001), the National Natural Science Foundation of China (31630074, 31272449 and 31902170), the National Key Research and Development Program of China (2016YFD0500506 and 2018YDF0501002), the 111 Project (B16044), and the Jinxinnong Animal Science Developmental Foundation.
Ethics approval and consent to participate
Consent for publication
All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
About this article
Cite this article
Jiang, L., Feng, C., Tao, S. et al. Maternal imprinting of the neonatal microbiota colonization in intrauterine growth restricted piglets: a review. J Animal Sci Biotechnol 10, 88 (2019). https://doi.org/10.1186/s40104-019-0397-7
- IUGR piglet
- Microbial colonization
- Maternal imprinting
- Nutritional intervention