JAS - Devt of Mammalian GI Tract

Development of the mammalian gastrointestinal tract, the resident microbiota, and the role of diet in early life R. K.
Buddington and P. T. Sangild J ANIM SCI published online January 14, 2011
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Running head: GI development, bacteria, and diet
Development of the mammalian gastrointestinal tract, the resident microbiota, and the role of diet in early life1
R. K. Buddington*2 and P.T. Sangild
*Dept Health and Sport Science, University of Memphis, Memphis, TN 38152, USA Dept Human Nutrition, University of Copenhagen, DK-1958 Frederiksberg C, Denmark
1 Based on a presentation at the Companion Animals Symposium, Microbes and Health, at the joint annual meeting of the American Dairy Science Association, Poultry Science Association, Asociacin Mexicana de Produccin Animal, Canadian Society of Animal Science, and American Society of Animal Science, July 11-15, 2010, Denver, CO. 2 Corresponding author: rbddngtn@memphis.edu
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Downloaded from jas.fass.org by guest as doi:10.2527/jas.2010-3705 Published Online First on January 14, 2011on February 1, 2012
ABSTRACT: Mammalian gastrointestinal (GI) development is guided by genetic determinants established during the evolution of mammals and matched to the natural diet and environment. Co-evolution of the host GI tract (GIT) and the resident bacteria has resulted in commensal relationships that are species and even individual specific. The interactions between the host and the GI bacteria are two-way and of particular importance during the neonatal period when the GIT needs to rapidly adapt to the external environment, begin processing of oral foods, and acquire the ability to differentiate between and react appropriately to colonizing commensal and potentially pathogenic bacteria. During this crucial period of life the patterns of gene expression that determine GI structural and functional development are modulated by the bacteria colonizing the previously sterile GIT of fetuses. The types and amounts of dietary inputs after birth influence GI development, species composition and metabolic characteristics of the resident bacteria, and the interactions that occur between the bacteria and the host. This review provides overviews of the age-related changes inGIT functions, the resident bacteria, and diet, and describes how interactions among these three factors influence the health and nutrition of neonates and can have lifelong consequences. Necrotizing enterocolitis is a common GI inflammatory disorder in preterm infants and is provided as an example of when the interactions go awry. Other enteric diseases are common in all newborn mammals and an understanding of the above interactions will enhance efforts to support neonatal health for infants and farm and companion animals. Keywords: bacteria, diet, development, gastrointestinal, mammal, ontogeny
INTRODUCTION We must cultivate our garden from Candide (Voltaire, 1759). When Candide left
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sheltered castle life and entered into the external world he faced challenges and hardships and his survival was dependent on discriminating between good and evil. Similarly, when the fetus emerges from the shelter of the womb the immature gastrointestinal tract must adapt rapidly to oral feeding, the challenges of extrauterine life, and to cultivating the garden of colonizing bacteria. Complex interactions have evolved between the mammalian host and the gastrointestinal (GI) microbiota (Ley et al., 2008). Apparently, the extreme costs that would be imposed on the host by trying to maintain a sterile GI tract (GIT) are outweighed by the benefits of instead establishing commensal relationships with bacteria that provide health and nutritional benefits and pose little or no risk to the host. Hence, the GIT has come to accept the presence of numerous species of bacteria at densities such that GI bacterial cells shortly after birth outnumber those of the host by about 10-fold. Much like the challenges faced by Candide, after birth the GIT must establish and maintain a delicate balance between the recognition and exclusion of pathogens and the tolerance of commensal bacteria. The GI disorder necrotizing enterocolitis (NEC) is exemplary of the consequences when the balance between exclusion and tolerance is disrupted and when members of the commensal bacteria trigger excessive inflammatory responses, thereby compromising health of the neonate (Claud, 2009). The interactions among the GIT, the resident microbiota and diet begin at birth when the sterile epithelium of the GIT first encounters the colonizing bacteria and begins processing the first meals. During this critical period of life genetic determinants of immune responses play a central role in the recognition of and the responses of the developing GIT to the colonizing bacteria. Although dietary inputs influence postnatal development of the GIT, less understood
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are how dietary inputs have the potential to influence the interactions between the GI epithelium and the colonizing bacteria. The contrasting responses of the neonatal GIT and the resident bacteria among infants fed breast milk and those fed formula (Hanson, 2007; Penders et al., 2007) highlight how interactions among the genetic determinants of GI characteristics, the resident bacteria, and dietary inputs must be considered together to understand postnatal GI development in health and disease. The objective of our review is to acquaint readers with the responses of the neonatal mammalian GIT to the bacteria that colonize and become established, and how diet is an important factor in those interactions. We first provide readers with a general understanding of mammalian GI development, the postnatal changes in the resident bacteria, and shifts in dietary inputs. Although the described changes are shared among different mammalian species, there are differences in the timing and specifics of the developmental events. Next, we describe the interactions that exist among genetic determinants of GI structure and functions, the resident bacteria, and diet. A subsequent section uses NEC, often observed in preterm infants, as an example to describe the consequences when the interactions among GI development, the resident bacteria, and diet go awry. We conclude by discussing some dietary strategies to improve health by optimizing the interactions between the developing GIT and the resident microbiota.
DEVELOPMENT OF THE GIT The GIT represents a critical and expansive interface between the external environment and the host. Organogenesis and maturation of the GIT during prenatal life prepares the fetus for the transition at birth from the sterile intrauterine environment and reliance on placental nutrition to the immediate and dramatic changes in the functional demands placed on the GIT by exposure to the contaminated environment, digesting food, and other challenges of extrauterine life. The
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importance of the GIT being functional at the time of birth is evident by the complications of preterm birth and the consequences of immature GI functions. A notable example is the increased risk of NEC among preterm infants, as discussed subsequently. During prenatal development the GIT acquires the capacities to: 1) digest food; 2) defend against pathogens; 3)contribute to osmoregulation; 4) secrete hormones and other signaling molecules that regulate the GIT and other host systems, and 5) detoxify and eliminate toxins produced by metabolism and acquired from the external environment. Some of the GIT capabilities that develop prenatally are vital for the fetus to process the large volumes of swallowed amniotic fluid; up to 750 ml per day by human fetuses (Pritchard 1966). At term the GIT is able to process milk, respond to bacterial colonization, and tolerate extrauterine environmental conditions. However, the specific structural and functional characteristics of the GIT at birth vary among species. This is exemplified by comparisons of the GIT among newborns of altricial and precocial species with different adult feeding habits and from different environments (Stevens and Hume, 1995). The changes in the GIT associated with weaning can be accelerated by advancing the transition from milk to the adult diet, as well as delayed, but not prevented by extending suckling. This highlights how the patterns and trajectories of GI development are established by genetic determinants (hard wired). Yet, the programmed series of events is responsive to dietary inputs (Drozdowski et al., 2010), to environmental conditions (Bailey and Halversen, 2006), and are capable of some flexibility to allow the developing GIT to adapt to existing conditions (Lebenthal and Lebenthal, 1999). There is also evidence for critical period programming of GI characteristics whereby dietary inputs early in life can induce epigenetic changes that persist past the period of exposure and can last for an individuals lifetime
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(Drozdowski et al., 2010). This includes early programming of the GI immune system by the colonizing bacteria and environmental antigens (Mulder et al., 2009). Digestion. At term the GIT is adapted for and ready to process the first food, which for most mammals is colostrum (Drozdowski et al., 1010). The immature digestive functions of preterm infants are considered to contribute to the increased risk of NEC (reviewed by Claud, 2009) and are why total parenteral nutrition (TPN) is used to meet nutrient and energy needs until the GIT develops adequate capacities to process food. Suckling mammals have minimal capacities to adaptively modulate digestive processes in response to changes in diet composition (Buddington, 1994) and do not acquire the abilities to process the adult diet until just prior to weaning (Drozdowski et al., 2010). When neonates are not fed breast milk, diarrhea can result when the alternate diet includes ingredients, such as sucrose, for which there is inadequate expression of sucrase. . Defense. The GI immune system provides a comprehensive, multi-layered defense (Winkler et al 2007). Much like a gardener, the GI immune system is able to differentiate among the numerous types of GI bacteria that represent a threat and those that should be tolerated and contributes to the selection of an assemblage of commensal bacteria (Ogra, 2010). This is the culmination of co-evolution between the resident bacteria and the innate and adaptive components of the GI immune system and is dependent on a diversity of extracellular Toll-like receptors (TLR) and intracellular nucleotide-binding oligomerization domain (NOD) receptors (Richardson et al., 2010; Shibolet and Podolsky, 2007). Aberrant and excessive reactions of the GI immune system to commensal bacteria and other antigens in the GIT causes inflammation and has been associated with several pathologies, including NEC in preterm infants and inflammatory bowel disease, celiac disease, and various food allergies in children and adults.
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Conversely, inadequate recognition or responses to pathogens pose obvious health risks. GI immune functions develop prenatally and at term are capable of recognizing and responding to pathogens, including bacterial DNA motifs and vaccines (Lacroix-Lamonde et al., 2009). Additional development and maturation occur after birth and the several phases described for the porcine GI immune system (Bailey and Halverson, 2006) are relevant to most mammals. The innate GI defenses include secretions of acid, antimicrobial peptides, lysozyme, mucous, the tight junctions that link epithelial cells and provide a physical barrier, activated defense cells (e.g., macrophages, neutrophils), motility, and glycoconjugates that function as receptor mimics (Eckmann, 2006). These are supplemented at birth by the transient ability of the enterocytes of neonates to absorb intact and transfer the antibodies present in colostrum to the systemic circuit of newborns (transcytosis), conferring passive immunity. This is dependent on the expression of a receptor (Fc) on the apical membrane of that binds the IgG in breast milk (Van de Perre, 2003). The adaptive component of the GI defenses includes the organized lymphoid tissues (e.g., Peyer=s patches, mesenteric lymph nodes) that are associated with the GIT and include the B and T classes of lymphocytes and the antigen presenting dendritic cells (Rumbo and Schiffrin, 2005). A key difference between the adaptive components of the GI and systemic immune systems, despite sharing similar cell types, is the development of oral tolerance whereby the GI immune system >learns= to discriminate between bacteria and antigens that pose little or no risk and those that are dangerous (Magalhaes et al 2007). The learning process has occurred during the co-evolution of hosts with their GI bacteria, resulting in receptors and associated signaling pathways and innate defense mechanisms that can discriminate between the good, the bad, and the ugly. At birth the cellular and tissue elements of the adaptive component are less abundant
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and immature compared with the adult, with maturation and learning occurring after birth (Mshvidadze and Neu 2010; Rumbo and Schiffrin, 2005). The even more immature status of the GI defenses of preterm infants with increased and less regulated NF-B signaling contributes to the hyperresponsiveness of the GIT, the increased risk of GI inflammatory disorders, such as NEC, and the increased incidence of sepsis (Claud 2009). Osmoregulation. The osmoregulatory challenges facing the GI tract differ markedly between fetuses dependent on placental exchange of water and electrolytes and neonates dependent on processing of milk to obtain electrolytes and water. Chloride channels exist in the fetal GI epithelium (Murray et al., 1996), but colonic expression of the sodium channel ENaC and absorption of sodium are underdeveloped or are suppressed in fetuses (Watanabe et al., 1998). This may contribute to the osmoregulatory problems, including sodium imbalances, and the special nutritional needs of premature infants. Postnatally, the osmoregulatory functions of the GIT respond to inflammatory cytokines by a combination of decreased ion absorption and increased chloride secretion. The resulting diarrhea and the loss of electrolytes and water are the major cause of morbidity and mortality among newborn animals and infants. Endocrine secretion. Collectively, the regions of the GI tract and the associated organs (e.g., pancreas) represent the largest endocrine system in the vertebrate body. Furthermore, a linkage exists between the GI endocrine and immune function, leading to the concept of the GI immuno-endocrine axis. Specifically, enteroendocrine cells express TLR=s and respond to lumenal antigens by the production of cytokines and defensins (Selleri et al., 2008; Palazzo et al., 2007), as well as respond to cytokines and other regulatory molecules originating from GI immune cells. Hence, GI immune responses to colonizing bacteria can alter endocrine secretions by the neonatal GI tract, thereby having GI and systemic implications.
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The vast diversity of secreted peptides is critical for regulating GI (e.g., gastrin, secretin, cholecystokin) and systemic functions (e.g., insulin, glucagon, ghrelin). Despite reports of prenatal development of GI endocrine cells (Alumets et al., 1983) and expression of receptors for epidermal growth factor (Chailler and Mnard, 1999), glucagon-like peptide 2 (Burrin et al., 2003), and cholecystokinin (Bourassa et al., 1999), there is only a fragmentary understanding of ontogenetic development of the GI endocrine functions. Detoxification. The GIT plays a role in the detoxification and elimination of ingested toxins, including drugs and metabolic wastes from the host and the resident bacteria (Buddington, 2009). This is accomplished by a combination of enzymes that convert and detoxify noxious molecules and export transporters that eliminate the resulting xenobiotic compounds. Although xenobiotic converting enzymes are expressed in the liver during late gestation, ontogenetic patterns of development for the numerous enzymes and transporters responsible for the detoxification functions of the GIT are not well characterized (Myllynen et al., 2009).
THE ASSEMBLAGES OF BACTERIA IN THE GIT The adult GIT is estimated to harbor 400 to 500 species of bacteria, with some estimates of >800 species and > 7,000 strains (OKeefe, 2008). The majority of the GI bacteria have yet to be cultured, and although molecular based approaches of detection have increased our understanding of the bacterial diversity, these methods have provided few insights into the functional characteristics of the bacteria and their influences on host health (Flint et al 2007). The GI microbiota also includes fungi, protozoa, yeasts, viruses and bacteriophages (Mackie et al., 1999) that influence host health and nutrition. Of critical interest are the interactions that develop between the microbiome and the GIT of infants (Mshvildadze and Neu, 2010).
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Regional distribution The GIT can be considered as a small ecosystem (Buddington and Weiher, 1999), with multiple habitats (regions). Within each region there are dynamic interactions among the resident bacteria, dietary inputs, and the structure and functions of the region that determine the physical, chemical, and biotic characteristics (Kelly et al., 2005). The interactions are even more pronounced during the postnatal period when the combination of dietary inputs, the developing GI functions, and inter-bacterial interactions play central roles in determining the densities, diversities, and distributions of species that become established within the different regions of the GIT ecosystem. The acidic stomach of adult monogastric mammals harbors a lower density (<104 cfu/g) and diversity of bacterial species compared to the small intestine and colon, despite the high input of nutrients. Bacterial densities and diversity are similarly low in the acid secreting portion of the ruminant stomach (abomasum), despite the complex and numerically abundant assemblages of bacteria present in the preceding rumen (Nelson et al 2003). The densities and diversity of bacteria increase distally along the small intestine, with the highest densities (1011 to 1012 cfu/g) and diversities in the colon. The declining gradient for oxygen from the proximal small intestine to the colon is paralleled by a reciprocal decline in the aerotolerant and an increase in the anaerobic species of bacteria. Additional environmental factors that contribute to the proximal-to-distal gradients along the small intestine and colon for the densities and diversities of species include more rapid movement of the digesta proximally and the introduction into the duodenum of bile acids from the gall bladder and antibacterial peptides secreted by the pancreas and the intestine itself (e.g., defensins from Paneth cells). Even within the colon there is a proximal to distal distribution of species and metabolic
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activities. The proportion of saccharolytic bacteria and SCFA production are higher in the proximal colon, whereas proteolytic bacteria and the production of putrefactive metabolites are more prevalent in the distal colon (Macfarlane and Macfarlane, 2003). This distribution corresponds with the greater distal production of ammonia, phenols, indoles, amines, and other toxic and carcinogenic metabolites, which in adults contributes to a higher incidence of colorectal cancer in the distal colon. Vertical gradients that extend from the epithelium into the lumen also exist for the distribution of species in the GIT (Kleesen and Blaut, 2005). The populations of bacteria adherent to or immediately adjacent to the epithelium have a profound impact on the GIT and the host, yet they are less understood. Colonization of the neonatal GIT The sterile GIT of fetuses is rapidly colonized and within 12 h after delivery bacteria can be detected throughout the entire GIT and at densities (i.e., cfu/g) that are comparable to those of adults (Mackie et al., 1999). The similar fecal densities of bacteria enumerated in the colons of infants and adults may reflect a maximum density of bacteria that can be supported by the GIT (i.e., carrying capacity). Colonization is a stochastic process and results in individual variation in GI bacterial assemblages. This is true even among littermates (Tannock et al., 1990), monozygotic twins (Stewart et al 2005), and even among identical twins (Dicksved et al., 2008). Infants delivered vaginally are colonized by bacteria originating from the maternal GIT, vagina, skin, and the surrounding environment (Huurre et al., 2008; Mackie et al 1999). Infants delivered by caesarian section are not immediately exposed to maternal fecal and vaginal bacteria. Instead, the initial colonizers are nosocomial, originating from medical staff and the hospital
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environments. Additional bacteria are eventually acquired from the mother (skin, mammary glands) and from outside the hospital environment. Corresponding with the different sources and timing of colonization, the assemblages of GI bacteria differ between infants born vaginally and by caesarian section. The influence of delivery mode on the assemblages is still apparent up to 7 years after birth (Salminen et al., 2004). Other non-diet factors considered to influence the GI assemblages that colonize and become established are gestational age at delivery, diet, antibiotic use, and the external environment (Penders et al., 2006). Infants with assemblages considered to be beneficial with fewer pathogens are typically delivered vaginally, outside of hospitals, and are exclusively fed breast milk. Which bacteria persist in the GIT is less random, providing supporting evidence for species specific host-bacteria relations. Notable are the different species of Helicobacter that have been isolated from different vertebrates (Schrenzel et al., 2010). Hence, not all species of bacteria entering the GIT, including probiotic species, are able to persist Ecological principles and the GI bacteria After the initial period of colonization, inter-bacterial interactions contribute to the changes in species composition and metabolic activities of the resident bacteria (Flint et al., 2007; Mackie et al., 1999). This includes the competitive exclusion of pathogens, probiotics, and other bacteria by commensal bacteria. The mechanisms of exclusion include competition for nutrients and binding sites and the production of metabolites that are toxic to other groups. The process of facilitation, which can be described as cooperative relationships among organisms, leads to further changes in the GI environment resulting in assemblages with different dominant species. In the GIT, the aerotolerant species that initially dominate reduce oxygen tension and thereby favor the emergence of anaerobic groups. Another example of inter-bacterial
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interactions is Ametabolic cross-feeding@ whereby one group of bacteria produces metabolites that are used by other groups (Flint et al., 2007). This includes the conversion of lactate produced by bifidobacteria into butyrate and other SCFA by other anaerobic members of the GI bacteria. Recent studies have described quorum sensing among the GI bacteria, triggering adaptive changes in the characteristics of individual bacterial species (Allan and Torres, 2008), and perhaps host cells (Sperandio et al., 2003). The gradual changes in the species composition and distributions of the resident bacteria that occur with increasing age are representative of the ecological principle of succession. Eventually the changes culminate in a Aclimax community@ of species. The composition and productivity of the resident species are also influenced by the stability and extremes of the local environment (Buddington and Weiher, 1999). Environments that are harsh (e.g., stomach) or subject to frequent and large disturbances (e.g., proximal small intestine) have lower densities and diversities of species. Ecosystems with the highest densities and diversities of species are characterized by benign conditions and with intermittent disturbances of intermediate magnitude that are sufficient to prevent one or a few species from becoming dominant. In the GIT, the proximal colon provides such an environment and correspondingly has the greatest densities, diversities, and species evenness of bacteria. Among infants the greatest disturbances to the GI ecosystem are caused by diarrhea and the administration of antibiotics. Both cause dramatic declines in the densities and diversities of the resident, with a shift in the dominant species (Tanaka et al., 2009). This has the potential to influence GI development (Mshvildadze and Neu, 2010) and actually increase the risk of NEC (Cotten et al., 2009). Importantly, the disturbances caused by even short term antibiotic administration may persist for at least 2 years (Jernberg et al., 2010).
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DIETARY INPUTS DURING POSTNATAL DEVELOPMENT There is growing appreciation of the influences of diet on the ontogeny of the GIT and the assemblages of bacteria that colonize and become established (Newburg and Walker, 2006). Neonatal mammals are dependent on breast milk to varying degrees, ranging from the extreme dependency of altricial species, such as marsupials and many laboratory rodents, to the very short periods of suckling for precocial species, such as guinea pigs that begin to eat the adult diet shortly after birth. Milk composition varies widely among species (Jenness and Sloan, 1970). Notable is the absence of lactose in the milk of pinnepeds, the high concentration of oligosaccharides in human milk (Newburg, 2009), and the wide species variation in protein, carbohydrate, and fat content. Milk composition is also not consistent during lactation. The first milk produced after birth, colostrum, has higher protein content due to the increased levels of immunoglobulins and a diversity of regulatory proteins. Within days after birth composition begins to shift from colostrum to mature milk, with the composition typical of the species. Apparently, milk composition has been refined over evolutionary time to match the unique species, age, and individual demands of infants. Manufacturers of formulas for human infants and milk replacers for companion and production animals attempt to mimic the composition of the target species milk. Present formulas are relatively simple, with far fewer components than breast milk. There are intense efforts to identify ingredients that can be added to formulas and milk replacers and will promote patterns of GI development and establishment of commensal assemblages of bacteria that are similar to those when infants are fed breast milk and sucklings of other species are allowed to nurse the dam. For most species and individuals weaning is a gradual process with a progressive decline
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in milk consumption and an increased dependency on the adult diet to provide energy and nutrients. During this period, GI functions and the resident assemblages of bacteria gradually become adult-like. When weaning is sudden or early, diarrhea often results and is accompanied by changes in the species composition and metabolic activities of the GI bacteria (Lalls et al., 2007). Influences of diet on GI development The rapid postnatal growth and maturation of the GIT are dependent on dietary inputs and are delayed when neonates are provided TPN rather than fed enterally. The importance of lumenal nutrients for development of the neonatal GIT has led to the concept of minimal enteral nutrition (Atrophic feeding@) whereby small amounts of oral nutrients are provided during TPN to encourage GI growth and maturation and reduce the risk of bacterial translocation and sepsis (Bombell et al., 2009). The composition of the food fed to neonates is a determinant of GI growth, maturation, and health. Colostrum includes immunoglobulins that provide passive immunity to the neonate and numerous hormones, cytokines, and other regulatory molecules that stimulate GI growth and maturation, including immune functions (Hanson, 2007). Even just coating the mouth of preterm neonates with colostrum may be adequate to stimulate development of GI and systemic immune functions (Rodriquez et al., 2010). The change in diet composition at weaning triggers changes in enterocyte cytokinetics and patterns of gene expression, coinciding with changes in absorptive and secretory functions (Drozdowski et al., 2010). The secretory characteristics of GI accessory organs, including the pancreas, are also responsive to the diet change at weaning.
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Influence of diet on the developing assemblages of bacteria The inputs into ecosystems are key determinants of the abundances, diversity, and production of the resident organisms. Similarly, the assemblages of GI bacteria are responsive to dietary and host inputs (Koenig et al., 2010; Buddington and Weiher, 1999). This is evident from the disturbance to the assemblages of GI bacteria induced by prolonged administration of TPN (Alverdy et al 2005), causing increases in pathogens and risks of secondary diseases (Harvey et al 2006). It is not surprising that the amount and composition of the diet fed to infants influence the postnatal changes in the GI bacteria. By doing so, diet indirectly influences postnatal GIT development and disease resistance (Amarri et al 2006). A central question surrounding neonatal health and nutrition is Ahow does breast milk adventitiously influence the developing assemblage of bacteria?@ The majority of studies report infants fed breast milk have a lower incidence of disease. This corresponds with higher fecal densities of lactic acid producing bacteria (e.g., bifidobacteria and lactobacilli) compared with infants receiving formula (Penders et al., 2006). Breast milk also reduces the densities of bacteria adherent to the mucosa and this may contribute to the reduced risk of NEC (Van Haver et al., 2009). Interestingly, providing infants with only a small volume of formula can elicit dramatic changes in the GI bacteria (Mackie et al., 1999). The different patterns of microbial gene expression among piglets fed by the sow or given milk replacer (Poroyko et al., 2010) raises an intriguing possibility that milk has evolved attributes that favor the establishment and dominance of commensal bacteria that provide health and nutritional benefits and remove undesired species. The discovery of immune modulation and health benefits of nucleotides (Yu, 2002), which include beneficially modulating the GI bacteria (Singhal et al., 2008), led to the inclusion of nucleotides in infant formulas. Other components of milk reported to provide more
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than energy and nutrients to infants and can modify the resident bacteria include IgA, human milk oligosaccharides (HMO), lactose, lysozyme, and lactoferrin (Newburg, 2009). A portion of the lactose in milk is not hydrolyzed during transit of the small intestine and is metabolized by colonic bacteria, causing an increase in breath hydrogen. This is particularly true among preterm infants (Kien et al., 1998), and exemplifies how diet influences bacterial metabolism (Gonzlez et al., 2008). Although lactose fermentation has been interpreted as lactase insufficiency, it may contribute to shifting the lumenal environment to be more conducive to commensals. The multi-functional and diverse HMO are the third most abundant component of human milk , with species and individual differences in the amounts, types, and proportions (Newburg, 2009). The majority of HMO are not digested during transit of the GIT and are considered to encourage the establishment of commensal, health promoting bacteria by a combination of prebiotic properties, serving as receptor mimics for pathogens, and by modulating mucosal immune functions (Newburg, 2009; Eiwegger et al., 2010). The protein lactoferrin, though abundant in human, but not cow milk, (Coppa et al., 2006), is absent in present infant formulas. Lactoferrin is considered to be immunomodulatory (Suzuki et al., 2005), has the potential to influence the assemblages of bacteria by being bifidogenic (Coppa et al., 2006), and may reduce sepsis among preterm infants (Venkatesh and Abrams, 2010). Collectively, the components of milk highlight a co-evolution between milk composition, the developing GIT, and the resident bacteria. Combined, they effectively enhance the ability of the neonate to cultivate a garden of health-promoting bacteria. There is also interest in novel ingredients that are not milk based, but may beneficially influence the species composition of the GI bacteria when fed to infants [e.g., prebiotics and probiotics (Sherman et al., 2009)].
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The historical emphasis has been on formula ingredients that improve the species composition of the GI microbiota. Less considered, but of critical importance, is the influence of diet on bacterial enzymes (Grnlund et al., 1999), hence metabolism. Bacterial metabolism and the production of short chain fatty acids (SCFA) and other metabolites is related to the types and amounts of substrates (Macfarlane and Macfarlane, 2003), such as the responses of the GI bacteria to lactose (Makivvokko et al., 2006). Although total concentrations of fecal SCFA are similar for preterm infants fed expressed breast milk or a commercial infant formula(P>0.9), those fed breast milk have higher concentrations of propionate, but relatively less acetate (Ps<0.05 unpublished data of RKB). Interestingly, the SCFA profiles of the preterm infants fed expressed breast milkare similar to those we have measured for healthy adults.
INTERACTIONS BETWEEN THE BACTERIA AND THE INTESTINE The interactions between the resident bacteria and the host GIT involve two-way communication. This results in gene expression being modulated in the bacteria and the host (Allen and Torres, 2008; Sharma et al., 2010). Moreover, by modulating the expression of host genes the resident bacteria modify the GI environment, which in turn alters the interactions and balances among the GI bacteria (Mahowald et al., 2009). The complex interactions result in GIT ecosystems that are unique for species, individuals, life history stages, and health states (Dunne 2001), and can have long-term immune and health implications (Conroy et al., 2009). The interactions between the host and the GI bacteria occur over three time scales. There are rapid and reversible interactions that span minutes to hours, others interactions that occur during the life history of individuals, and there are those that occur over evolutionary time scales. There is ample evidence for the co-evolution of the host GIT and the resident bacteria (Ley et al., 2008). This results in commensal and symbiotic relationships that are species specific and
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involve genetic adaptations of the bacteria to the host GIT (Schell et al., 2002). The cooperative responses of the GI immune system to the different bacteria have established mutualisms (Slack et al., 2009). The interactions that occur during an individuals life influence the characteristics of the host and the assemblages of bacteria (densities, diversity, evenness, regional distribution, and functional attributes). These interactions are particularly relevant to neonates and have been the subject of numerous studies and reviews. Specifically, the early responses of the GIT and the resident bacteria can have lifelong health consequences through epigenetic mechanisms. These include the ability of some bacteria to alter the patterns of host gene expression, such as patterns of glycosylation for extracellular proteins (Freitas et al., 2002) in ways that benefit both the commensal bacteria and the host (Bry et al 1996). Another relevant example is the relationship between early antigen exposure and risk of allergy and asthma later in life; the hygiene hypothesis (Schreiner et al., 2008). Less understood are the rapid and reversible interactions during infancy between the GIT and the bacteria. These transient interactions occur over periods of minutes to hours and allow the GIT and the resident bacteria to adapt to changing conditions, such as those that occur during and between meals of varying size and composition. The interactions between the bacteria and the GIT can be direct, via cell-to-cell contacts. Typically, the adverse influences of pathogenic bacteria require direct contact with epithelial cells and are mediated by surface molecules (Zoumpopoulou et al., 2009). Exemplary is how attachment of pathogenic E. coli, Salmonella, Clostridia, and other pathogens is required to trigger the expression of virulence genes, such as those coding for toxins, invasive mechanisms, or Type III secretion systems that alter the characteristics or cause the death of the attached
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enterocytes. Members of the commensal bacteria and some probiotic strains are considered to inhibit pathogen adherence and pathogenesis by occupying sites of attachment and by inducing enterocyte expression of the mucin encoding gene MUC2 and other defense genes that inhibit attachment (Kim et al., 2008) by the production of immunomodulatory molecules (Mazmanian et al., 2005). The influences of the bacteria can also be indirect and mediated by metabolites that alter host gene expression, beneficially or adversely. Some species of Bifidobacteria release soluble factors that decrease epithelial cell secretion of inflammatory cytokines (Heuvelin et al., 2009) and chloride (Heuvelin et al., 2010). SCFA produced by bacterial fermentation of undigested feedstuffs provide up to 10% of the total metabolic energy requirement of humans and even higher percentages among animals with larger hindguts or rumens (Rechkemmer et al 1988). Corresponding with this, gnotobiotic rodents require 30% more dietary energy and vitamin supplements compared with conventional rodents harboring commensal bacteria capable of fermenting undigested feedstuffs. SCFA influence colon health (Wong et al., 2006), alter patterns of epithelial cell gene expression (Sanderson, 2004; Vanhoutuin et al., 2009), and stimulate secretion of regulatory peptides that enhance growth and functions of the proximal small intestine (Bartholme et al., 2004). The responses to butyrate are more pronounced than to acetate and propionate (Basson et al., 2000). However, excessive production of SCFA, including butyrate, has been associated with damage to the GI epithelium and may contribute to NEC (Lin et al., 2005). Often overlooked is the competition between the GIT and the resident bacteria for nutrients. Maintaining lower densities of bacteria in the proximal small intestine by peristalsis and antibacterial secretions from the pancreas and intestine provides the GIT with the first access
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to readily available, digestible nutrients. Food not available to the host can and will be metabolized by the bacteria. The resident bacteria influence the developing GIT There are profound differences between germ-free and conventional rodents with respect to villus architecture, and enterocyte patterns of proliferation, differentiation, and gene expression (Zocco et al., 2007) and mucosal immune responses (Williams et al., 2006; Hrncir et al., 2008). Bacteria isolated from the GITs of neonates are reported to enhance maturation of the GIT by modulating gene expression (Are et al., 2008). This includes the age-related shifts in the activities of the fucosyl- and sialyltransferases responsible for the weaning related changes in the glycosylation of enterocyte glycoproteins (Nanthakamur et al., 2005). Even patterns of intestinal motility are responsive to the resident bacteria (Lesniewska et al 2006). The interactions between the colonizing bacteria and the developing GI immune functions have immediate and long-term consequences on host health (Dimmitt et al., 2010; Mshvildadze and Neu, 2010). The combination of colonizing bacteria, food, and environmental antigens activate the immature GI immune system of the neonate by triggering the rapid maturation, proliferation, and migration of the cellular components of the adaptive immune division. The interactions during infancy are critical for development of tolerance and the risk of allergies to food and other environmental antigens later in life (Kukkonen et al. 2008) and are a key factor in the risk of atopic disorders (Penders et al., 2007). The interactions between the bacteria and GI epithelial cells also influence innate immune functions, such as the secretion of mucous and antimicrobial peptides. Additional immunologic challenges at weaning caused by the concurrent shifts in diet and the GI bacteria trigger further changes in GI defense functions. Different species of colonizing bacteria have varying influences on the expression of pro-
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inflammatory genes (Zeuthen et al., 2010), the balance between Th1 (antibody mediated) and Th2 (cell mediated) immune responses (Ogra, 2010), including immunoglobulin production (Huurre et al., 2008), the patterns of expression for the TLR and NOD that are critical for antigen discrimination (Lundin et al 2008), and development of tolerance to endotoxins (Lotz et al., 2006). These findings have stimulated interest in providing probiotics to infants to adventitiously modulate the developing immune responses. Conversely, changes in the GI bacteria caused by administration of antibiotics during suckling increases the densities and responses of mast cells, apparently predisposing to development of allergies (Nutten et al., 2007) and potentially altering GI immune development (Schumann et al., 2005). There is much less known about if and how the assemblages of bacteria influence the postnatal development of other GI functions. Despite the impact of pathogen-induced diarrheas on neonates, the short and long-term responses of the osmoregulatory functions to the colonizing bacteria have not been described. There is evidence that enteroendocrine cells can directly respond to resident bacteria by the secretion of hormones (Palazzo et al 2007). The hyperactive immune responses of the neonate, if stimulated, can be expected to influence the other GI functions. For example, inflammatory cytokines secreted in response to pathogenic bacteria are likely to reduce digestive secretions and nutrient absorption and increase the secretion of electrolytes and water. The developing GIT influences the resident bacteria The GIT functions are key determinants of the chemical characteristics of the lumenal environment. Digestive secretions present barriers to the introduction of species, even probiotics as well as pathogens. Therefore, the changes in the physicochemcial environment of the developing GIT (Sanderson, 1999) and the developing innate and adaptive components of the GI
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immune system have the potential to influence the developing assemblages of bacteria (Salzmann et al., 2010). The immature gastric acid production of neonates (Grahnquist et al., 2000) coincides with higher densities of bacteria in the stomach until acid production increases. Postnatal changes in patterns of enterocyte glycosylation of apical membrane glycoproteins (Nanthakumar et al., 2005) influence bacterial metabolism and may represent a co-evolved symbiosis between the host and the commensal GI bacteria.
NECROTIZING ENTEROCOLITIS: WHEN THE INTERACTIONS GO AWRY The interactions among the resident bacteria, the developing GIT, and diet are of key importance for the adaptation of neonates to postnatal life (Mshvildadze and Neu, 2010). They are even more important following preterm birth because of the immature state of GI development, the intolerance of many preterm infants to feeding, and the adverse reactions they have to colonizing bacteria. Necrotizing enterocolitis is an inflammatory reaction that is the most common GIT disorder of neonates, and particularly those born premature, with the incidence varying from 1 to 8% among neonatal intensive care units (Koloske, 2008). The NEC disease process is multifactorial, with prematurity, bacterial colonization of the GIT, and feeding recognized as the key contributors. Necrotizing enterocolitis has also been associated with altered GI bacterial assemblages (Hllstrm et al., 2004), an immature epithelial barrier and immune defenses, and fetal enterocytes that are hyper-responsive (Claud, 2009). This has led to the routine prophylactic administration of antibiotics to preterm, low birth weight infants. Unfortunately, this may actually predispose preterm infants to NEC (Cotten et al, 2009) by destabilizing the assemblages of GI bacteria. Additionally, the majority of preterm infants are delivered by caesarian section, which may compromise the normal postnatal spontaneous activation of intestinal epithelial cells (Lotz et al., 2006) and the already impaired recognition of
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lipopolysaccharide (LPS) characteristic of preterm birth (Wolfs et al., 2010). Another issue facing preterm infants is the initial dependence many have on parenteral nutrition, which delays GI growth and maturation (Hay, 2008). As a consequence, development of the GI ecosystem is often compromised among preterm infants (Mshvildadze et al., 2008). The absence of NEC among germ-free animals demonstrates the essential role of the resident bacteria in the disease process. Moreover, the risk of NEC is elevated when formula is fed, whereas infants fed breast milk are protected. This has been corroborated in studies with animal models (newborn mice and rats) that indicate diet is a determinant of NEC risk via effects both on microbiota composition and the hosts response pathways (Sodhi et al., 2008). Because newborn laboratory rodents have limited physiological, anatomical and developmental relevance to preterm humans, we recently developed a preterm pig model of NEC to better understand the diet-microbiota interactions during early GI development in humans (Sangild et al., 2006). Our studies confirmed that caesarean section and vaginal birth of preterm pigs (at 92% of gestation) resulted in widely different patterns of GI bacterial colonization, yet resulted in similar incidences of NEC (Siggers et al., 2010). When preterm, caesarean-delivered pigs are reared in infant incubators and fed an infant formula, 50% or more spontaneously develop NEC symptoms and the characteristic lesions. The incidence of NEC is about 5% when preterm pigs are instead fed sow or cow colostrum (Bjrnvad et al., 2008). This parallels the benefits of providing colostrum to preterm human infants. The protection provided by colostrum versus the increased risk associated with formula indicates dietary inputs play a central role in NEC. If and how diet influences bacterial colonization of the GIT and the role in NEC has been investigated in the pig model in several studies (reviewed by Siggers et al., 2010). Overall, there were few diet-dependent differences in
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gut colonization, except that certain pathogenic species (e.g. Clostridium perfringens) were consistently associated with intestinal lesions associated with NEC. Moreover, the patterns of bacterial colonization correlated more closely with the degree of intestinal lesions and gestational age at birth (maturity of the epithelium) than with specific diets (colostrum vs. formula). Reviews of clinical trials with human preterm infants that evaluated the efficacy of probiotics as a prophylactic for NEC suggests NEC risk is reduced (Alfaleh et al,, 2010). However, the use of different strains of probiotics and administration regimes confounds interpretations. The administration of probiotics to preterm pigs did not induce notable changes in the GI bacteria, nor did it consistently reduce the incidence of NEC (Siggers et al., 2010). Although the potential benefits of including prebiotics in formula fed to preterm infants have not been adequately investigated and remain uncertain (Sherman et al., 2009), studies with animal models suggest adding prebiotics may reduce the risk of NEC (Butel et al 2002). However, the addition of prebiotic compounds to the formula fed to preterm pigs failed to improve NEC resistance relative to the formula alone (Mller et al., 2010). Collectively, these studies lead to the conclusion that the presence of bacteria is essential for intestinal inflammatory reactions in newborns. Furthermore, the state of the mucosa is an important determinant of whether the contact with the colonizing bacteria results in severe inflammation and NEC. Controlling the process of bacterial colonization in preterm newborns using diet is difficult. Even so, the species composition of the GI bacteria appears to be less important for NEC risk than the digestive capacity and immune responses of the immature GIT. The detrimental effects of feeding formula may be related to the absence of immunomodulatory factors and nutrients that are present in breast milk and the responses of the preterm GI ecosystem to novel, non-milk ingredients that are present in formula (e.g., corn syrup
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solids). Preterm pigs fed formula prepared with corn syrup solids have a higher incidence of NEC compared with when lactose is the dominant source of carbohydrate (Buddington et al., 2008). The beneficial effects of the lactose-based formula were more closely related to improved functions of the intestinal mucosa rather than to an improved gut microbiota (Thymann et al., 2009). Even though bacteria colonize the GIT immediately after delivery and are present during the period of TPN, the onset of NEC-related inflammatory reactions in the majority of preterm pigs occurs within hours after the onset of enteral feeding with formula (Oste et al., 2010). The importance of diet is again evident from the overfed, preterm rat pup as a model for NEC (Okada et al., 2010). The importance of diet for inducing NEC in animal models is similar to the development of NEC in preterm human infants after the start of enteral feeding. These findings highlight how adverse interactions between the colonizing bacteria and diet in conjunction with immaturity of the GIT are central to the NEC disease process. Despite the role of GI microbiome in contributing to disease in infants, it is very likely the metabolic functions of the GI bacteria and the responses to enteral nutrients are more important in triggering NEC. Rectal introduction of SCFA induces mucosal damage (Lin et al., 2002) and introducing a combination of lactose and lactose-fermenting bacteria that generate high concentrations of SCFA (WaligoraDupriet et al., 2009) induces mucosal damage and NEC-like characteristics in animal models. Although the etiology of NEC remains uncertain, the interactions between the GI bacteria and diet are key determinants of the sensitivity of the immature GIT to stimuli that elicit detrimental inflammatory reactions.
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PERSPECTIVES FOR DIETARY MANAGEMENT OF THE DEVELOPING GIT ECOSYSTEM The type (breast milk or formulas with novel ingredients) and amount (full, minimal, or absence) of enteral diet in conjunction with bacterial colonization play significant roles in mediating postnatal development of GI structure, functions, and the resident microbiota. Present infant formulas fail to replicate the important protective effects of breast milk, which can be attributed to the lack of bioactive constituents that modulate GI gene expression, growth and maturation of GI functions, possess antimicrobial functions and provide the neonate with passive immunity, and others with prebiotic properties that contribute to the selection and dominance of the commensal microbiota. In addition to providing adequate energy and nutrients, the optimal diet for the neonate, term or preterm, needs to include components that reduce or prevent the harmful actions of the resident GI microbiota on the neonatal mucosa. There is understandable interest in increasing the proportion of beneficial bacteria in the GIT of infants to modulate enteric immune functions and thereby improve resistance to GIT pathogens and other health challenges (Dogi et al., 2008). Three principal approaches have been used to date. Although antibiotics remain a mainstay for neonatal care, there is a growing appreciation and concern of the long-term consequences associated with the disturbances they cause in the developing GI ecosystem (Cotton et al., 2009; Jernberg et al., 2010). Probiotics are of widespread interest and there are numerous reports of efficacy. However, the benefits are generally transient and do not persist after the probiotic is no longer administered. It has proven possible to provide probiotic bacteria during pregnancy to facilitate colonization of infants born vaginally (Buddington et al., 2010). However, the numerous strains available, the varying responses that can be elicited, and likely individual
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specific responses complicate the selection of strains that provide benefits. The emergence of prebiotics as ingredients in infant formulas mimics the presence of oligosaccharides in breast milk and has shown promise for encouraging the growth of beneficial bacteria already resident in and presumably adapted to the host GIT (Veereman, 2007), thereby providing health benefits (Arslanoglu et al., 2008). Animal models will remain important for investigating development of the GI ecosystem human infants, agricultural species, and companion animals and for evaluating the influences of bacteria and diet. The variation in the GI microbiota among species, individuals, ages, and health states will complicate extrapolating results from one species to another. It is not surprising responses to probiotics and prebiotics vary among species and even individuals (Sullivan and Nord, 2005). A better understanding of how diet influences host-microbiome interactions during the neonatal period will greatly enhance efforts to improve management of the GIT ecosystem and thereby the health and nutrition of newborns.
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