Microbes and the developing gastrointestinal tract.

During the course of mammalian evolution, there has been a close relationship between microbes residing in the gastrointestinal (GI) tract and the mammalian host. Although the host provides the microbes with a warm environment and nutrients, they, in turn, undergo various metabolic processes that aid the host. The host has developed weapons against microbes that are considered foreign, as well as mechanisms to tolerate and live synergistically with most of the microbes in the GI tract. This relationship is proving to be important not only in the neonatal period and during infancy, but it is becoming increasingly evident that microbial colonization in early life may affect the individual's health throughout life. Here we will review this relationship in terms of health and disease, with a focus on the aspects of this relationship during maturation of the host.     

Developmental microbial ecology of the neonatal gastrointestinal tract

The gastrointestinal tract of a normal fetus is sterile. During the birth process and rapidly thereafter, microbes from the mother and surrounding environment colonize the gastrointestinal tract of the infant until a dense, complex microbiota develops. The succession of microbes colonizing the intestinal tract is most marked in early development, during which the feeding mode shifts from breast-feeding to formula feeding to weaning to the introduction of solid food. Dynamic balances exist between the gastrointestinal microbiota, host physiology, and diet that directly influence the initial acquisition, developmental succession, and eventual stability of the gut ecosystem. In this review, the development of the intestinal microbiota is discussed in terms of initial acquisition and subsequent succession of bacteria in human infants. Intrinsic and extrinsic factors influencing succession and their health significance are discussed. The advantages of modern molecular ecology techniques that provide sensitive and specific, culture-independent evaluation of the gastrointestinal ecosystem are introduced and discussed briefly. Further advances in our understanding of developmental microbial ecology in the neonatal gastrointestinal tract are dependent on the application of these modern molecular techniques.     

Manipulation of the Intestinal Microbiome in Newborn Infants

The mammalian gastrointestinal tract harbors a highly diverse microbial population termed the microbiome, which plays a major role in nutrition, metabolism, protection against pathogens, and development of the immune system. It is estimated that at least 1000 different bacterial species cohabit the human intestinal tract. Herein we provide a brief review of the developing intestinal microbiome, with the understanding that its development often begins before birth and that disturbance in the microbiome during fetal life, birth, and shortly thereafter may result in adverse consequences. Postnatally, numerous environmental factors including premature delivery, mode of delivery, antibiotic usage, and diet can play an important role in how the intestinal microbiome of infants is shaped. The fact that human milk contains microbes is likely to have important ramifications. We discuss where these microbes come from and their potential role.     

Characterization of the Luminal and Mucosa-Associated Microbiome along the Gastrointestinal Tract: Results from Surgically Treated Preterm Infants and a Murine Model

Environmental factors, including nutritional habits or birth mode, are known key determinants for intestinal microbial composition. Investigations of the intestinal microbiome in different species in a multiplicity of studies during recent decades have revealed differential microbial patterns and quantities along the gastrointestinal (GI) tract. Characterization of the microbial pattern in various aspects is a prerequisite for nutritional interventions. In this 16S rRNA amplicon-based approach, we present a characterization of the mucosa-associated microbiome in comparison with the luminal community of four infants at the time of the closure of ileostomies and perform a systematic characterization of the corresponding luminal and mucosal microbiome from jejunal, ileal and colonic regions, as well as collected feces in mice. The most dominant taxa in infant-derived samples altered due to individual differences, and in the mucosa, Enterococcus, Clostridium sensu stricto 1, Veillonella, Streptococcus and Staphylococcus were the most abundant. Two less abundant taxa differed significantly between the mucosa and lumen. In murine samples, relative abundances differed significantly, mainly between the intestinal regions. Significant differences between mouse mucosa- and lumen-derived samples could be found in the observed species with a trend to lower estimated diversity in mucosa-derived samples, as well as in the relative abundance of individual taxa. In this study, we examined the difference between the mucosal and luminal bacterial colonization of the gastrointestinal tract in a small sample cohort of preterm infants. Individual differences were characterized and statistical significance was reached in two taxa (Cupriavidus, Ralstonia). The corresponding study on the different murine intestinal regions along the GI tract showed differences all over the intestinal region.     

Building a Beneficial Microbiome from Birth

The microbiota has recently been recognized as a driver of health that affects the immune, nervous, and metabolic systems. This influence is partially exerted through the metabolites produced, which may be relevant for optimal infant development and health. The gut microbiota begins developing early in life, and this initial colonization is remarkably important because it may influence long-term microbiota composition and activity. Considering that the microbiome may play a key role in health and disease, maintaining a protective microbiota could be critical in preventing dysbiosis-related diseases such as allergies, autoimmunity disorders, and metabolic syndrome. Breast milk and milk glycans in particular are thought to play a major role in shaping the early-life microbiota and promoting its development, thus affecting health. This review describes some of the effects the microbiota has on the host and discusses the role microbial metabolites play in shaping newborn health and development. We describe the gut microbiota structure and function during early life and the factors that determine its composition and hypothesize about the effects of human milk oligosaccharides and other prebiotic fibers on the neonatal microbiota.     

Microbiology and ecology are vitally important to premedical curricula

Despite the impact of the human microbiome on health, an appreciation of microbial ecology is yet to be translated into mainstream medical training and practice. The human microbiota plays a role in the development of the immune system, in the development and function of the brain, in digestion, and in host defense, and we anticipate that many more functions are yet to be discovered. We argue here that without formal exposure to microbiology and ecology—fields that explore the networks, interactions and dynamics between members of populations of microbes—vitally important links between the human microbiome and health will be overlooked. This educational shortfall has significant downstream effects on patient care and biomedical research, and we provide examples from current research highlighting the influence of the microbiome on human health. We conclude that formally incorporating microbiology and ecology into the premedical curricula is invaluable to the training of future health professionals and critical to the development of novel therapeutics and treatment practices.     

Development of the Gastrointestinal Tract in Newborns as a Challenge for an Appropriate Nutrition: A Narrative Review

The second and third trimesters of pregnancy are crucial for the anatomical and functional development of the gastrointestinal (GI) tract. If premature birth occurs, the immaturity of the digestive and absorptive processes and of GI motility represent a critical challenge to meet adequate nutritional needs, leading to poor extrauterine growth and to other critical complications. Knowledge of the main developmental stages of the processes involved in the digestion and absorption of proteins, carbohydrates, and lipids, as well as of the maturational phases underlying the development of GI motility, may aid clinicians to optimize the nutritional management of preterm infants. The immaturity of these GI systems and functions may negatively influence the patterns of gut colonization, predisposing to an abnormal microbiome. This, in turn, further contributes to alter the functional, immune, and neural development of the GI tract and, especially in preterm infants, has been associated with an increased risk of severe GI complications, such as necrotizing enterocolitis. Deeper understanding of the physiological colonization patterns in term and preterm infants may support the promotion of these patterns and the avoidance of microbial perturbations associated with the development of several diseases throughout life. This review aims to provide a global overview on the maturational features of the main GI functions and on their implications following preterm birth. We will particularly focus on the developmental differences in intestinal digestion and absorption functionality, motility, gut–brain axis interaction, and microbiomes.     

A multivariate distance‐based analytic framework for microbial interdependence association test in longitudinal study

Human microbiome is the collection of microbes living in and on the various parts of our body. The microbes living on our body in nature do not live alone. They act as integrated microbial community with massive competing and cooperating and contribute to our human health in a very important way. Most current analyses focus on examining microbial differences at a single time point, which do not adequately capture the dynamic nature of the microbiome data. With the advent of high‐throughput sequencing and analytical tools, we are able to probe the interdependent relationship among microbial species through longitudinal study. Here, we propose a multivariate distance‐based test to evaluate the association between key phenotypic variables and microbial interdependence utilizing the repeatedly measured microbiome data. Extensive simulations were performed to evaluate the validity and efficiency of the proposed method. We also demonstrate the utility of the proposed test using a well‐designed longitudinal murine experiment and a longitudinal human study. The proposed methodology has been implemented in the freely distributed open‐source R package and Python code.     

肠道微生态研究技术在代谢综合征中的应用

哺乳动物肠道内定居着数量庞大且组分复杂的微生物群,它们共同构成了肠道微生物组。近年来,人们逐渐认识到肠道微生物与一些疾病的发生和发展密切相关,如代谢性疾病、炎症性肠病、肿瘤、免疫系统以及神经系统疾病等,使得肠道微生物成为研究的热点。迅猛发展的微生物研究技术为我们提供了高效有力的技术平台,推动了对肠道微生态的系统认知,也为疾病的诊断及治疗开辟了新思路。本文旨在总结与分析目前常用微生态研究技术的最新进展及其局限性,为进一步的肠道微生物组研究提供参考,并简要介绍肠道微生态与代谢综合征的相关研究成果。     

Role of the intestinal microbiome in health and disease: from correlation to causation

Recorded observations indicating an association between intestinal microbes and health are long-standing in terms of specific diseases, but emerging high-throughput technologies that characterize microbial communities in the intestinal tract are suggesting new roles for the supposedly normal microbiome. This review considers the nature of the evidence supporting a relationship between the microbiota and the predisposition to disease as associative, correlative, or causal. Altogether, indirect or associative support currently dominates the evidence base, which now suggests that the intestinal microbiome can be linked to a growing number of over 25 diseases or syndromes. While only a handful of cause-and-effect studies have been performed, this form of evidence is increasing. The results of such studies are expected to be useful in monitoring disease development, in providing a basis for personalized treatments, and in indicating future therapeutic avenues.     

Role of nutrients in the development of neonatal immune response

Nutrients exert unique regulatory effects in the perinatal period that mold the developing immune system. The interactions of micronutrients and microbial and environmental antigens condition the post-birth maturation of the immune system, influencing reactions to allergens, fostering tolerance towards the emerging gastrointestinal flora and ingested antigens, and defining patterns of host defense against potential pathogens. The shared molecular structures that are present on microbes or certain plants, but not expressed by human cells, are recognized by neonatal innate immune receptors. Exposure to these activators in the environment through dietary intake in early life can modify the immune response to allergens and prime the adaptive immune response towards pathogens that express the corresponding molecular structures.     

中国国家出生队列母婴肠道微生物亚队列研究

肠道微生物对人类健康的重要性逐渐被人们关注。动物模型揭示了孕期母体微生物通过对子代微生物、代谢和免疫发育的作用影响了子代健康结局。然而,人体生理机制更为复杂,并受到多种暴露因素的交互影响,在动物模型中得到的研究结果往往与人群研究不一致。目前,孕期母体肠道微生物对子代微生物定植和健康的影响尚不明确。在大型前瞻性出生队列的...     

Nutritional management of gut health in pigs around weaning

Early weaning of piglets is often accompanied by a severe growth check and diarrhoea. It is well established that this process is multi-factorial and that post-weaning anorexia and undernutrition are major aetiological factors. Gastrointestinal disturbances include alterations in small intestine architecture and enzyme activities. Recent data indicate transiently-increased mucosal permeability, disturbed absorptive-secretory electrolyte balance and altered local inflammatory cytokine patterns after weaning. These responses appear to operate according to two distinct temporal patterns, an acute response followed by a long-lasting adaptation response. Pigs coexist with a diverse and dense commensal microbiota in their gastrointestinal tract. Most of these microbes are beneficial, providing necessary nutrients or protection against harmful pathogens for the host. The microbial colonisation of the porcine intestine begins at birth and follows a rapid succession during the neonatal and weaning period. Following the withdrawal of sow's milk the young piglets are highly susceptible to enteric diseases partly as a result of the altered balance between developing beneficial microbiota and the establishment of intestinal bacterial pathogens. The intestinal immune system of the newborn piglet is poorly developed at birth and undergoes a rapid period of expansion and specialisation that is not achieved before early (commercial) weaning. Here, new insights on the interactions between feed components, the commensal microbiota and the physiology and immunology of the host gastrointestinal tract are highlighted, and some novel dietary strategies are outlined that are focused on improving gut health. Prebiotics and probiotics are clear nutritional options, while convincing evidence is still lacking for other bioactive substances of vegetable origin.     

Measuring Dietary Botanical Diversity as a Proxy for Phytochemical Exposure

The study of natural plant molecules and their medicinal properties, pharmacognosy, provides a taxonomy for botanical families that represent diverse chemical groupings with potentially distinct functions in relation to human health. Yet, this reservoir of knowledge has not been systematically applied to elucidating the role of patterns of plant food consumption on gut microbial ecology and function. All chemical classes of dietary phytochemicals can affect the composition of the microbes that colonize the gut and their function. In turn, the gut microbiome affects the host via multiple mechanisms including gut barrier function, immune function, satiety and taste regulation and the activity of biological signaling pathways that influence health and disease. Herein, we report the development of a botanical diversity index (BDI) to evaluate plant food consumption as a novel metric for identifying and quantifying phytochemicals to which an individual is exposed. A rationale is advanced for using the BDI to investigate how plant food diversity impacts gut microbial ecology and functionality.     

Lactose digestion by yogurt beta-galactosidase: influence of pH and microbial cell integrity

Lactase-deficient subjects more effectively digest lactose in yogurt than lactose in other dairy products, apparently due to yogurt microbial beta-galactosidase (beta-gal) which is active in the GI tract. We evaluated the effects of buffering capacity of yogurt, gastric pH, and microbial cell disruption on beta-gal activity and lactose digestion. Three times more acid was required to acidify yogurt than to acidify milk. Yogurt beta-gal was stable at pH 4.0 but inactivated at lower pH. When yogurt was sonicated to disrupt microbial cell structure, only 20% activity remained after incubation at pH 4.0 for 60 min. In vivo gastric pH remained greater than 2.7 for 3 h after ingestion of yogurt. Acidified milk alone or with disrupted yogurt microorganisms caused twice as much lactose malabsorption as did acidified milk containing intact yogurt microorganisms. The results provide a possible explanation for the survival of beta-gal activity from yogurt in the GI tract.     

Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease

The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn’s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.     

Managing the Microbiome: How the Gut Influences Development and Disease

The microbiome lies at the forefront of scientific research, as researchers work to uncover its mysterious influence on human development and disease. This paper reviews how the microbiome is studied, how researchers can improve its study, and what clinical applications microbiome research might yield. For this review, we analyzed studies concerning the role of the microbiome in disease and early development, the common methodologies by which the microbiome is researched in the lab, and modern clinical treatments for dysbiosis and their possible future applications. We found that the gut microbiome is essential for proper development of various physiological systems and that gut dysbiosis is a clear factor in the etiology of various diseases. Furthermore, we found that germ-free animal models and microbiome manipulation techniques are inadequate, reducing the efficacy of microbiome research. Nonetheless, research continues to show the significance of microbiome manipulation in the clinical treatment of disease, having shown great promise in the prevention and treatment of dysbiosis. Though the clinical applications of microbiome manipulation are currently limited, the significance of dysbiosis in the etiology of a wide array of diseases indicates the significance of this research and highlights the need for more effective research methods concerning the microbiome.     

Recovery of Long-term Maternal Behavioral Deficiencies of Neonatally Underfed Rats by Early Sensory Stimulation: Effects of Successive Parturitions

The study examines the effects of two paradigms of neonatal food deprivation (daily mother-litter separation, Experiment 1 or nipple-ligation of mothers, Experiment 2) associated or not to early sensory stimulation (daily handling or the exposure to an enriched sensory environment) during the preweaning period of Wistar strain female rats. The effects of experimental manipulations were evaluated by measuring the nest building, retrieving latencies and nursing time of adult dams along three successive parturitions. Undernourished dams of Experiment 1, showed significant alterations in maternal responsiveness in the first delivery, which were attenuated by the maternal experience of two additional parturitions. Moreover, maternal alterations were importantly compensated by the association to early sensory stimulation (except nest building). Underfed mothers of Experiment 2 exhibited less alterations of the maternal response during the first parturition, and these were ameliorated by the maternal experience of successive parturitions. Additionally, complete recovery of maternal responsiveness alterations was obtained when sensory stimulation was associated to the maternal experience. Data suggest differential vulnerability to neonatal food and sensory deprivation of the neural mechanisms underlying maternal performance.     

The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery

Background: Breast milk is recognized as the most important postpartum element in metabolic and immunologic programming of health of neonates. The factors influencing the milk microbiome and the potential impact of microbes on infant health have not yet been uncovered. OBJECTIVE: Our objective was to identify pre- and postnatal factors that can potentially influence the bacterial communities inhabiting human milk. Design: We characterized the milk microbial community at 3 different time points by pyrosequencing and quantitative polymerase chain reaction in mothers (n = 18) who varied in BMI, weight gain, and mode of delivery. Results: We found that the human milk microbiome changes over lactation. Weisella, Leuconostoc, Staphylococcus, Streptococcus, and Lactococcus were predominant in colostrum samples, whereas in 1- and 6-mo milk samples the typical inhabitants of the oral cavity (eg, Veillonella, Leptotrichia, and Prevotella) increased significantly. Milk from obese mothers tended to contain a different and less diverse bacterial community compared with milk from normal-weight mothers. Milk samples from elective but not from nonelective mothers who underwent cesarean delivery contained a different bacterial community than did milk samples from individuals giving birth by vaginal delivery, suggesting that it is not the operation per se but rather the absence of physiological stress or hormonal signals that could influence the microbial transmission process to milk. Conclusions: Our results indicate that milk bacteria are not contaminants and suggest that the milk microbiome is influenced by several factors that significantly skew its composition. Because bacteria present in breast milk are among the very first microbes entering the human body, our data emphasize the necessity to understand the biological role that the milk microbiome could potentially play for human health.