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Clinical Gastroenterology and Hepatology 2019;17:231–242 Influence of Early Life, Diet, and the Environment on the Microbiome ,‡ ,‡,§ Tien S. Dong* and Arpana Gupta* *Vatche and Tamar Manoukin Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California; ‡David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and §G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, California Advances in sequencing technology and bioinformatics disease models, such as obesity and irritable bowel syn- have greatly enhanced our ability to understand the hu- drome (IBS), are discussed to highlight how environ- man microbiome. Over the last decade, a growing body mental perturbations in the human microbiome of literature has linked nutrition and the environment to contribute to disease. the microbiome and is now thought to be an important contributor to overall health. This paper reviews the Environmental Factors literature from the past 10 years to highlight the influence of environmental factors such as diet, early life adversity and stress in shaping and modifying our microbiome to- The environment plays a critical part in the compo- wards health and disease. The review shows that many sition of the human microbiome (Figure 1). A total of factors such as the mode of delivery, breast milk, stress, 22%–36% of the interperson microbiome variability is diet and medications can greatly influence the develop- associated with environmental factors and only 1.9%– mentofourgutmicrobiomeandpotentially make us more 9%bygenetics.2 Environmental factors start in the early prone to certain diseases. By incorporating environmental days of life and extend well into adulthood. Next we factors into models that study the microbiome in the highlight how environmental factors, such as the mode of setting of health and disease, may provide a better un- derstanding of disease and potentially new areas of treat- delivery, breastfeeding, and introductions of foods, are ment. To highlight this, we will additionally explore the critical steps in the development of a mature adult role of the environment and the microbiome in the devel- microbiome. We later show how such environmental opment of obesity and functional bowel disorders. factors as diet, smoking, home life, and stress can induce shifts in the microbiome during the lifespan and make Keywords: Gut Microbiome; Environment; Early Life Diet; humans more prone to certain diseases. Stress; Obesity; Irritable Bowel Syndrome. Early Life Events n the last decade, advances in sequencing technol- Early life events are critical to the development of the Iogyandbioinformaticshave enhanced the ability to humanmicrobiomebecausetheycanshapethesequence understand the human microbiome, and how the envi- of microbial community establishment and ultimately the ronment contributes to shifts in these complex systems final composition of the mature adult microbiome.6 This over time.1,2 The human microbiome represents a mi- section summarizes how the microbiome matures during crobial community that encompasses 10 times more cells the transition from inside the womb, which is a relatively andapproximately 100 times more genes than contained sterile environment, into the external environment after in the human body alone.3 Although the major function birth when ingestion of milk and solid food are intro- of the gut microbiome is to aid in the fermentation and duced. Microbial community differences during each key energy extraction of indigestible dietary fiber, multiple early life process are summarized in Table 1. studies have linked the microbiome to energy homeo- Prenatal. Studies have suggested that the introduc- stasis, immune function, and the development of certain tion of microbes can occur as early as during the prenatal 4 diseases. An increased understanding of the relation- period. Although certain intrauterine infections and ship between humans, their microbes, and the environ- bacteria from such groups as Burkholderia, ment can help better understand the maintenance of health and the development of disease.5 This review explores the recent literature related to the influence of Abbreviations used in this paper: C-section, cesarean section; IBS, environmental factors, such as early life events, diet, irritable bowel syndrome; SCFA, short-chain fatty acid. pathogens, social factors, and stress, on the complex Most current article host-microbe interactions and how these interactions ©2019bythe AGA Institute contribute to or are protective against disease. Example 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.08.067 232 Dong and Gupta Clinical Gastroenterology and Hepatology Vol. 17, No. 2 Figure 1. Environmental factors shape and change the microbiome over time and perturbations can lead to disease. Maternal factors: vaginal infections and gut microbiome can lead to bacterial translocation into the uterus. Postnatal factors: mode of delivery, breastfeeding versus formula feeding, introduction of solid food, and early life adversity and antibiotic exposure can shape the developing microbiome in early childhood. Environmental factors across the lifespan: long-term diet and exposure to animals can modify the microbiome throughout childhood and adulthood. Perturbations to the microbiome: medications, suchasantibiotics, proton pump inhibitors, and metformin, and a variety of different diets can make individuals more prone to disease, such as inflammatory bowel disease, IBS, and obesity. Stress can lead to changes in the microbiome that affects intestinal permeability and SCFA production. Smoking can cause microbial shifts that change inflammatory signaling and colonic mucin production, all of which can be mechanisms that lead to the development of disease. Actinomycetales, and Alphaproteobacteria are associated abundant phyla isolated from first-pass meconium were withpretermdelivery,ithasbeenshownthatavarietyof Firmicutes, Proteobacteria, and Bacteriodetes.10 All bac- other microbes may be present in the placenta, umbilical teria isolated from the umbilical cord blood of healthy cord, amniotic fluid, and meconium of normal preg- neonates belonged to the genus Enterococcus, Strepto- 7–9 11 nancy. Thematernal microbiome is likely translocated coccus, Staphylococcus,orPropionibacterium. In the into the uterus via the bloodstream, an idea supported by placenta, the genus Bifidobacterium and Lactobacillus the detection of labeled Enterococcus faecium in the were identified.8 meconium of inoculated pregnant mice.7 In a recent However, the role and function of these microbes in population-based study, researchers found the most human health or disease during the prenatal period re- mains unclear. Because of the possibility of maternal contamination, it is difficult to definitively establish the presence of a prenatal microbiome.12 Further studies are Table 1.Microbial Communities Described by Type of Early required to confirm the existence of a viable Life Environmental Factors intrauterine-resident microbiota with the use of Bacterial adequate controls (such as maternal blood or sampling Environmental factors community References at a site nearby delivery) to determine if the existence of Vaginal delivery vs [Lactobacillus 18,19 such a microbiome might affect the future development cesarean section delivery [Prevotella of the newborn. [Sneathia Delivery. Although the existence of a prenatal micro- [Bifidobacterium biome may be controversial, many agree that the first [Bacteroides major introduction of a microbial community to a YStaphylococcus newborn is through delivery.6 As the newborn is passing YPropionibacterium through the vaginal canal, it is ultimately introduced to YCorynebacterium Breastfeeding vs [Bifidobacteria 31,32 the commensal vaginal and fecal microbiome of the formula feeding [Lactobacillus mother.13 This community of microbes seems to be YClostridiales distinct from the community of nonpregnant women YProteobacteria because the vaginal microbiome changes during preg- Introduction of solid food [Lachnospiraceae 35,36 nancy.14 For example, healthy pregnant women, when [Ruminococcaceae [Bacteroidaceae compared with nonpregnant women, had lower vaginal YLactobacillaceae bacterial diversity with higher levels of Lactobacillus, YBifidobacterium Clostridiales, Bacteroidales, and Actinomycetales; these YEnterococcaceae levels were associated with gestational age.15 Beyond YEnterobacteriaceae the vaginal microbiome, there is also evidence that the community of the maternal gut also changes during the January 2019 The Environment Impacts the Microbiome 233 course of pregnancy. For example, a Finnish cohort of studies demonstrated that the direct mother-to-infant 91 healthy pregnant women demonstrated decreased transmission changes over time as different floras are bacterial diversity as evidenced by increased levels of introduced through processes, such as skin contact and high-energy-yielding fecal microbiota with increasing breastfeeding.23,24 gestational age.16 From the first to the third trimester, Breastfeeding and introduction of solid food. The the proportion of Proteobacteria, including species of the other major early life events that affect the development Enterobacteriaceae family and Streptococcus genus, and maturation of the newborn microbiome are breast- decreased, whereas the proportion of Faecalibacterium feeding and the introduction of solid food. Breast milk prausnitzii increased. These changes in the microbiome bacteria, such as Corynebacterium and Rothia, can seed were independent of prepregnancy body weight, gesta- the infant gut and influence the bacteria that follows, 25 tional diabetes, diet, and antibiotic use, suggesting that affecting the communities even through adulthood. they were caused by the changes of normal pregnancy. These early seeding events may be the mechanism by These changes in the microbiome have a beneficial role which breast milk can protect children against autoim- for the mother and neonate by protecting against certain mune diseases, such as asthma and type 1 diabetes.26 infections, such as Neisseria gonorrhea and bacterial Similar to the vaginal microbiome, it has been shown vaginosis, and also by permitting greater efficiency for that the microbiome of breast milk also varies with energy harvest to support the growth of the mother and increasing gestational age, and is related to maternal fetus.16,17 health and mode of delivery.26,27 The breast milk mi- With these specific pregnancy-related changes crobial community is dominated by Corynebacterium, effecting the vaginal and fecal microbiome of the mother, Ralstonia, Staphylococcus, Streptococcus, Serratia, Pseu- it is unsurprising that the mode of delivery also greatly domonas, Propionibacterium, Sphingomonas, and Bra- affects how the newborn microbiome develops. The dif- dyrhizobiaceae.26 In a study of 107 healthy women who ferences seen between cesarean section (C-section) and were breastfeeding their infants for the first 30 days of vaginally delivered babies are drastic. Compared with life, the gut microbiome changed in a dose-dependent vaginally born babies, those that are born by C-section manner with 27.7% of the mean bacteria being derived without membrane rupture have no vaginal microbes, from breast milk and 10.3% from areola skin.26 such as Lactobacillus, Prevotella, and Sneathia. Instead, Breast milk also contains many important prebiotic babies born by C-section are colonized with skin mi- compounds, such as human milk oligosaccharides. These crobes, such as Staphylococcus, Propionibacterium, and sugar polymers are almost exclusively metabolized by Corynebacterium.18 These babies have a delayed coloni- the gut microbiome28 and they can promote the growth zation of intestinal microbes, such as Bacteroides and of key communities including Bifidobacterium spp.29 Bifidobacterium.19 Although the exact length of time Bifidobacteria has been shown to inhibit the growth of these differences exist is unknown, microbial differences pathogenic organisms and improve barrier function in between C-section and vaginally delivered babies have the infant gut.30 In a mouse model, human milk oligo- been observed to as far out as 7 years of age.20 The saccharides were found to be protective in the develop- deficits in the human microbiome associated with ment of autoimmune disease and obesity.31,32 C-section deliveries have been implicated in certain There are clear differences in the composition of the childhood autoimmune disease, such as celiac disease, microbiome in infants who are breastfed versus those asthma, and type I diabetes.21 These studies also suggest who are formula fed. Infants who are breastfed have a that restoration of a more “normal” microbiome after higher proportion of Bifidobacterium and Lactobacillus C-section deliveries may therefore be beneficial. “Vaginal spp, whereas infants who are formula-fed have a higher seeding,” or the process by which vaginal fluids are proportion of Clostridiales and Proteobacteria.33,34 applied to a newborn child delivered by C-section, has Formula-fed infants also have lower diversity and rich- been a method used to restore the human microbiome. ness even after the first year of life as compared with Although a small pilot study of 4 babies demonstrated their breastfed counterparts.33 In a study of 30 preterm the feasibility of restoring the early microbiome of babies infants, breastfeeding was found to be protective against born by C-section,22 the long-term health consequence of gut immaturity and possibly necrotizing enterocolitis.35 such a procedure remains unknown and may even in- Several other epidemiologic studies have provided sup- crease the risk of transmittable diseases to the newborn. port for the beneficial role of breastfeeding in the Therefore, further prospective studies are needed to development of disease. Formula feeding has been determine the safety and potential benefits, if any, of associated with various inflammatory and autoimmune these methods used to restore the human microbiome. diseases.36 In contrast, breastfeeding, through its effects Even though the mode of delivery is important to onthemicrobiome,hasbeenassociatedwithaprotective microbial seeding, it may not be the only mode for ver- role against asthma, autism spectrum disorder, and type tical transmission. Recent human studies have high- 1 diabetes.26,36 lighted maternal vertical transmission from multiple One of the last major events in early life affecting mi- different sources, such as the skin, mouth, and gastro- crobial development is the introduction of solid food. intestinal track.23,24 By examining strain-level data, these Although breast milk keeps the microbiome in a state that 234 Dong and Gupta Clinical Gastroenterology and Hepatology Vol. 17, No. 2 is characterized by low diversity and Bifidobacterium Diet predominance, the introduction of solid food and the cessation of breastfeeding increases adult-associated mi- During the early stages of life, breast milk and the 37 crobes, such as Lachnospiraceae and Ruminococcaceae. introduction of solid food are critical events in the In a Danish study of 330 children between 9 and 36 development of the human microbiome. Therefore, it is months of age, Lactobacillaceae, Bifidobacteriaceae, not surprising that the introduction of diet throughout Enterococcaceae, and Enterobacteriaceae decreased, life has large effects on the human microbiome. The gut whereas Lachnospiraceae, Ruminococcaceae, and Bacter- microbiota can change within days of a new diet, but to oidaceae increased during the period when solid foods what extent these changes are permanent once the new 38 48 was being introduced. Another study of 531 children diet has terminated remains uncertain. In this section, born in 5 different countries showed similar results in- we review the current literature, focusing on popular dependentoflocation, use of antibiotics, mode of delivery, diets and how the microbiome is connected (summarized or milk feeding practices, suggesting that these changes in Table 2). were typical of the normal developing microbiome as Westerndiet. The Western diet or standard American 39 diet is a diet characterized by high fat, high sugar, high solid foods are being introduced. This transition is necessary and beneficial. It allows for a microbial com- level of red and processed meat, high levels of refined munity that is better equipped to extract energy and grains, and a lower level of fiber.48 Many studies have process a diet that is no longer dependent on milk to a linked the Western diet to inflammation, diabetes, car- diet that is higher in fiber and protein, similar to the diet diovascular risks, obesity, and metabolic syndrome.48,49 of a mature adult. Although a Western diet affects many different cell Early life adversity. Recently, researchers are discov- types, such as adipocytes, immune cells, and endocrine ering that early life adverse events can manipulate the cells, there is also a strong link that connects the dele- microbial community in significant ways. In rats, limited terious effects of a Western diet to shifts in the micro- nesting stress during postnatal days 2–10 led to a biome.48 Compared with other indigenous diets, the delayed maturation of the hypothalamic-pituitary- microbiome on a Western diet is characterized by a adrenal axis that was associated with decreased micro- significantly lower microbial diversity and species rich- bial diversity, an increase of gram-positive cocci, and a ness.50 The Western diet microbial composition is clas- reduction of fiber-degrading bacteria.40 Similar findings sically characterized by an overabundance of the phyla were demonstrated in mice and rhesus monkeys when Firmicutes and a decrease in Bacteroidetes.51 On a genus exposed to stress at an early age.41,42 Finally, in patients level, a Western diet shows a decrease in Bifidobacterium with IBS, those that had a microbiome profile distinct and Lactobacillus, whereas being high in Enterobacter.52 from healthy control subjects were more likely to have a Consequently, the Western diet has been linked to an history of early adverse events and trauma than those increase in endotoxemia, a state characterized by with a microbiome that was more similar to healthy decreasedintestinal barrier function and increased levels control subjects.43 Although these studies are predomi- of bacterial lipopolysaccharides and inflammatory nantly associations, exploring how adverse events and signaling.53,54 Furthermore, a Western diet can possibly early gut dysbiosis can cause such diseases as IBS is an lead to permanent microbiome changes that may be active research area. responsible for postdieting weight regain or the common Antibiotic use can also play a significant role during concept of yo-yo dieting, which has been linked to higher early life. The average U.S. child receives about 1–3 long-term weight gain, increased obesity-related risk antibiotic courses by the age of 2 years.44 Several studies 55 factors, and increased difficulty reducing weight. have highlighted how antibiotic exposure in children can Mediterranean diet. In contrast to a Western diet, a beassociated with an increased risk for obesity, diabetes, Mediterranean diet is considered a healthier diet. It is allergies, asthma, IBS, and inflammatory bowel dis- characterized by a beneficial fatty acid profile; higher ease.33,45 Children exposed to antibiotics have delayed intake of fiber, vegetables, and fruits; and with lower maturation of their microbiome as compared with their intake of sugar and red meat.56 A recent study demon- respective control subjects, but whether this is the exact strated that out of 153 participants, those who were mechanism by which early antibiotics predisposes chil- more adherent to a Mediterranean diet had an increased dren to disease is still unclear.33 In animal models, per- level of short-chain fatty acids (SCFA), Prevotella, and ipartum antibiotic exposure in the mother can lead to certain Firmicutes, which have all been associated with persistent gut dysbiosis in the offspring and colitis in decreased cardiovascular events.57 Additionally, they susceptible individuals.46,47 Although these studies do also showed that low adherence to the Mediterranean not provide an exact mechanistic explanation of the ef- diet led to decreases in urinary trimethylamine oxide fect of antibiotic use on microbiome development or on levels, which is associated with higher cardiovascular disease susceptibility, they do highlight that early anti- risk.57,58 Several studies have shown that consumption of biotic exposure is linked in some way to the normal foods encompassing the typical Mediterranean diet development of microbial community and to disease improved obesity, inflammation, and lipid profile and development. were associated with increases in Lactobacillus,
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