Emerging concepts are innovative ideas or interventions which are surfacing and hold potential for eventual adoption into clinical practice. IFM has a strong history of successfully identifying and accelerating the acceptance of emerging concepts. We are pleased to bring you this monthly update, to keep you in-the-know on exciting innovations in Functional Medicine.
The microbiome has been a burgeoning area of study within the medical research community for over a decade, with the initiation of the Human Microbiome Project by the National Institutes of Health in 2007.1 But the idea that there are a variety of microbes living on and in the human body is not itself a new concept: “I then most always saw, with great wonder, that in the said matter there were many very little living animalcules, very prettily a-moving,” wrote Antonie van Leeuwenhoek (1632-1723), one of the first scientists to study the human microbiome.1
Yet it has taken some time for scientists to understand that these microbes are more than just pathogens but microorganisms that help maintain our health and well-being.1 Cataloguing them alone is an immense task; the human microbiota is a composite organism, composed of 10 trillion to 100 trillion microbial cells (bacteria, archaea, and microbial eukaryotes) and viruses.2,3
The most varied microbiome is found in the gastrointestinal tract,4 and it is believed to have far-reaching metabolic, nutritional, and immunological effects on human health.5 This fragile ecosystem continues to evolve after birth and is shaped by multiple factors, including the adaptive and innate immune system; external factors such as diet, antibiotic, and toxicant exposures; and stress and illness.5-7 Scientists are now focusing their attention on the distinct evolution of the neonatal intestinal microbiome—its evolution beginning in utero and during early infancy.5
Does the pediatric intestinal microbiome exist before birth, and if so, how is it shaped? Could the mother’s lifestyle affect her child’s microbiome? What factors influence a pediatric microbiome, and how might they lead to health or disease? These are just some of the myriad questions asked by scientists in the field, which will be explored in the sections below, along with several significant caveats.
The Pediatric Intestinal Microbiome
The intestinal microbiome may evolve with the human host over its entire lifespan—from conception to death—and, as such, it is a cause for speculation into the development of health and disease.8 Conception to the first year of life is considered to be the intestinal microbiome’s early-life “critical window”—a time when it is most vulnerable to environmental influences.2,9 Some scientists posit that early-life environmental exposures alter the development of the microbiome, and that these changes may shift the immune system toward a hypersensitive and/or hyperinflammatory state.2,9Emerging research on the pediatric microbiome suggests that changes to the composition of the intestinal microbiome, or dysbiosis, may affect the development of a variety of diseases2,20,11—including, but not limited to, asthma and atopic disease,2,11,12 irritable bowel syndrome and inflammatory bowel disease,11,12 and obesity.2,11-13 Researchers also speculate that caesarian delivery, formula feeding, and antibiotic use may alter the microbiome and promote the development of disease.10
Maternal-to-Fetal Microbial Transfer: In-Utero Hypothesis
Many scientists are investigating the validity of an in-utero hypothesis, which proposes that the fetus is exposed to microbes from the mother’s placenta, amniotic fluid, and umbilical cord.10-12,14-16
Some studies suggest the infant gut colonization process may be initiated prenatally by a distinct microbiota in the mother’s placenta and amniotic fluid,2,10,12,17,18 but other scientists are questioning whether the placenta has a distinct microbiome at all. Scientists questioning the in-utero hypothesis point out the likelihood of contamination and the lack of suitable controls to evaluate this contamination,11 as well the difficulty of proving the significance of the bacteria detected in the amniotic fluid and placenta.10,19,20 Additionally, research to date has been mostly conducted using molecular methods, which may not be appropriate for the study of low-abundance microbial communities.11
Microbial Transfer During & After Birth
Research also suggests that vaginal delivery, breastfeeding, maternal health, and nutrition may help shape a healthy pediatric microbiome.2,5,10,11 At the moment of a vaginal birth, neonates are exposed to the maternal vaginal microbiota, and the fecal microbiota of these neonates is dominated by Prevotella spp. and Lactobacillus.11 Those born via cesarean section (CS) are more likely to have a microbiome dominated by microbes derived from maternal skin, the hospital environment, or hospital staff, including Corynebacterium, Staphylococcus, and Propionibacterium spp.11,21 Differences in the microbial population for vaginal versus CS-delivered infants also exists during the first week after birth; a dominance of Actinobacteria (mainly comprising the genus Bifidobacterium) has been observed for vaginally delivered infants, while Firmicutes has been the most prevalent for CS infants.11,22
CS delivery has been associated with increased risk for immune and metabolic disorders.23 Domingues-Bello et al conducted the first study aimed at recolonizing infants delivered via CS delivery with vaginal bacteria.2,23 After swabbing CS neonates with maternal vaginal fluids within two minutes after birth, the authors reported partial restoration of the microbiota.2,23 However, the long-term health effects and composition of the infant microbiome are not yet known.
Breastfeeding may also influence the intestinal microbiota of neonates, through contact with maternal areolar and breast milk microbes.2,5,11,12,24 Differences in intestinal microbes between exclusively breastfed vs. formula-fed infants have been well documented.11 In a study of 107 mother and infant dyads, infants who were breastfed during the first 30 to 40 days of life received a mean of ~28% of their bacteria from breast milk and ~10% from maternal areolar skin.2,25 The authors also report a dose-dependent association between the infant gut microbiome composition and the proportion of daily breastfeeding.2,25
It is interesting to note that there is a compositional distinction between breastfed and formula-fed infants, with breastfed infants being populated with higher proportions of Bifidobacteria and Lactobacillus spp. and formula-fed infants being populated with a greater prevalence of Clostridiales and Proteobacteria.2 Studies also suggest that formula-fed infants also exhibit decreased diversity and bacterial richness, even after the first year of life (12-24 months of age), and decreased diversity has been associated with poorer health overall.2,26 A number of studies have reported that the stools of breastfed infants contain more Lactobacilli and Bifidobacteria and fewer potential pathogens than the stools of formula-fed infants, which contain a more diverse intestinal microbial flora dominated by Bacteroides, Clostridia, Staphylococci, enterobacteria, enterococci, and Atopobium.11,27,28
Breastfeeding may reduce both upper and lower respiratory tract infections and gastrointestinal infections in infants and reduce the development of atopic dermatitis, asthma, and even the development of obesity later in life.5,10 Early breastfeeding, within the first hour of life, compared to 2-23 hours of life, or greater than 24 hours of life, may also significantly reduce infant mortality due to neonatal infections and other complications.10 The first milk (colostrum) contains bioactive immune factors that protect a neonate against a variety of infections and allergic diseases. The microbiota associated with human breast milk contributes to creating the “initial” intestinal microbiota of infants, having also a pivotal role in modulating and influencing the newborns’ immune system.29
Other environmental factors like maternal diet,2,10 early life stressors,2 and geographical location11 may also influence the health of the infant intestinal microbiome.
Pediatric Microbial Dysbiosis
A significant early-life stressor on the pre- and postnatal microbiome is antibiotic exposure, as this has been shown to alter the diversity of the microbiota both in the mouth and in the gut.2,5,26 In the gut, specifically, postnatal antibiotic courses given to the infant in the first three to nine months of life were reported to alter abundances of Ruminococcus and Clostridiales.2,26 Antibiotic use in the first 6 to 12 months of life has also been associated with a decreased maturation of the infant microbiota.2,26 A 2017 study showed that ?-diversity, an important ecosystem characteristic, was disturbed by delivery mode, antibiotic use, and by diet, but whether ?-diversity influences disease development or is only a marker remains unknown.26 Some scientists speculate whether the intestinal ecosystem can recover from temporary disturbances,26 or if antibiotic-induced dysbiosis in infancy promotes the development of disease into adulthood.2,30,31
Epidemiologic studies to date do not address whether these diseases are causally related to early-life antibiotic use or whether they are indicative of early-life immune deficiencies or propensity for infection.2 Postnatal early-life dysbiosis in the human gut has been associated with asthma and atopic disease development in children;2,11,12 however, the majority of human studies in asthma research reveal only correlative evidence to link early-life dysbiosis.2,11 Similar to asthma and atopic disease, prospective studies illuminate early-life gut microbiome compositional variations that may precede the development of obesity.2,11-13 Other diseases that may be correlated with postnatal intestinal dysbiosis include irritable bowel syndrome and inflammatory bowel disease.11,12
Caveats & Concerns Within the Literature & in the Field
Research into the pediatric intestinal microbiome is in its early stages and continues to expand. While there is evidence that the makeup of the pediatric microbiome may have lasting consequences on health, it is important to note some caveats and concerns within the current literature—first and foremost, there is a wealth of variability among healthy microbiomes. Researchers in this field are often the first to point out that they are still largely in the dark about what makes microbiomes different from one another, let alone whether one is healthier than another.32
Challenges within the field include:
- Making sense of the data – Microbiome studies yield vast amounts of data with huge variability,33-35 and several external factors may also impact this variability.35
- Getting the right data – Many of the techniques used to characterize bacteria may not be precise enough.33
- Risk of contamination – There is a current controversy underway whereby some scientists believe the placenta has its own microbiome, which may help create the neonatal microbiome. Others believe the placenta does not have its own distinct microbiome but is contaminated by the vaginal microbiome during birth.34,36,37
- Too much hype – A search of the literature on PubMed for the term “microbiome” in the title and abstract illustrates the fast progression of microbiome science. From 2006 to 2010, there were just 304 papers that used the word microbiome in their title and/or abstract, whereas the number has increased to 11,128 in the time from 2011 to 2017.38 Hanage, writing in Nature, warned that “microbiomics risks being drowned in a tsunami of its own hype,” and called for those interpreting research to ask five crucial questions: 1) Can experiments detect differences that matter? 2) Does the study show causation or just correlation? 3) What is the mechanism? 4) How much do experiments reflect reality? 5) Could anything else explain the results?38,39
- Privacy issues and biobanks – With the increased interest in the human microbiome, it is likely that biobanks will include a collection of microbiota for genomic studies.38 Some researchers are looking at the ethical considerations of this. “This re-understanding of ourselves will have important implications on how we address and manage identity, privacy and property issues related to human microbiome, for example, how integral is the microbiome to our conception of self?” writes Ma et al in a recent commentary published in Protein & Cell. “To what extent do we own our microbiome, given that the source of some microbiome is traditionally considered as waste, e.g., feces? Who can share the benefit when someone’s microbial profile is unique and potentially has commercial value?”38
- Selecting the right type of treatment – There are multiple ways to target the microbiome.33 Just one example is the new therapeutic modality of fecal microbiota transplantation (FMT). Some researchers feel that FMT runs the risk of being perceived as a panacea for a multitude of illnesses.34 And although FMT has seen some limited success in treating Clostridium difficile infection, it may come with significant risk to the patient.
Functional Medicine Considerations
“The physician must be able to tell the antecedents, know the present, and foretell the future—must mediate these things, and have two special objects in view with regard to disease, namely, to do good or to do no harm.” – Hippocrates
Functional Medicine is patient-centered rather than disease-centered. This is a particularly important distinction when it comes to microbiome research and application, as all humans have unique microbiomes, and these communities may be shaped, in large part, by lifestyle factors. Clinicians who practice Functional Medicine seek to understand the antecedents, triggers, and mediators that underlie illness or dysfunction in each individual patient.
This approach requires a detailed examination of the patient’s timeline and facilitates the recognition of disturbances that are common in people with chronic illnesses, many of which may be traced back to the intestinal microbiome. Since a balanced symbiosis of the gut microbiota is closely associated with human health, it stands to reason that research in the field of the microbiome may be of great importance to Functional Medicine clinicians.
From a patient perspective, altering one’s diet, nutrition, and exposure to environmental toxins comes at a very low risk. Many of these methods are showing promising results in restoring a healthy microbiome. A deeper understanding of these factors and how they can be manipulated could alter the trajectory of disease, beginning as early as the preconception period. It’s an exciting time. With deepening knowledge comes the hope of new approaches to improve wellness.
Learn more about the pediatric microbiome at IFM’s GI Advanced Practice Module, October 15 – 17, 2020.
- Institute of Medicine. The Human Microbiome, Diet, and Health: Workshop Summary. National Academies Press; 2013. doi:17226/13522
- Stiemsma LT, Michels KB. The role of the microbiome in the developmental origins of health and disease. Pediatrics. 2018;141(4):e20172437. doi:1542/peds.2017-2437
- Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 2012;70(Suppl 1):S38-S44. doi:1111/j.1753-4887.2012.00493.x
- Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369-2379. doi:1056/NEJMra1600266
- Griz EC, Bhandari V. The human neonatal gut microbiome: a brief review. Front Pediatr. 2015;3:17. doi:3389/fped.2015.00017
- Berrington JE, Stewart CJ, Cummings SP, Embleton ND. The neonatal bowel microbiome in health and infection. Curr Opin Infect Dis.2014;27(3):236-243. doi:1097/QCO.0000000000000061
- Putignani L, Del Chierico F, Petrucca A, Vernocchi P, Dallapiccola B. The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood. Pediatr Res. 2014;76(1):2-10. doi:1038/pr.2014.49
- Brunham RC. The genome, microbiome and evolutionary medicine. CMAJ. 2018;190(6):E162-E166. doi:1503/cmaj.170846
- Shreiner A, Huffnagle GB, Noverr MC. The “Microflora Hypothesis” of allergic disease. Adv Exp Med Biol. 2008;635:113-134. doi:1007/978-0-387-09550-9_10
- Gaufin T, Tobin NH, Aldrovandi GM. The importance of the microbiome in pediatrics and pediatric infectious diseases. Curr Opin Pediatr. 2018;30(1):117-124. doi:1097/MOP.0000000000000576
- Zhuang L, Chen H, Zhang S, Zhuang J, Li Q, Feng Z. Intestinal microbiota in early life and its implications on childhood health. Genomics Proteomics Bioinformatics. 2019;17(1):13-25. doi:1016/j.gpb.2018.10.002
- Ihekweazu FD, Versalovic J. Development of the pediatric gut microbiome: impact on health and disease. Am J Med Sci. 2018;356(5):413-423. doi:1016/j.amjms.2018.08.005
- Dogra S, Sakwinska O, Soh SE, et al. Dynamics of infant gut microbiota are influenced by delivery mode and gestational duration and are associated with subsequent adiposity. mBio. 2015;6(1):e02419-14. doi:1128/mBio.02419-14
- Perez-Muñoz ME, Arrieta MC, Ramer-Tait AE, Walter J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome. 2017;5(1):48. doi:1186/s40168-017-0268-4
- Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014;6(237):237ra65. doi:1126/scitranslmed.3008599
- Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016;6:23129. doi:1038/srep23129
- Mshvildadze M, Neu J, Shuster J, Theriaque D, Li N, Mai V. Intestinal microbial ecology in premature infants assessed using non-culture based techniques. J Pediatr. 2010;156(1):20-25. doi:1016/j.jpeds.2009.06.063
- Younge N, McCann JR, Ballard J, et al. Fetal exposure to the maternal microbiota in humans and mice. JCI Insight. 2019;4(19):127806. doi:1172/jci.insight.127806
- Lauder AP, Roche AM, Sherrill-Mix S, et al. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota. Microbiome. 2016;4(1):29. doi:1186/s40168-016-0172-3
- Lauder AP, Roche AM, Sherrill-Mix S, et al. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota. Microbiome. 2016;4(1):29. doi:1186/s40168-016-0172-3
- Biasucci G, Rubini M, Riboni S, Morelli L, Bessi E, Retetangos C. Mode of delivery affects the bacterial community in the newborn gut. Early Hum Dev. 2010;86(Suppl 1):13-15. doi:1016/j.earlhumdev.2010.01.004
- Hill CJ, Lynch DB, Murphy K, et al. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET cohort. 2017;5(1):4. doi:10.1186/s40168-016-0213-y
- Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22(3):250-253. doi:1038/nm.4039
- Cabrera-Rubio R, Collado MC, Laitinen K, Salminen S, Isolauri E, Mira A. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr. 2012;96(3):544-551. doi:3945/ajcn.112.037382
- Pannaraj PS, Li F, Cerini C, et al. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr. 2017;171(7):647-654. doi:1001/jamapediatrics.2017.0378
- Bokulich NA, Chung J, Battaglia T, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016;8(343):343ra82. doi:1126/scitranslmed.aad7121
- Martin R, Makino H, Cetinyurek Yavuz A, et al. Early-life events, including mode of delivery and type of feeding, siblings and gender, shape the developing gut microbiota. PLoS One. 2016;11(6):e0158498. doi:1371/journal.pone.0158498
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- Ilan Y. Why targeting the microbiome is not so successful: can randomness overcome the adaptation that occurs following gut manipulation? Clin Exp Gastroenterol. 2019;12:209-217. doi:2147/CEG.S203823
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