The maternal vaginal and gut microbiome (and paternal seminal microbiome) plays an important role in fertility, pregnancy, assisted technology procedures, and preterm labor risk.  As well, the maternal vaginal microbiome inoculates and seeds the newborn starting in utero and at vaginal birth with it’s own microbiome which influences the risk of chronic diseases and mood disorders in the neonate and throughout life.  [Garcia-Velasco et al 2017] What Fertility Specialists Should Know About the Vaginal Microbiome: A Review and [Morris, 2017 Natuopathic Doctor and News and Review] THE VAGINAL MICROBIOME: ITS ROLE IN FERTILITY, PREGNANCY, & PRETERM LABOR RISK 2017] are two excellent  summary reads.

AMAZING NEWBORN GUT MICROBIOME FINDINGS

“The Human Microbiome, Diet, and Health: Workshop Summary”  book (Institute of Medicine (US) Food Forum. Washington (DC): National Academies Press (US); 2013) details much about the human newborn’s gut microbiome as does the below cited studies.

But first, spend 2:46 minutes and check out the below YouTube “The assembly of an infant gut microbiome framed against healthy human adults” for seeing microbiome maturation for vaginal delivery which is vastly different than that of C-Section delivery (from the University of Colorado Boulder, framed around the data generated by the Human Microbiome Project):

MODE OF DELIVERY RAMIFICATIONS

• • Next, recognize the prevalence of C-Section delivery: United States, C-sections have increased from 24 to 34 percent over the past 15 years; the rate of C-sections 20 yrs ago was 20 percent or 1:5; today this is 1:3.  In large cities in China, C-section delivery rates reach 60 percent.  In some South American countries (e.g. Argentina and Brazil) C-section deliveries in private hospitals approximate 100 percent.

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    Watch NPR’s 5 minute YouTube “The Invisible Universe Of The Human Microbiome” for a leap up the learning curve of C-section and antibiotic impact on the newborn microbiome.

  • C-section delivery outcomes include allergic rhinitis, asthma, celiac disease, diabetes mellitus, and gastroenteritis.
  • C-section delivery results in “abnormal” microbial seeding of the GI tract and “abnormal” development of immunity due to the lack of exposure to the vaginal microbiota.
  • The baby’s first stool microbiota closely resembles the mother’s vaginal microbiota for vaginal delivery, whereas with C-section delivery, the baby’s first stool microbiota closely resembles the mother’s skin microbiota. 
  • In addition to the differing microbial presence for C-section delivery, this presence also changes over time for C-section delivery:  Major phylum-level differences that exist at week 1 (e.g., greater Proteobacteria abundance in C-section babies versus greater Bacteroides abundance in vaginal babies) disappear by week 4, while certain genus-level differences that are not present at week 1 emerge at week 4 (e.g., relative abundance of Enterococcus).
  • In answering questions such as: Does the vaginal microbiome change once pregnant and does it change during pregnancy, this researcher found surprising results:  they could  determine whether a woman is pregnant, with a test looking at her vaginal microbiome that’s predictive 98.2 percent of the time.  “It turns out, the microbiome does change in pregnancy—especially in the posterior fornix—with species becoming less diverse and less abundant. Dr. Aagaard finds this fascinating, “Here’s an example where you don’t have a disease—you have a state of health that is absolutely essential to a species propagating, and the vaginal microbiome changes just by being pregnant…”  The clinical implications of her work are still unknown. Would it make sense, for example, to monitor the changes in the vaginal microbiome during pregnancy?  “We’ve done some of that work initially. It’s a great question, and we hope NIH will want us to answer it,” she says with a laugh.”   Dr Aagaard continues discussion on the emerging work of Dr. Michael Blaser, MD, NY University School of Medicine, author of “Missing Microbes” which suggests that human beings’ microbiomes have shifted in recent years: “Now we eat processed foods, we don’t drink as much wine, the fermentation processes that used to be very important to establishing our microbiomes have changed,” she says, which leads her to another unknown: Are important microbiotic communities disappearing as a result?“
  • Dr. Aagaard’s PLOS study found: “…robust evidence that the structure of the vaginal microbiome significantly differs in pregnancy (Figures 1 [see below] and 2), and further evidence suggesting that the pregnant microbial community is less diverse and rich (Figure 3), … with an overall predominance of the order Lactobacillales (and Lactobacillaceae family), followed by Clostridiales, Bacteroidales, and Actinomycetales.” I particularly appreciate her sentiment that this work “…lends to the growing understanding of the remarkable dynamic nature of our metagenome and its role in vertical transmission of the microbiota through subsequent generations.“
    

    

  • This study showed  that the gut microbiota changed dramatically from first to third trimesters, with vast expansion of diversity between mothers, an overall increase in Proteobacteria and Actinobacteria, and reduced richness.  These are also more common in people who are obese or have metabolic syndrome, says Ley. “Proteobacteria in particular are often the bad guys in these studies. They are associated with inflammation, and stools collected during the third trimester contained more inflammatory markers than those collected during the first trimester. What’s more, the trends held true regardless of whether women were of normal weight or overweight before falling pregnant, had actually developed diabetes, or had taken antibiotics or probiotics (supplements taken to provide or boost populations of ‘healthy’ bacteria) during pregnancy. The microbial diversity shift did not affect mothers’ health,  Meanwhile, after birth, the children’s microbiotas resembled those of the mothers’ first trimester samples.  Ley speculates that physiological changes that occur during pregnancy alter the microbial community, which, in turn, creates a positive-feedback loop sustaining conditions seen in metabolic syndrome. “The body might be using the microbes as a tool,” she says. “You alter the microbiota, and they give you the changes in metabolism that you want.”
  • I think it important that I digress for a moment and talk about the cohort used for this study (see below slide) since it interestingly included a large number of those pregnant on antacid/H2 antagonists (11 of 24) which are known to change up the small intestine pH.  These changes have ramifications to the microbiome as undigested food becomes food for differing microbiome species upstream and downstream.  Micronutrient absorption too is affected.  For example,  in this study, “the antacid was found to precipitate folic acid at a pH of greater than 4.0, thus removing it from the aqueous phase. This appears to be the explanation for the lowered folate absorption in the presence of antacid. Although the effects of these drugs on reducing folic acid absorption were relatively small, such reductions could become clinically significant in chronic antacid or H2 receptor antagonist use or intensive antacid or H2 receptor antagonist use by individuals eating diets that are marginal in folate content.”  And this cycles over to the current ubiquitous enrichment of ynthetic “folic acid” due to newborn neural-tube concerns, but recent studies indicate such may increase breast cancer (another study here) and prostate cancer.  In a nutshell:  About 40% of Americans carry a genetic mutation in the enzyme MTHFR and have problems converting the less active forms of folate (a.k.a. the” folic acid” synthetically enriched in the food system) into more active forms.  Folate is one micronutrient we need for methylation:  tissue growth and repair, cellular communication, turns genes on and off, cellular energy production, synthesis of nucleic acids and production and repair of DNA and mRNA, as well as detox and neurotransmitter production like dopamine and acetylcholine,  and amino acid conversions.  Folate is present in many whole foods (see below slide).  Folate deficiency is more likely due to the MTHFR gene mutation rather than inadequate dietary intake.  The more active forms of folate supplementation  for those with the defect (read your vitamin labels), would be folonic acid, Metfolin brand, 5-methyltetrahydrofolate,  methylfolate, 5-MTHF and methyl B12.  I have no comment about the selection of this studies sample population other than to say that I was surprised to see such a large number of those pregnant on these meds (11 out of 24), and I’ll note that testing for the MTHFR gene mutation is easily done via a simple blood test (Quest or LabCorp, or the 23andMe type of genetic profiles…)  Ok… sorry to digress but it’s important, and you can dive more into this if interested by reading Dr. Benjamin Lynch over at MTHFR.net, or Dr. Jill Carahan’s “Holistic Primary Care” news article here, or this Chris Kresser post.
  • Usually, human birth narratives focus on the origins of a new individual, focusing on the mother and fetus. This essay discusses birth as the origin of a new community, in particular the pregnant mom/fetus microbiome:  “A holobiont birth narrative: the epigenetic transmission of the human microbiome”.  The author is Scott F. Gilbert, Department of Biology, Swarthmore College, Swarthmore, and Biotechnology Institute, University of Helsinki.
  • In this interview, Dr. Martin Blaser explains,  “…the first bacteria they’re [the newborn] exposed to is their mother’s bacteria in the birth canal. So as labor proceeds, the babies are in contact with the microbes lining their mother’s vagina and, as they’re going out, they’re covered by these bacteria. They swallow the bacteria; it’s on their skin. … That’s their initial exposure to the world of bacteria. That’s how mammals have been doing it for the last 150 million years, whether they’re dolphins or elephants or humans. … And we know a little about what those bacteria are. The most common bacteria are lactobacillus and there’s evidence that over the course of pregnancy the microbiome in the vagina changes, just as many other parts of the body are changing. The microbiome is changing in its composition in terms of maximizing lactobacilli, and these are bacteria that eat lactose, which is the main component of milk. So the baby’s mouth is filled with lactobacilli. The first thing that happens is they go up against their mom’s breast and they inoculate the nipple with lactobacilli and now milk and lactobacilli go into the new baby and that’s the foundation for their microbiome and that’s how they start their life.”
  • On comparing the microbiomes of babies born via C-section and those born vaginally: In this interview, Dr. Martin Blaser explains,  “Shortly after birth, they compared the microbiomes in the babies that came out. The babies that were born vaginally, their microbiome, not surprisingly, looked like the mom’s vagina everywhere in the body — in their GI tract, on their skin, in their mouth. But the babies born by C-section, their microbiome looked like skin and it didn’t even necessarily look like the mom’s skin, maybe it was somebody else in the operating room. So it’s clear that the microbiome is different immediately depending on the kind of birth.”
  • This study and this study (entitled “The “Perfect Storm” for Type 1 Diabetes”) found significant differences in the microbial ecology between children who develop type 1 diabetes and children who do not:  “Studies examining the microecology of the gastrointestinal tract have identified specific microorganisms whose presence appears related (either quantitatively or qualitatively) to disease; in type 1 diabetes, a role for microflora in the pathogenesis of disease has recently been suggested. Increased intestinal permeability has also been observed in animal models of type 1 diabetes as well as in humans with or at increased-risk for the disease. Finally, an altered mucosal immune system has been associated with the disease and is likely a major contributor to the failure to form tolerance, resulting in the autoimmunity that underlies type 1 diabetes. Herein, we discuss the complex interplay between these factors and raise testable hypotheses that form a fertile area for future investigations as to the role of the gut in the pathogenesis and prevention of type 1 diabetes.”
  • Epidemiologic evidence has shown a correlation between cesarean delivery and obesity, asthma, celiac disease and type 1 diabetes.  

  MICROBIOME DIFFERENCES DUE TO FEEDING

  • • For Background, the Guidelines: The American College of Obstetricians and Gynecologists (ACOG) recommends 6 months of exclusive breastfeeding for all infants. The American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) similarly recommend exclusive breastfeeding for the first 6 months of life, continuing at least through the infant’s first birthday, and as long thereafter as is mutually desired. The World Health Organization (WHO) recommends at least 2 years of breastfeeding for all infants.
    • Rates of breastfeeding in the US fall far short:  Check out the below charts for “Breastfeeding Among U.S. Children Born 2001–2011, CDC National Immunization Survey.”  In 2005, 74.2% of US infants were breastfed at least once after delivery, but only 31.5% were exclusively breastfed at age 3 months, and just 11.9% were exclusively breastfed at age 6 months.
    • The Human Microbiome, FAQ. A Report from the American Academy of Microbiology explains that in addition to the nutrients, vitamins, and antibodies present in breast milk, it supplies many different kinds of bacteria to populate the baby’s gut and nutrients that are specifically used by those bacteria to grow and thrive.  There are oligosaccharides (complex carbohydrates) and glycosolated proteins that the infant cannot digest.  The bacteria Bifidobacterium species consumes these, and in fact, Bidifobacteria is the dominant species in the breastfed gut microbiome.  We think their role is to coat the intestinal surface preventing pathogen attachment.  Breast milk therefore contains both prebiotics (compounds that support the growth and establishment of beneficial microbes) and probiotics (beneficial microbes).
    • Breast milk doesn’t just feed the newly acquired intestinal real estate, it tunes the immune system.   A tiny fraction of its sugars appear to find their way into a newborn’s bloodstream because a newborn’s gut is permeable.
      Bode and others have detected oligosaccharides in the urine of infants, suggesting that the sugars and their influence could extend well beyond the gut. “Milk oligosaccharides may be able to reduce inflammation throughout the body,” he says. In one study, oligosaccharides reduced interactions between inflammatory immune cells and cells that line blood vessels. “The oligosaccharides,” Bode says, “are able to keep the immune system in check.”
    • Another role of sugars in breast milk may be as defenders, flushing pathogens out of an infant’s body before they get a chance to wreak havoc.  In particular, This study, dated Dec 2013, demonstrated that the sugars block the attachment of a nasty strain of E. coli to the cells that line the intestine, thwarting the pathogen’s ability to infect neonatal mice.
      

      

    • Infant formula contains easily synthesized oligosaccharides called galacto-oligosaccharide.  They were thought to be similar to the oligosaccharides found in breast milk.  Bode and others :  We now know better:  Their structure differs greatly and their promotion of the growth of beneficial bacteria and protection against certain pathogens additively falls way short compared to that of the full spectrum of oligosaccharides found in breast milk.
    • Interestingly, this study out of Italy randomized 544 newborns in nine pediatric units to the probiotic Lactobacillus reuteri or placebo during the first 3 months of life for the following conditions with the results:  “Driving a change of colonization during the first weeks of life through giving lactobacilli may promote an improvement in intestinal permeability; visceral sensitivity and mast cell density and probiotic administration may represent a new strategy for preventing these conditions, at least in predisposed children,” the authors conclude.
      

      – Crying time: 71 min reduced to 38
      – Regurgitations: 4.6 reduced to 2.9
      – Bowel Movements 4.2 went to 3.6
      – Families saved $119 (reduced missed work & less doctor appointments)

    • For infants, breastfeeding has been associated with a decreased risk of obesity, diabetes Type 1 and Type 2, leukemia, sudden infant death syndrome, and diarrheal diseases, see Table 2  below.  For mothers, failure to breastfeed is associated with an increased incidence of premenopausal breast cancer, ovarian cancer, retained gestational weight gain, type 2 diabetes, myocardial infarction, and the metabolic syndrome.
      

      

    • Breast milk research is in its infancy; there is so much yet to be learned as noted in this Glcobiology Oxford Journal report:  “An accumulating body of evidence suggests that HMO are antiadhesive antimicrobials that serve as soluble decoy receptors, prevent pathogen attachment to infant mucosal surfaces and lower the risk for viral, bacterial and protozoan parasite infections. In addition, HMO may modulate epithelial and immune cell responses, reduce excessive mucosal leukocyte infiltration and activation, lower the risk for necrotizing enterocolitis, and provide the infant with sialic acid as a potentially essential nutrient for brain development and cognition. Most data however, stems from in vitro, ex vivo or animal studies, and occasionally from association studies in mother-infant cohorts. Powered, randomized and controlled intervention studies will be needed to confirm relevance for human neonates.”
    • Europe has more than 200 milk banks.  Brazil has a similar number.  The United States and Canada are slow to develop milk banks; the US has only 13.  Users of breast milk are: Neonatal NEC, chemo ravaged biomes, and antibiotic ravaged biomes.  Since it is very unlikely that donor’s breast milk  will supply these needs, business considered stepping in.  The conclusion: the  process is expensive and tedious (tremendous regulations); adding synthesized oligosaccharides to grocery infant formula is very unlikely as the price would be ridiculous.
    • There is effort underway however for “designing” microbes that make other oligosaccharides through fermentation which is how our gut bacteria ferments and makes vitamins, minerals, and every antibiotic under the sun (as Natasha Campbell McBride,the GAPS founder, likes to explain).  Completion is expected within the next few years.  The expectation is that these synthesized milk oligosaccharides can supplant antibiotic use since unlike antibiotics which breed resistance, “human milk oligosaccharides have been ‘used’ for millions of years without resistance.”  For those interested in the concerns of using bovine milk for this project check out my slide:
      

      

    Ongoing birthing microbiome manipulation studies…

    Lastly, check out this post DELIVERY & BREASTFEED STUDIES & MICROBIOME MANIPULATION for details concerning current ongoing studies addressing newborn microbiome manipulation especially for Cesarean births.

    

    PATERNAL FOLATE DEFICIENCY TRANSFERS RISK TO UNBORN

    The role of maternal folate deficiency in neural tube defects(NTDs) has long been known.  The paternal role due to folate deficiency is becoming equally recognized as well and may explain why despite folic acid fortification in foods and maternal supplementation, the incidence of NTDs has stabilized in the United States and many other countries.

    Paternal exposure to dioxins and spermatozoid folate deficiency was found to have a statistically significant causal link to spina bifida. See References  [41–43].  Dioxins accumulate throughout the food chain, with increasing concentrations. The highest levels of these compounds are found in some soils, sediments, and food, especially dairy products, meat, fish, and poultry. Once the human body has absorbed dioxins, they persist for a long time because of their chemical stability and their ability to accumulate in fat tissue.  

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