On shouting, "SEED MY BABY WITH MY VAGINAL MICROBES!"

Co-authored by Emily Pereira, Anthropology major, University of Rhode Island

When I was pregnant, the human microbiome was hot. And news about the microbiomes of newborns was even hotter, at least to my eyes and ears because I was on the verge of having one.

This was in 2014. Studies were starting to find that babies born via c-section have different microbiomes than babies born vaginally. These findings were being interpretively linked to health problems down the road. 

Here’s a write-up of one study of a few 4-month-olds that I came across while pregnant: “Infant gut microbiota influenced by cesarean section and breastfeeding practices; may impact long-term health”

And today studies continue to pop-up that find differences in baby microbial composition and then suggest those differences may be linked to future health problems. For example, here’s a recent one from 2016 in JAMA Pediatrics: 

“CONCLUSIONS AND RELEVANCE The infant intestinal microbiome at approximately 6 weeks of age is significantly associated with both delivery mode and feeding method, and the supplementation of breast milk feeding with formula is associated with a microbiome composition that resembles that of infants who are exclusively formula fed. These results may inform feeding choices and shed light on the mechanisms behind the lifelong health consequences of delivery and infant feeding modalities.”

These discoveries about c-sections seem important because microbes are now famous for being linked to all kinds of health troubles. 

According to the American Microbiome Institute... 

“studies are finding that our bacteria (or lack thereof) can be linked to or associated with: obesity, malnutrition, heart disease, diabetes, celiac disease, eczema, asthma, multiple sclerosis, colitis, some cancers, and even autism.”

And of course many of those same things have been epidemiologically traced back to birth by c-section. Here’s a report on one study, “published in the British Medical Journal, [that] found that newborns delivered by C-section are more likely to develop obesity, asthma, and type 1 diabetes when they get older.”

Another found that, “people born by C-section, more often suffer from chronic disorders such as asthma, rheumatism, allergies, bowel disorders, and leukaemia than people born naturally."

One can’t help but assume it’s all connected. If microbes are to blame for this list of problems and if c-sections are too and if c-sections are causing babies to have different microbiomes, then the following conclusion seems like a no-brainer: we need to be wiping c-sected babies with their mother’s vaginal juices.

So although I did basically nothing to prepare for a c-section (d’oh!), I imagined that if my childbirth came to surgery, that it would be really easy to avoid the risks to my baby's health by simply wiping him down with something soaked in my lady fluids.

I had even caught wind of a trial of this procedure, written-up somewhere, and so I mentioned it to my OB at a prenatal visit. She said she’d heard of it and that there was a term for it but the term escaped her. The idea excited her, but it wasn’t even remotely close to being part of regular clinical practice yet. Remember, this was summer 2014. Sensing it was too soon and out of reach, I changed the subject of conversation. Yet, I continued to believe that someone would just help me out with the whole vaginal swabbing thing if need be. It seemed simple enough. No biggie.

At the time, I didn’t Google around for tips or instructions so I don’t know what the Internet was offering up to would-be mothers/vaginal-microbe believers like me. But today it’s quite easy to find encouragement to D-I-Y transform your kid’s c-sected microbiome into a naturally-born one.

Here, let Mama Seeds explain:

“In the event of a c-section, be proactive. Mamas, we know this recommendation is not without its “icky-factor," but WOW it makes perfect sense when you think about it, and some believe it will be a standard recommendation in the future. Here goes: if your baby is born via c-section, consider taking a swab of your vaginal secretions and rubbing it on your baby’s skin and in her/his mouth. I know, ick. But when babies traverse the birth canal, they are coated in and swallowing those secretions/bacteria in a health-promoting way, so all you’re doing is mimicking that exposure. Don’t be afraid to ask your midwife or OB to help you collect the vaginal swabs—or do it yourself, if you’re comfortable. You have all the available evidence on your side.” - Michelle Bennett, MD is a full-time pediatrician, a Fellow of the American Academy of Pediatrics, a mother of two, and a founder of Mama Seeds.

Like I said, I didn’t have Mama Seeds. But I didn’t need Mama Seeds. While I was being wheeled into emergency cesarean surgery, I still shouted “SEED MY BABY WITH MY VAGINAL MICROBES!”

The reaction from the hospital staff? There was no reaction and, surprise surprise, there was no artificial seeding of my baby’s microbiome.

And that’s good. That’s how it should have gone down because my request was not based on scientific thinking. I hope you'll forgive me. I was pregnant. I wasn’t myself.

Slowly I’m becoming myself again, though, and thanks to a keen student, Emma Pereira, this post’s co-author, I’ve learned quite a bit about the science behind whether I should have seeded my newborn with my vaginal microbes. And the answer to anyone who’s wondering is a resounding NO. At least for now.

Here’s why.

1.   We don’t know if it’s necessary. Despite the increasing numbers of studies, no one to our knowledge has looked longitudinally at the microbiomes of humans born via c-section to find out if the changes detected (in very small samples) early on in these studies actually last, let alone if they can be causally linked to differences in health. It seems like the money and the technology is there to identify (via genetic sequencing) myriad microbial species, but the time and energy just isn’t there to do much else. So, although there is a growing literature, the dots aren’t connected yet. A graphic may help explain what we've learned: 

2.  You could actually harm your baby. Because there is currently no known good to come of seeding one’s c-sected baby with one’s vaginal microbes, there can only be bad. Yes, authors of this study published recently in Nature Medicine took a bunch of gauze that had been sitting in the mother’s vagina for an hour and swabbed 4 babies for a duration of about 15 seconds right after their birth by c-section and then found a significant difference in their microbiome at 30 days-old compared to babies who weren’t treated.  The microbiome wasn’t identical to vaginally born babies, but at least it wasn’t identical to those poor c-sected controls who didn’t get swabbed, right? Well, maybe wrong. First, please revisit number 1. And, second, maybe causing a baby to have a c-sected microbiome is not worse than seeding a baby with genital herpes, which is a very real possibility in practice, outside of these early, highly controlled pilot studies. As reported in Should C-section babies get wiped down with vagina microbes?, “the procedure could unknowingly expose newborns to dangerous bugs, pathogens that babies born by C-section usually avoid. Group B streptococcus, which is carried by about 30 percent of women, can trigger meningitis and fatal septicemia... Herpes simplex virus can lead to death and disability in newborns. And chlamydia and gonorrhea can cause severe eye infections.”

So, again, as of right now, there is no reason to seed one's c-sected baby with one's vaginal microbes. And there are very good reasons not to! 

We think that the temptation to blame the rise of numerous complex health problems to something as simple (and easily knowable) as the way we’re born is similar to the temptation to reduce these very same complexities to what’s coded in the genome. For some people, maybe even many, it may turn out to be this simple! But we’re far from knowing whether that’s true. 

Spare your baby from meddling with his microbes until the evidence is there. 

Intestinal microbes and heart disease -- we are what we eat

And now another in our irregular series on the role of anything-but-genes in chronic disease.  We've posted about the possible role of inflammation in many late onset or chronic heart disease, diet and lifestyle in heart disease, inflammation in asthma, cleanliness in asthma, inflammation in macular degeneration, and so on.  Diseases, it must be noted, for which hundreds of millions of dollars have been spent on the search for risk factor genes.  The excuse for this, used by geneticists to garner many huge grants, and with little other rationale for obviously environmental problems, was that they'd find important (major) segments of the population that were genetically susceptible to these environments.  We need not here belabor the thinness (from the beginning) of that rationale, because there are more important things to think about.

Steak; Wikimedia

For decades, primarily thanks to findings from the Framingham Study, it has been accepted wisdom that red meat is a risk factor for heart disease.  Why?  Because eating red meat was thought to raise cholesterol, which leads to hardening of the arteries, and then cardiovascular disease.  That led the pork and chicken industries to promote their implied-safer products (e.g., "the other red meat!").  Eggs, too, were implicated for a while because the yolks are high in cholesterol, though they were taken off the danger list some time ago (unfortunately, too late for some of us, who have developed a reflex egg-aversion, but given the cycling of risk factors, maybe that egg-aversion is a good thing).

Recent meta-analyses were not able to confirm the association between saturated fat and cholesterol and cardiovascular disease, a rather stunning finding that suggested that there may be other, perhaps correlated, environmental factors involved.  Two recent stories by Gina Kolata in the New York Times present just such alternative risk factors.

Kolata's story on April 7 suggested that indeed it's not the saturated fat or the cholesterol in meat that's to blame but the response of microbes in the gut to a constituent of the meat, carnitine in particular.  In a paper published in Nature Medicine, researchers at the Cleveland Clinic propose that when we eat meat the microbes in our gut convert carnitine into trimethylamine (TMA), which the liver then converts into TMAO, trimethylamine N-oxide, thought to be the real culprit in cardiovascular disease (CVD) because it causes atherosclerosis, hardening of the arteries.

The researchers compared the response of meat eaters and vegans to ingesting carnitine, and found that vegans didn't produce TMAO. Studies have shown that microbial composition of the gut does indeed vary with diet, among other things (geography, pregnancy, etc.) and meat eating presumably feeds a subset of microbes that vegans don't host.  Theirs don't make TMAO.    

Hard boiled eggs; Wikimedia

Kolata's story in yesterday's Times reports that a constituent of eggs might also be converted into TMAO by microbes in the gut.  In a paper published in the New England Journal of Medicine on Wednesday, the same researchers propose that when we digest the phosphatidylcholine, or lecithin, in eggs, one of the constituents is choline.  Intestinal microbes convert choline into TMA which, again, the liver converts into TMAO.  Other major sources of lecithin include liver, beef and pork.

Damn!  Do we have to stop the meat and eggs again?

Researchers confirmed the middleman (or middle-microbe) effect of intestinal flora by having their subjects take an antibiotic that wiped out the gut bacteria before they ate hard-boiled eggs.  With the microbes gone, TMAO levels in the blood didn't rise.  Only when the microbes were back to normal levels did TMAO rise. 

So, yes, foods high in fat and cholesterol may be associated with risk of heart disease.  But it's not because of the fat and cholesterol per se, but because these substances are present in foods that also have the constituents that gut microbes convert into what seems to be a true risk factor for atherosclerosis, TMAO. Not to mention that gut microbes are heavily determined by what we eat, as well.

We've 'known' for decades that red meat was a heart disease risk factor, and it was clearly because of fat and cholesterol.  This became lore.  The beef industry provided beef with less fat, the pork industry sold us on 'the other red meat', the poultry industry crowed, especially when eggs went back on the list of foods okay to eat.  

Vegan food pyramid; Wikimedia

And there was clearly a genetic component to heart disease risk, and/or to obesity, because CVD seems to run in families, and obesity is a risk factor, and this made many genetics labs crow.  Except that it was confusing when people with no family history of heart disease or thin people had heart attacks.

Despite the billion dollar industry that investigating, preventing and treating heart disease has become, it remains the leading cause of death in the US and other countries.  Number one.  Clearly we're doing something wrong -- including throwing a lot of money away on genetic studies that we knew really were going nowhere fast.  The intestinal microbe connection might turn out to be a huge advance in our understanding of heart disease, and it might well be that simple dietary changes and pharmaceutical approaches to cultivating 'good' microbes in our gut will prevent heart disease in many people -- leading the pharmaceutical industry to be the big crowers this time around. Of course, we can expect the genetic industry to say that some people are susceptible to the bugs' in their guts, but others (once we do the GWAS, whole genome sequencing, and 'personalized genomic medicine') will be cleared to go for the Egg McBreakfasts (with bacon).

But, this isn't likely to be the next health-research miracle, even if it gets promoted as one.  We would caution that this explanation will account for only some heart disease, even if the findings, which would be quite valuable to know, hold up.  Just as with every other complex disease, there are multiple pathways to this trait.  Why, for example, is smoking such a clear major risk factor?  Heart disease will remain a heterogeneous trait, difficult to predict, and not always possible to prevent.  But still, it's always refreshing when some innovative researcher breaks free of group think and provides new ideas on perplexing subjects.

The greatest irony, or should we say the last laugh, goes to the bugs who continue to outwit us and take us to our graves.

Getting in each other's jeans....or genes?

Life, evolution, is about reproduction, how effectively we get into each other's jeans, so to speak.  As individuals, we may be independent most of the time, but we can't make a new individual alone.  To do that we must conjugate our genome with someone else's, and getting into their jeans is how we do that.

Or is it?

Perhaps we've been making a big evolutionary mistake
Maybe what is as important is how we and other species get into each other's genes.  Organisms--all of us--are collections of large numbers of cells descended from a single starting cell (the fertilized egg).  We tend to view ourselves as having one genome, and in that sense being a unitary, biological whole.  Evolutionary theory is about how collections of such wholes, the fertilized eggs of a population in a generation, change over time.

But increasing evidence shows several important facts.  First, each time a cell divides into two 'daughter' cells, mutations occur, and these are then transmitted to the next generation of daughter cells.  And, at the molecular level, the division of one cell into two, even forgetting mutations, is never exactly equal.  One gets more of one protein than the other, the other gets more mRNAs and so on. You are a huge collection of cells with such a branching history of variation from a single fertilized egg cell.

But our life is not just what happens to that set of cells.  Instead, as evidence is now showing more clearly, we are colonized by countless other cells--bacteria and other micro-organisms--and they, too, divide on and in us, accumulating mutations along the way.  And, more importantly, we are unable to live without them, nor they without us.  The simple classical and perhaps clearest example is our intestinal flora, that is responsible for vital aspects of our digestion and hence our survival.

A burgeoning area of investigation called microbiomics (every field needs a sexy label, of course), the study of the many different microbes that inhabit various parts of our bodies, is off and running.  This work is finding a wealth of relationships between us and others, so much so that researchers are suggesting that our genome can't in fact be fully understood on its own, but rather must be thought of as just one part of a larger genome that also includes the genes of all our colonizers.  Or from the microbes' perspective, their own and their host's genomes.

Many different common chronic diseases that for several decades have been thought to be due to wear-and-tear of long life and modern lifestyles, are being shown to involve genes involved in aspects of our immune systems. So in both regard to disease and to the microbiome of normal variation, our traits may be more 'infectious' than we had thought.  The term 'infection' implies the old idea that we're normally bug-free unless we are sick.  Instead, perhaps we are sick if we are bug-free!

Going further: what, after all, is an organism?  What is evolution about?
Maybe our entire concept of organism and its traits is biologically badly mistaken.  Perhaps metazoans really are often, or largely, a colony of cells with one genome plus adherent colonies of cells with other genomes.  Neither can do without the other.  They've evolved jointly.  Aberration in either can cause cell death.  When it's of the 'organism' we give it different name from when it's just of one of the cells.

We might call this 'coevolution' and perhaps it could lead to substantial rethinking about what we are, or what species are, or their evolution.  Or how we use our notion of organism to dichotomize vis-à-vis the 'environment', when basically they are more unitary?  The ultimate in co-operation.

Again, as with sex, we may have been misled by Noah's ark, Linnaeus, and Darwin into life science based on organism, when that is only one aspect of how things are organized.  The idea that Nature is composed of a series of distinct species, a legacy of classical thinking up to the present, is actually a large subject with much that is interesting and perhaps truly profound to think about.  We'll discuss it in a subsequent post.

Meanwhile, the idea of meddling in, or the responsibility to keep out of,  or delve into, each others' genes is not just something for Levi Strauss to consider.

Metagenomics in action

'Metagenomics', the direct sequencing of all the DNA found in environmental samples.  From one perspective, this is yet another 'omics', a way to keep all those expensive sequencing machines going.  And a way to avoid having to have hypotheses about what's going on in nature before you start your project--a somewhat strange twist in modern biology.  Still, 'omics' is done because we have the tools to do it and because it does promise to find something, on the single underlying assumption, namely, that something is there, even if we don't know what it might be.

In fact an interesting use of this methodology is reported in Nature this week, in a paper about the sequencing of all the microbes in Alaskan permafrost soil samples pre- and post-thaw.  The paper reports rapid changes in the abundance of many phylogenetic and functional genes and pathways, suggesting a rapid response to changing environment.  In this case, there need not have been any kind of a priori hypothesis about what one would specifically find for this to be a valuable kind of work, which this study has proven to be.

Mackelprang et al. collected 3 frozen soil cores from an area in Alaska that they had previously characterized.  They removed samples from these and let them thaw over 7 days.  They monitored the carbon dioxide and methane concentrations in the headspace of the helium filled tubes in which the samples were incubated, and extracted DNA for 16S ribosomal RNA and metagenome sequencing.

The authors were particularly interested in what happened to the methane and carbon dioxide because, of course, these are greenhouse gases.  They document changing levels of these gases as the soil samples thawed, and corresponding increases in genes in their metagenome from microbes that produce these gases as metabolic byproducts.  

Specifically:

The metagenome data revealed core-specific shifts in some community members, including the orders Proteobacteria, Bacteriodetes and Firmicutes. We found that Actinobacteria increased in both cores during thaw. Actinobacteria have previously been found at high abundance in permafrost, which is thought to be caused by their maintenance of metabolic activity and DNA repair mechanisms at low temperatures. Most archaeal sequences identified in the metagenomic data were methanogens in the phylum Euryarchaeota (62–95%), including the Methanomicrobia that was represented in our draft genome. In total, four orders of methanogens (Methanosarcinales, Methanomicrobiales, Methanomicrobia and Methanobacterales) were detected. As the permafrost thawed, the methanogens (including Methanomicrobia) increased in relative abundance. These orders are known to be metabolically versatile and can use a variety of substrates.

They also found that methane was consumed post-thaw.  But, to us what is most interesting about this, not being climatologists or microbiologists, is what they found about the differences between samples post-thaw, as they describe here.

We tracked simultaneous shifts in the total gene complement from the metagenome data to obtain a global view of functional response to thaw. The active layer samples were relatively similar before and after thaw. By contrast, the two frozen permafrost metagenomes differed dramatically before thaw. In addition, functional genes in frozen active layer and permafrost samples were distinct from each other, including differences in several key metabolic pathways such as energy metabolism, nitrogen fixation, amino-acid transport, oxidative phosphorylation and anaerobic respiration. During thaw, the permafrost metagenomes rapidly converged and neared those in the active layer samples. The convergence of function was not matched by a convergence of phylogenetic composition during this short-term incubation, suggesting that disparate community responses to thaw can have similar functional consequences.

As we said yesterday in our post about ostrich penises, however the job can get done, evolution can support it.  Whether or not the job being done here is good or bad for humans vis-à-vis climate change is another story.  But, convergence of function in the communities of microbes analyzed by these researchers happened in communities with very different compositions of microbes.

Organisms have responsive genomes. Indeed, the 'job' of cells is to sequester their special ingredients within, but to monitor the external environment to determine how to behave most successfully.  They are changeable, within their genomic repertoire.  Mutation followed by natural selection can lead to specific genetically committed responses, but that isn't always necessary, because due to whatever earlier processes, even humble microbes have evolved to be able to respond to the conditions they find themselves in.  And, whether or not warming temperatures are beneficial to specific microbes, the community adapts. 

Based on comparative morphology and modern-day science, roughly 4 billion-year-old aggregates of bacteria (fossil biofilms calleld  'stromatolites') look strikingly like their modern descendants.  Today, biofilms are known to be bacterial responses to changes in conditions--even different species can aggregate in the same biofilm.  This means that not that long after the origin of life (and, indeed, of the earth itself), fundamental facultative adaptability had already been built by evolution into the genomes of the earliest cells--and that means it is a basic property of cells.  This is a point we stress in our book, The Mermaid's Tale, and we're always gratified to see it confirmed.