Bacteria And Pregnancy
    By Gerhard Adam | September 3rd 2012 03:00 PM | 24 comments | Print | E-mail | Track Comments
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    There was an interesting study published recently that addresses the changes that occur to gut bacteria in pregnant women and the role this fulfills in maintaining a healthy pregnancy.

    There are two primary points that need to be addressed in order to appreciate these findings.

    In the first, we note the fact that the human body is host to over 100 trillion bacteria, both in and on us that are instrumental in maintaining health.  These commensual bacteria outnumber our own cells by about 10 to 1 [the genetic ratio is 100 to 1 - often called the second genome].  Of late, it is becoming increasingly clear that these "partners" aren't merely casual elements of our existence, but are required for our very survival.  

    In this respect, the conventional view of life being controlled and driven by genes, is insufficient in producing a viable, healthy organism.  While much is still unknown, there are strong implications regarding the relationship of these bacteria to the host organism, as well as the role of their genetic diversity.

    It appears that bacteria are also responsible for "training" the host's immune system to recognize "friendly" versus pathogenic bacteria.  Commensual bacteria also play a role in preventing pathogenic bacteria from taking up residence, killing nonindigenous bacteria, producing nutrients, and affecting tissue development (1).

    In short, we can see that the role of the microbiota is quite significant.  I am reluctant to simply consider the relationship as commensual, symbiotic or parasitic, but would rather consider it to be much more integrated than such definitions presume.

    Now in considering the second part of this issue; human pregnancy, we find that body fat increases early in pregnancy, with a reduction in insulin sensitivity later.  This reduction in insulin sensitivity is related to changes in immune status and appears to drive obesity-associated metabolic inflammation.

    Of interest is that while excess accumulation of fat and loss of insulin sensitivity are normally detrimental to long-term health, they are beneficial within the context of a normal pregnancy, by supporting growth of the fetus and preparing for lactation.

    Now for the good bit.

    It appears that throughout pregnancy the gut bacteria (Proteobacteria and Actinobacteria) undergo a radical alteration [between the first trimester and the third] in population diversity such that the bacteria promote the changes necessary for a healthy pregnancy, despite their presence being detrimental in a normal healthy adult.  Moreover, the bacterial diversity continues after birth for about one month in the mothers, while the infants return to normal levels (diversity similar to those of the mother's first trimester state) by 4 years of age.   It is also important to note that this abrupt change in population diversity was present in the mothers, regardless of their individual states of health, so these changes cannot be attributed to be artifacts associated with any specific condition of the mother.

    Further confirming the role of the gut bacteria was accomplished by transferring the bacteria to germ-free mice and noting the effect.
    "The transfer of specific gut microbiotas to otherwise healthy germ-free wild-type mice is sufficient to induce symptoms of metabolic syndrome, which, in addition to inflammation, include reduced insulin sensitivity and excess weight gain."
    "Dysbiosis, inflammation, and weight gain are features of metabolic syndrome, which increases the risk of type 2 diabetes in nonpregnant individuals. These same changes are central to normal pregnancy, where they may be highly beneficial, as they promote energy storage in fat tissue and provide for the growth of the fetus. Our work supports the emerging view that the gut microbiota affect host metabolism; however, the context (pregnant or not) defines how the outcome is interpreted (healthy or not). Metabolic changes are necessary to support a healthy pregnancy, which in itself is central to the fitness of a mammalian species. We hypothesize that, in mammalian reproductive biology, the host can manipulate the gut microbiota to promote metabolic changes. Thus, the origins of host-microbial interactions that skew host metabolism toward greater insulin resistance, and which underlie much of the present-day obesity epidemic, may lie in reproductive biology."
    Cell 150, 470–480, August 3, 2012 ª2012 Elsevier Inc.
    In my view the significance of this study is in suggesting that the microbiota plays a fundamental role in supporting human fitness.  This would have significant ramifications on simplistic views of what is being "selected for" by natural selection.  This could provide a strong basis for considering living organisms as being much more integrated than is generally thought.  Another avenue of consideration is that if the host is capable of manipulating the microbiota, then this also creates an interesting perspective since a host may be capable of taking advantage of a "trait" which is already present in another organism.  As a result, this also would profoundly change the view of "selection".  In the latter case, it is entirely possible that the genome may never "evolve" to contain the desired trait, but instead the organism becomes dependent on commensuals to fulfill that role [NOTE: This would be similar to many other instances where such bacteria provide the necessary mechanisms to digest food that would otherwise be indigestible].

    Just as termites are dependent on symbiotic protozoa to digest the cellulose they eat, we find that the necessity of microbiota in organisms is a necessary condition for survival.  This raises the point that selection of specific genetic traits is insufficient in establishing the fitness of an organism without correspondingly considering the coevolution of commensual organisms.   What is becoming increasingly clear is that many organisms may acquire the necessary "adaptations" of their survival by exploiting commensuals rather than possessing those traits in their genes.

    (1)  For more information regarding the effect of microbes on host systems:

    Citation: Omry Koren, Julia K. Goodrich, Tyler C. Cullender, Ayme ´ Spor, Kirsi Laitinen, Helene Kling Backhed, Antonio Gonzalez, Jeffrey J. Werner, Largus T. Angenent, Rob Knight, Fredrik Ba ¨ ckhed, Erika Isolauri, Seppo Salminen, and Ruth E. Ley,  Cell, Volume 150, Issue 3, 470-480, 3 August 2012, 'Host Remodeling of the Gut Microbiome and Metabolic Changes During Pregnancy'


    Gerhard Adam
    For more details regarding the influence on the brain:
    Mundus vult decipi
    entirely possible that the genome may never "evolve" to contain the desired trait
    Little new here since we know mitochondria.

    With increasing frequency you write stuff like:
    this also would profoundly change the view of "selection".
    Without clearly stating that you refer to extreme gene centrism, you may be misinterpreted as questioning evolution (perhaps with religious/mystic hidden agendas). There is no news to the less naive among us, so writing "profoundly change" can sound cranky.

    What needs profound change is to start the comparison with social systems. "What if everybody did that?" is like asking "What if all my cells had the same genome as the archaea in my sclera?". The gut flora during pregnancy and the number of miniskirts during economic crisis are fundamentally the same. We are the gut bacteria of systems we refuse to accept as evolving, this is the profound insight from studies revealing tight co-evolved integration.
    Gerhard Adam
    Without clearly stating that you refer to extreme gene centrism, you may be misinterpreted as questioning evolution...
    Perhaps you're right, but I'm also talking about the pervasiveness of the view that somehow genes are the singular element that needs to be considered in natural selection.  In truth, you seem to be much more in tune to the idea of tightly co-evolved systems, than many biologists. 

    In addition, the "profound change" is also to the general perception that people hold of the genes representing the beginning and end in the evolution of organisms.  In my view, we are only beginning to appreciate the significance of the microbiome and the integration with which it operates in organisms.

    Mundus vult decipi
    John Hasenkam
    In my view the significance of this study is in suggesting that the microbiota plays a fundamental role in supporting human fitness. 

    That can be turned around. 

    In my view the significance of this study is in suggesting that human physiology is fundamental to supporting microbiota.

    It also raises the question of just what is "being human". We cannot survive without these bugs. 

    Little new here since we know mitochondria. 

    The mitochondrial genome encodes for 37 proteins, 24 mRNAs and 13 proteins. Not enough for an organism, the implication being that over time the mitochondria lost elements in the genome. Plasmids  may have played a role, transferring the relevant genes to the host organism. 
    Gerhard Adam
    In my view the significance of this study is in suggesting that human physiology is fundamental to supporting microbiota.
    Well, I think that would be stretching the terminology, since the human is deriving the benefit from this.  More importantly the point is made that in the infants, the diversity of the gut bacteria changes, returning to the state more comparable to the "normal" or mother's first trimester levels.  This suggests that this is a manipulation by the human physiology, since it appears to be controlling the "selection criteria" that causes the population diversity to change.

    Ultimately it's as Sascha indicated, the elements are inextricably woven together so that it does become difficult, if not impossible to separate out the elements and claim any particular biological uniqueness for it.
    Mundus vult decipi
    John Hasenkam
    I was playing around with the idea that changes in our physiology induce changes in gut bacteria. A quick look at the data though indicated the problem could be much worse .... 
    1. Ann N Y Acad Sci. 2003 May;992:21-9.

    HPA axis activation and neurochemical responses to bacterial translocation from
    the gastrointestinal tract.

    1. Gut. 2007 Nov;56(11):1522-8. Epub 2007 Mar 5.

    Probiotic treatment of rat pups normalises corticosterone release and ameliorates
    colonic dysfunction induced by maternal separation.


    Gerhard Adam
    Could you be a bit more specific?  I haven't reviewed the two articles you referred to, but I'm not clear on what you're trying to say.
    Mundus vult decipi
    John Hasenkam
    What I am saying is that our physiology also impacts on gut flora and changes the populations, in the abovementioned case to our detriment. These studies suggest that flora of various species have a preferred physiological state and the popn numbers will vary with the changes in physiology. 
    Gerhard Adam
    OK ... yes.

    I find it useful to envision it as more of an ecosystem/environmental issue.  So, that the micro-organisms affect the environment, but similarly the environment affects their population.

    In a very LOOSE analogy, one can almost imagine a group of individuals living in a particular geographic location, suddenly being impacted by a drought, while simultaneously modifying their environment [i.e. perhaps with irrigation].  The two become inextricably linked so that every change made to the environment has ramifications in how the environment responds to other external conditions.

    While I don't believe you're suggesting any such thing, I think it's important to dispense with considering these bacteria as "good" or "bad", any more than we would assess such a value to our humans in the previous analogy.

    These bacteria will exchange genetic information with pathogens as readily as each other.  They can be dangerous to us when they are present in the wrong "geographies".   In short, these bacteria are neither "friends" nor "enemies" but rather a biological contingent that we have somehow co-evolved with for mutual exploitation.

    Interestingly enough, the microbiota don't appear to be very consistent between individuals, so even within that context there is a large amount of diversity in the microbiota between individuals.  Of course this raises the question of whether this produces certain incompatibilities between human individuals that may have different microbiota.
    Mundus vult decipi
    John Hasenkam

    Interestingly enough, the microbiota don't appear to be very consistent between individuals, 

    I have finished reading this text yet but it provides some fascinating insights into cross cultural variations in how we respond to stress. The author mentions how in some Asian communities depression might be evidenced more by joint pain and vague pain, whereas we tend to express more mood issues. So I am wondering if the different diets and subsequent flora directly impact on how we respond to stress. 

    The text is: Beyond HUman Nature, by Jesse J Prinz. So glad to find this text because it serves as a valuable rebuttal to the nativist perspective, it reinforces the role of nurturism and how modern psychology has focused far too much on genetics and that bloody medical model of mental illness. I suspect behaviorists would very much like this text. The cross cultural comparisons are surprising, even at the most basic levels there can be varying cognitive styles. Whatever "innateness" with respect to knowing exists, it exists at a very rudimentary level.  
    Gerhard Adam
    That raises the point I addressed in a recent post on heritability.  I primarily brought it up, because it is often used in evolutionary psychology to argue that if a particular trait exists everywhere, then it must be adaptive and therefore has a heritability of zero.  When this is done with behaviors, it provides a jumping off point to make all kinds of genetic pronouncements regarding how things shape up or not.

    Of course, those arguments fail if there is no actual genetic link, but since that is often presumed, it provides a vehicle for some of the more exotic claims.
    Mundus vult decipi
    John Hasenkam
     if a particular trait exists everywhere 

    The author of the text I mentioned provides a number of examples where Evol. Psych generalised far too much with respect to universal traits. Evol. Psych was always a steaming pile of shit. 

    Thanks Gerhard.

    I found this subject fascinating and multifaceted. Haven't wrapped my brain around implications to evolution as my brain is better trained to deal with more concrete clinical facets. Clinically speaking it explains some of the things we see in practice; where so much of the time, we find that pets with inflammatory bowel disease respond to medications active against the link showing elevation of anaerobes was very interesting.
    It also sheds some light on the very common practice employed in agriculture over the past 50 yrs of feeding antibiotics for growth promotion.

    John: you might find the following article interesting. It does not speak of microflora, but touches on the HPA axis and longevity in animals-- where evolutionary psychology has limited effects compared to people.

    Gerhard Adam
    Thanks for the response.  Glad to hear from you.
    Mundus vult decipi
    Thank you for posting, Gerhard. Your article in truth "blew my mind" a little.

    As luck would have it, though, I spent this weekend trying to figure out what to do for my old friend--a 13yr old rescued Cane Corso (mastiff) who I discovered this weekend has terminal cancer..... science will have to take a back seat for awhile.... and there is much to digest in the science you brought to my attention... implications to obesity(?) for example.

    Gerhard Adam
    Yes, it's quite interesting to see all these new issues surfacing.  Reminds me of physics at the beginning of the 20th century, thinking that the only "interesting" problems left involved black-body radiation.  Suddenly the entire quantum universe fell in on them and they've been scrambling ever since.

    Similarly in biology, it seems that we had our hearts set on the human genome project filling in all the blanks.  Now there's the human microbiome project, and I expect we'll find out that things weren't nearly as simple and tidy as was being proposed [i.e. if we understood the genes then we would understand everything pertinent to life].

    It appears there really are "bugs" in the system, and they know far better than we do, how everything works. :)  I'm still waiting for the other shoe to drop, because I suspect another huge unexplored area regarding biological ramifications will occur with viruses.
    Mundus vult decipi
    Gerhard Adam
    ...I spent this weekend trying to figure out what to do for my old friend--a 13yr old rescued Cane Corso (mastiff) who I discovered this weekend has terminal cancer...
    Sorry to hear that.  I know how that goes.  We also recently lost one of our Corgi's to lung cancer, so I understand what you're dealing with [unfortunately she was only about four years old]. 
    Mundus vult decipi
    >>>We also recently lost one of our Corgi's to lung cancer, so I understand what you're dealing with [unfortunately she was only about four years old]. <<<

    Thank you for your thoughts. It is very shocking when they die so very young, and it is tough when you've had the pleasure of enjoying them longer than you had a right to have them. Watching for signs of pain... trying to spend more time with him and gauging every night whether the bad days outweigh the good.... so he doesn't suffer and yet doesn't miss out on an extra good day. One day at a time.

    Gerhard Adam
    Yes ... I have always had a fair number of dogs, so its always difficult when something happens that forces you to put them down.  I also have cats and we've encountered the same situation recently with one of our older ones.

    In any case, you're doing the only thing you can, so I'm sure he'll be as comfortable as he can be.  Good luck to you.
    Mundus vult decipi

    Not to mention that we are still in the very early stages of understanding the human genome.

    We are scratching the surface. Philosophically speaking, I think every discovery makes it easier for man to think we understand how things work and it seems we get more arrogant, while we should be getting more and more humble at the complexity of these interactions between genes, microbes, our endocrine and immune systems.

    Gerhard Adam
    One can hope, but that's not likely.  We are ultimately tinkerers, and we always think we can do a better job.  In my view, part of the problem is that we don't want the rules to apply to us, so we keep believing that we can modify "nature" to be more human-friendly. 

    Fortunately, "nature" is simply too complex and doesn't pay much attention to our politics to be swayed by our choices. 
    Mundus vult decipi
    John Hasenkam
    Mice deficient in IGF-1 are not only smaller, but live longer and have significantly reduced prevalence of age-related physical complications such as cataracts, atherosclerosis, and cancer 

    Thank you Dr. Ena. Caloric restriction lowers IGF1, though that may be somewhat misleading because it also increases IGFBPs(binding proteins). I suggest any analysis of IGFs should include the binding proteins. What is little appreciated is that growth factors can promote cancers(association with IGF and cancers) and can also induce oxidative stress. I am not a fan of CR but believe fasting is useful to promote autophagy, which is inhibited via MTOR function, the major nutrient pathway. This can be a delicate balancing act though, too much autophagy and cells can literally eat themselves, an approach used to address some cancers. A study published a few years indicated that smoking promotes endothelial damage through excessive autophagy. 

    While many perceive the loss of growth factors as promoting aging it may serve a valuable protective function, the data seems to indicate that. Here's a fascinating eg.

    I read a study on transgenic mice that had increased growth factor production. The mice did great early on, learning very quickly but by middle age were showing signs of cognitive frailty, which was not evidence in the control mice. However in the  transgenic mice provided with a special diet, rich in nutrients and antioxidants, behavior was preserved in middle age and even closely matched that of the younger mice. Caveat: yeah living in a lab is a relatively easy life for animals so extrapolating from these studies is fraught with risk. 

    Lung cancer at 4 years seems odd Gerhard. Here is something I came across just the other day, though the data has been around for a few years now. Apparently lung cancer rates in non-smoking humans are increasing. Pollution? 
    Gerhard Adam
    Yes, it is odd, but then sometimes it's just bad luck.  She had very large tumors, with one whole lung practically blocked.  In addition, it happened very quickly since she didn't really show an external symptoms of any problems until nearly 3-4 days before she had to be put down.

    Of course, she didn't eat, which was our first real indication.  The reason I know as much as I do about it, is that the vet specifically wanted to open her up to see what the cause was [my wife manages the hospital].  So, this wasn't simply a matter of guessing at causes.
    Mundus vult decipi
    Gerhard Adam
    Interesting side note/observation.  I was just watching a program ("Mars Rising") which dealt with the issues of keeping astronauts alive during a mission to Mars.  All manner of technologies were discussed as well as medical issues.  In addition, even genetic level screening was mentioned as a means of trying to ensure the least risk was incurred for the astronauts.

    What was notably missing, was that there was absolutely no consideration for the effect of such a trip on the microbiota.  Not a mention.  So, despite the fact that we already know that some normal microbes may become pathogenic, it doesn't seem like this is much of a topic of discussion [in terms of general awareness].
    Mundus vult decipi