Wednesday 13 July 2016

Bugging the uterus

I grew up as a geneticist and evolutionary biologist,  at the top of my modest game when analysing DNA sequences on a computer. I was safe there, although a disaster in the lab. Then about 15 years ago I got a billet in a comparative immunology lab on the theory that my expertise could bring a needed new dimension to their research.  It was hard for everyone because geneticists go all weak at the knees with B-cells, T-cells and dendritic cells and affect to be unable to understand the difference between CD4 and CD8 and the other proteins which coat the surface of these immune cells. Immunologists, on the other hand, have a model where CD4 and CD8, and the other proteins poking out of the membranes of cells, are just there without ever reflecting that they are there because of the DNA in the cell's nucleus.

I have a long-standing interest in microbiomes: the invisible freight of bacteria on which a lot of our health and happiness depends. The intestinal flora is one such ecosystem which you should cherish with kale and strawberries straight from the field. If you wage war down there with oral antibiotics for an earache, then you can get yourself in serious trouble with Clostridium difficile or worse.

Now here comes an interesting study of the uterine microbiome which gives a clue about two of the great immunological mysteries of mammalian reproduction.  The first is the miracle of bearing young at all.  Birds get their eggs fertilised and then unload them in a convenient hard-shelled package where they continue their development until hatching.  Mammals otoh hold these ever growing cluster of 'foreign' cells inside.  Immunity is all about recognising the difference between self and non-self.  The embryo may have half its genes in common with its mum but the other half is clearly foreign, yet women tolerate this interior growth for nearly 40 weeks.  If it was a tumour (which is much closer genetically than a fetus), the mother would be f**ked.  Lots of people have theories about how this tolerance is achieved but we're still short of data and evidence to clear up the conundrum.

The other mystery was mostly in my head and hinged on a false premise. If the uterus is effectively sterile and delivery is such a one-way ticket, then how come so many cows get endometritis [inflammation of the uterine lining] immediately after birth.  This is a major cause of bovine infertility and so economic loss to the dairy industry.  I was wrong about the sterile uterus.  Like every other warm wet place about us, bacteria like to set up home there. Endometritis occurs when the balance among the uterine flora changes with the disruption - physical and hormonal - of delivery.

It turns out that the uterine flora is more similar to that in the oral cavity than the wild bunch in the vagina next door.  I've shown that oral, fecal and vaginal bacteria are as different from each other, despite being in the same person, as the ecosystems of the Serengeti and a Rwandan jungle are different despite being on the same continent.  For a long time we couldn't get a handle on the microbial diversity in real ecosystems because swab we might but most bacteria have never been grown on a Petri dish and were effectively uncharacterisable because of this. Non-culturable bacteria are no longer invisible because of next generation sequencing NGS.  This allows researchers to pick up a mess of potage, give it a good whizz in a Moulinex blender and then sequence all the DNA. In particular they tend to pick out all the 16S RNAs which will tell them what sort of bacteria were present in the sample before they were turned into soup.  We have, for example,  the complete sequence of Neisseria meningitidis, which can be grown in the lab. If they pull out similar but not identical 16S RNA they can surmise that Neisseria unknowniditis is present. And the researchers can even get a quantitative estimate of what's present.

The paper gives a really interesting insight into the complexity of microbial interactions.  Several adverse conditions including premature birth depend on (are caused by) the presence of more than one species of microbe: it's the interactions, stupid. But normal full-term pregnancy seems to be mediated by the bacterial flora of the uterus as well. The solution to the mystery of pregnancy may well lie with our beneficial bacteria.

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