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Not Exactly Rocket Science
« I’ve got your missing links right here (29 October 2011)
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Our bodies are a global marketplace where bacteria trade genes

There is a vast, unseen marketplace that connects us all. The traders are the trillions of bacteria that live on or within our bodies; the commodities they exchange are genes. This flow of genes around our bodies allows bacteria to rapidly evolve new skills, including the abilities to resist antibiotics, cause disease, or break down environmental chemicals. In the past, scientists have caught glimpses of individual deals, but now the full size of the marketplace is becoming clear.

The human body is home to 100 trillion microbes, whose cells outnumber ours by ten to one, and whose genes outnumber ours by a hundred to one. These genes are not only more numerous than ours, but they operate under different rules. While we can only pass down our DNA to our children, bacteria and other microbes can swap genes between one another. For example, the gut bacteria of Japanese people have a gene that helps them to digest seaweed. They borrowed it from an oceanic species that hitched its way into Japanese bowels, aboard uncooked pieces of sushi.

This was an isolated example, but such ‘horizontal gene transfers’ are fairly commonplace. When Chris Smillie and Mark Smith from MIT looked at the genomes of over 2,200 species of bacteria, they found 10,000 genes that had been recently swapped. These genes were more than 99 percent identical, even though they came from bacteria that were distantly related*. Standing out like beacons of similarity amid seas of difference, they must have been transferred from one species to another, rather than inherited from mother cell to daughter.

Our bodies turn out to be hotbeds of horizontal transfers. Around half of the bacteria species from Smillie and Smith’s study are part of the human microbiome – a term that refers to our collective microbes and the genes they carry. These species are 25 times more likely to have swapped genes with one another than those that have nothing to do with humans. The x-axis represents the evolutionary relationships between two species of bacteria: the further to the right, the more distantly they’re related. The y-axis shows the frequency of genetic trades.

The graph also shows that these exchanges are largely dictated by the environments that different species live in. To bacteria, our bodies are worlds of different habitats, from rainforest-like armpits to desert-like forearms. Perhaps unsurprisingly, species that inhabit the same body parts are particularly strong trading partners. Even those that live in the gums, for example, are more likely to swap genes with other gum species than those from elsewhere in the mouth.

In this way, ecology trumps history and geography. Bacteria that are separated by billions of years of evolution can still transfer genes to one another, as can species that live on different continents – what matters is that they share the same environment. If that’s the case, they’re more likely to swap genes than close relatives from different habitats.

These incoming genes probably make bacteria even better adapted to their particular niches, just like seaweed-digesting genes allowed Japanese gut bacteria to break down a commonly encountered food. The most beneficial genes are likely to spread quickly through the local species. By searching for them, Smillie and Smith hope to identify the genetic ace cards that give bacteria an edge in a given environment. They have already started to identify transferred genes associated with life in hot springs or soil, and those that allow disease-causing bacteria to cause infections and resist antibiotics.

The latter group could be particularly useful to us. For example, the bacteria that cause meningitis have 24,000 mystery genes. No one knows what they do, and it would take too long to test them all to see which, if any, help the bacteria to infect humans. But Smilie and Smith found that 13 of these genes have been recently acquired from other species – they are a good place to start.

They also identified 42 antibiotic-resistance genes that had hopped into the human microbiome from bacteria that contaminate food, or live in farm animals. These microbes can act as proving grounds for genetic defences that eventually find their way into human infections.

Smillie and Smith also found that 43 resistance genes in the human microbiome hadn’t just transferred between bacteria, but across national borders. The genes were identical in different bacterial species sampled from different countries. Nothing makes it clearer that our bacteria are connected in ways that transcend our bodies and even our nations. If we introduce new genes, say for resisting antibiotics, into a local pool, we can soon pay an international price.

Reference: Smilie, Smith, Friedman, Cordero, David & Alm. 2011. Ecology drives a global network of gene exchange connecting the human microbiome. Nature http://dx.doi.org/doi:10.1038/nature10571

Photo by Ester Inbar

An introductory slideshow to the microbiome:

<p>You could be sitting alone and still be completely outnumbered for your body is home to trillions upon trillions of tiny passengers – bacteria. Your body is made up of around ten trillion cells, but you harbour <em>a hundred </em>trillion bacteria. For every gene in your genome, there are 100 bacterial ones. This is your ‘microbiome’ and it has a huge impact on your health, your ability to digest food and more. We, in turn, affect them. Everything from the food we eat to the way we’re born influences the species of bacteria that take up residence in our bodies.</p>
<p>This slideshow is a tour through this “<a href="http://www.nytimes.com/2010/07/20/opinion/20tue4.html?_r=1">universe of us</a>”. Every slide has links to previous pieces that I’ve written on the subject if you want to delve deeper. Or download a podcast of <a href="blogs.discovermagazine.com/notrocketscience/2011/10/19/i-microbes-my-radio-4-talk-on-the-hordes-of-microbes-inside-us/">my Radio 4 programme on these hidden partners</a>.</p>
<p>Image by David Gregory &amp; Debbie Marshall, Wellcome Images</p><p>To our microbiome, the human body must seem like an entire planet, full of different ecosystems. This is especially true for those that <a title="Permanent Link to The bacterial zoo living on your skin" href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/06/23/2009/05/28/the-bacterial-zoo-living-on-your-skin/">live on our skin</a>. At the microscopic scale, the hairy, moist surface of your armpits is as different from the smooth, dry skin of your forearms as a rainforest is to a desert.</p>
<p>In a thorough survey of our skin microbiome, Elizabeth Grice identified species from at least 205 different genera. Your forearm has the richest community with an average of 44 species, while your nostril, ears and inguinal crease (between leg and groin) are the most stable habitats. Grice also found at bacteria from a specific body part have more in common than those from a specific person. Your butt microbes have more in common with mine than they do with your elbow microbes.</p><p>Despite its diversity, the skin microbiome is a tiny country village compared to the <a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/06/23/2010/03/03/the-bacterial-zoo-in-your-bowel/">bustling metropolis inside your bowels</a>. The dark corridors of your intestine house more bacteria than any other part of your body. A team of international scientists led by Junjie Qin and Ruiqiang Li discovered that each of our bowels carries at least 160 bacterial species. Together, our collective guts have just under 3.3 million bacterial genes, more than 150 times as many as reside in our own genomes. They also showed that the gut microbiome of a healthy person looks very different to that of someone with a bowel condition like Crohn’s disease or ulcerative colitis.</p>
<p>Despite this diversity, Peer Bork has shown that the gut bacteria of people from Europe, North American and Japan collapse <a href="http://blogs.discovermagazine.com/notrocketscience/2011/04/20/divided-by-language-united-by-gut-bacteria-%e2%80%93-people-have-three-common-gut-types/">into three enterotypes, or gut types</a>. These clusters cut across age, gender, body weight and nationality. Each produces energy in a slightly different way, manufactures a different vitamin and may affect our susceptibility to different diseases.</p>
<p>The quest to understand gut microbes may seem like an arcane niche of science, but it’s actually very important for public health. We rely on these microscopic passengers more than we realise. They harvest energy from our food, provide us with nutrients that would otherwise be denied to us, prevent the growth of harmful bacteria, and more. In many ways, they’re like a forgotten organ. They can also go rogue, changing their community in ways that are linked to obesity or bowel diseases.</p>
<p> </p>
<p>Image by Med. Mic. Sciences Cardiff Uni, Wellcome Images</p><p><a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/06/23/baby%e2%80%99s-first-bacteria-depend-on-route-of-delivery/">We inherit our microbiomes from our mother</a>, picking up billions of them as we slide from her largely bacteria-free womb through her microbe-laden vagina. Being slathered in vaginal microbes might not seem like much of a treat but it’s vital for a newborn.</p>
<p>Babies end up with a very different portfolio of skin and gut bacteria depending on how they are delivered. Those who are born naturally harbour a more diverse array of bacteria, which resemble those in their mother’s vagina, including several species that are important for digestion. Those who are delivered by C-section are colonised by a less diverse array of bacteria, including some like <em>Staphylococcus</em> that are picked up from the hospital environment.</p>
<p>These early differences could directly affect a baby’s health for these first colonisers determine which the species that will follow. The bacterial heirlooms that babies inherit from their mothers might act as a shield, preventing more dangerous microbes like from setting up shop. By changing baby’s first bacteria, C-sections could alter the make-up of their later communities, leading to long-term effects on health and nutrition.</p><p><a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/08/03/you-are-what-you-eat-%e2%80%93-how-your-diet-defines-you-in-trillions-of-ways/">Our microbiome is like a hidden organ</a>, helping us to break down foodstuffs that our own cells cannot cope with. And in turn, our food affects our microbiome. Our first set is laden with genes for digesting milk proteins, allowing us to make full use of our only source of nourishment as babies. Breast milk might even have evolved to nourish the most beneficial bacteria with special sugars.</p>
<p>Just before we move onto solid foods, our microbiome starts activating genes that break down the complex sugars and starches in plants, preparing us for the menu to come. As our diet diversifies, so do our bacteria. They activate genes that use carbohydrates effectively, produce vitamins, and break down unusual and diverse chemicals. As adults, our microbiome becomes relatively stable, but its membership roster depends on the food we eat. The guts of African villagers who eat high-fibre diets are dominated by plant-digesting specialists, which are much rarer in the guts of Europeans who eat high-fat diets.</p><p>Before the age of better food hygiene, our meals used to provide a rich source of foreign bacteria that our microbiome could plunder for genetic tools. Bacteria trade genes as easily as humans trade gifts. For example, the gut bacteria of Japanese people have borrowed genes from a marine species, which now <a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/04/07/gut-bacteria-in-japanese-people-borrowed-sushi-digesting-genes-from-ocean-bacteria/">allows them to digest the special carbohydrates in seaweed</a>. The marine bacterium eats seaweed, including the types that are used to make nori, a common sushi ingredient.  In the past, when diners wolfed down morsels of nori, some also swallowed seaweed-eating bacteria, which traded genes with those in their own guts.</p>
<p>This wouldn’t happen nowadays because nori is roasted before being eaten. In fact, processing food presents a blockade to bacteria from the outside world and as a result, Western gut communities have become gentrified. They lack genetic diversity, and they have few ways of increasing it.</p>
<p>Images by Alice Wiegand, Alex Kovach, Tristan Barbeyron and Mirjam Czjzek</p><p>The microbiome is more than just our partners-in-digestion – they affect our health too. They have been linked to a variety of medical conditions, including allergies, immune diseases, and even obesity. For example, the balance of the two major groups – the Bacteroidetes and Firmicutes – <a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/06/23/2008/10/06/human-gut-bacteria-linked-to-obesity/">could influence our body weight</a>.</p>
<p>Fat mice and humans have a less diverse milieu of gut bacteria, with a <a href="http://blogs.discovermagazine.com/notrocketscience//notrocketscience/2008/12/01/gut-bacteria-fat-or-thin-family-or-friends-shared-or-unique/">greater proportion of Firmicutes to Bacteroidetes in their bowels</a>. This ratio increases if we eat high-fat diets and falls if we eat low-fat diets. And if the gut bacteria from fat mice are transplanted into mice with no gut bacteria of their own, they can make the new hosts overeat and pile on the pounds. This research suggests that gut bacteria could be manipulating us for their own ends. Some species send out signals that make us hungrier, encourage us to eat more, and affect the way we store fat. And some of our immune genes help to moderate these signals.</p>
<p>As we learn more about our bacterial partners, we might eventually find ways of influencing them to improve our health. This is already happening. In 2008, Alexander Khoruts from the University of Minnesota managed to cure a woman with a “vicious gut infection” by giving her <a href="http://www.nytimes.com/2010/07/13/science/13micro.html?_r=2&amp;pagewanted=1">a transplant of her husband’s gut bacteria</a>.</p><p>What happens in the gut doesn’t stay in the gut – it sometimes affects the brain. Animal studies have started to show that the microbiome, from its staging ground in the bowel, can influence the development of its host’s brain.</p>
<p>Rochellys Diaz Heijtz found that <a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2011/01/31/gut-bacteria-steer-the-development-of-the-young-brain/">germ-free mice, without any microbiome</a>, were more active, less anxious and less risk-averse than usual. Their brains differed in the activity of over a hundred genes that provide cells with energy, influence chemical communications in the brain and strengthen the connection between nerve cells. Heijtz could even shift her germ-free mice towards “normal” behaviour and genetic activity by giving them a microbiome transplant, but this only worked early in their lives.</p>
<p>But later,  Javier Bravo  at University College Cork managed to<a href="http://blogs.discovermagazine.com/notrocketscience/2011/08/29/from-guts-to-brains-%e2%80%93-eating-probiotic-bacteria-changes-behaviour-in-mice/"> change the behaviour of normal adult mice</a> by feeding them with a probiotic bacterium  called <span id="apture_prvw1" class="aptureLink"><span class="aptureLinkIcon" style="background-position: right -1348px;"> </span><span class="aptureLink snap_noshots"><em>Lactobacillus rhamnosus</em></span></span>,  often found in yoghurts and dairy products. The bacterial menu changed  the levels of signalling chemicals in the rodents’ brains, and reduced  behaviours associated with stress, anxiety and depression.</p>
<p>Meanwhile, Gil Sharon found that <a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/11/01/gut-bacteria-change-the-sexual-preferences-of-fruit-flies/">gut bacteria can shape the sexual choices of flies</a>. Flies that are raised on diets of starch prefer to mate with other “starch flies” while those raised on maltose prefer “maltose flies”. When Sharon dosed the flies with antibiotics, she killed both their gut bacteria <em>and </em>their sexual preferences. If she inoculated the sterile flies with the microbiome of their peers, their preferences reappeared instantly. It’s possible that the bacteria influence the levels of sex pheromones that affect the fly’s attractiveness.</p>
<p>These studies show that you can’t understand an animal’s evolution simply by considering the evolutionary pressures that act on its genome. You also have to consider the genes of the bacteria and other passengers that live inside it. We’re each like a superorganism – a unified alliance between the genes of several different species, only one of which is human.</p>The teeming masses of the microbiome also contain a record of our evolutionary past. Howard Ochman found that the <a href="http://blogs.discovermagazine.com/notrocketscience/notrocketscience/2010/11/16/gut-bacteria-recap-the-evolution-of-apes/">evolution of the gut microbes in great apes</a> perfectly recaps that of their host. The bacteria from the two species of gorilla are more closely related to each other than they are to human gut bacteria. Geography, diet and disease aside, the main thing that influences the members of these bacterial cities is the species of the host. You could reconstruct the evolution of the apes, simply by comparing the bacteria in their bowels.<p>The bacteria of our microbiome are mostly our allies. <a href="http://blogs.discovermagazine.com/notrocketscience/2011/10/13/beneficial-gut-bacteria-can-become-virus-collaborators/">But they can also they can be turned against us.</a> Two new studies in mice have found  that viruses - including one that causes polio, and another that causes cancer - can exploit gut bacteria to infect our bodies.</p>
<p>They use molecules on the bacteria's surfaces as reins, to ride towards host cells, or backstage passes to sneak past the immune system. Our microscopic allies can turn into  unwitting collaborators for dangerous infections.</p>
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October 31st, 2011 by Ed Yong in Bacteria, Genetics, Horizontal gene transfer, Microbiome | 4 comments | RSS feed | Trackback >

4 Responses to “Our bodies are a global marketplace where bacteria trade genes”

  1. 1.   Rebecca Says:
    November 2nd, 2011 at 10:44 pm

    Mark Smith, the lead scientist on this project is answering questions from users about the study here: http://www.zopost.com/article?articleId=6

  2. 2.   James Freeman Says:
    November 6th, 2011 at 9:16 pm

    Mark,

    Some very interesting research. I do have some questions:

    1. Does it follow from your findings that each human, in creating a unique “market-place”, could have a unique population/species of bacteria found no where else? Is it possible to define separable species in this context, when there is such widescale trading of genetic material?

    2. How quickly in the life of a human does the “marketplace” get established? Does it happen in utero (and if so, how do they get there?), or, within the days and weeks after birth?

    3. Do the residents change with changes in age and diet, or, do the existing residents adapt to the changing environment genetically, or, do they simply switch on/off existing protein catalysts (where they have them) to respond to shifts in food availability?

    4. How does the production of IgA in the mucosal lining of the intestine influence the “marketplace”?

  3. 3.   Mark Says:
    November 9th, 2011 at 4:48 pm

    Hi James,

    These are insightful questions!

    1) Although many bacterial strains and genes are common and shared among many of us, we do suspect that each person harbors their own, unique bacterial community (possibly enabling forensic use as described here: http://www.pnas.org/content/107/14/6477). Although we know this is true at the species level, we’re still unclear whether its true at the level of transferred genes – this is an active area of research in our lab at the moment. Your second question about the difficulty of defining bacterial species in the context of promiscuous HGT highlights a deep, open problem in the microbiology community. I’m afraid I don’t have much additional insight to offer here, although I’ll point out that its possible that a core set of genes are transferred much less than the mobile set that we studied. Although the promiscuous nature of HGT means that the concept of ‘species’ among bacteria is undoubtedly quite different from what we think of among vertebrates etc, it is possible to trace bacterial lineages from these core genes which are transferred much less frequently.

    2) Bacterial communities are established quickly after birth (http://www.pnas.org/content/early/2010/07/27/1000081107) but are not believed to assemble in utero. This community assembly process is likely critical for proper immunological development and inadequate or inappropriate exposure underlies the so called ‘hygiene hypothesis’ for many immunological disorders observed in developed countries.

    3) You’ve addressed another very important open question in the field here. This is an area of very active research in ours and other groups. You can expect some interesting results will be published to address these questions in the near future!

    4) IgA is one of several important mechanisms by which our immune systems interact with our microbiota. Although it is almost certain that host immunity plays an important role in shaping our bacterial communities, we haven’t yet determined exactly what the implications are of these interactions.

    These are great points – we’re happy to answer more questions as they arise!

    All the best,
    Mark

  4. 4.   James Freeman Says:
    November 11th, 2011 at 11:49 am

    Mark,

    As I get older (I’m 43), I find myself coming back to my love of science (MSc in Electrical Engineering, but that was half my life ago….) in part, prompted by questions my children ask. As a sometimes sufferer of “IBS”, I’m interested in following the latest science in this area, and your work very much hits home. Please keep it up, and thank you for taking the time to respond to my modest questions.

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