Microbes Are Promiscuous Swingers, and That's a Problem

How can we rely on microbes when they are wildly swapping their DNA?

Posted Apr 03, 2019

Brooke Anderson, used with permission
Even in the lab, microbes are promiscuous.
Source: Brooke Anderson, used with permission

Humans enjoy a stately pace of evolution. Over the last million years, perhaps 1% of our genes have changed.[1] Compared to microbes, we are total slackers. Two new studies show that microbes can pick up and swap out entire genes wholesale, seemingly on a whim. 

These tiny creatures have a few thousand genes that describe every detail about how to build and operate a microbe. Vertical gene transfer, in which genes pass down to descendants after cell division, works for both humans and microbes. But microbes have an edge: They can also gain or swap genes from neighboring cells and viruses, a process called horizontal gene transfer. These genes can come from literally anywhere they can find them; microbes are not fastidious.

Our adaptive immune system tries to keep up with this manic morphing, but when your enemy makes you look like a snail, you have a problem. That's why, millions of years ago, our ancestors struck a deal with microbes: In return for some moisture and three meals a day, humans recruited "good" microbes to protect them from the "bad" ones. It takes a mutating microbe to fight a mutating microbe.

They live by the trillions in our colon, and they are our first line of defense against the foul pathogens that carpet the planet. We have evolved together with our gut microbes – our microbiota – for long enough that we even talk the same molecular language. Shockingly, microbes produce human hormones and neurotransmitters, psychoactive chemicals that can lift our moods if we treat them well. They can also leave us depressed and anxious when things get unbalanced.

For the most part, it's a beautiful partnership. But it is a partnership without a written agreement. At any time, our "friendly" microbes can turn against us. Their allegiance to our health is pretty much what you would expect from a microbe. Sometimes, that loyalty comes down to just a few genes here or there. But a mere gene or two? How bad can that be?

Consider diphtheria, botulism, and cholera. We blame these diseases on bacteria, but they are really caused by a toxin gene injected into the hapless bacteria by bacteriophages – viruses that prey on bacteria.[2] That's right, even your bacteria can pick up an infection. Without the injected genes these bacteria are decent guests, but once infected they can become deadly.

Microbes Are Adventurous

Our gut houses a seething meet market of gene-swapping microbes. Viruses are a major facilitator of these hookups. Viruses can transfer genes into and out of bacteria, yeast – and even animals. That is likely how microbes and humans came to share the genes that code for neurotransmitters. That common language allows our microbes to "talk" to us directly, using the vagus nerve as the conduit between the gut and the brain.

Genes also code for enzymes that are involved in metabolism – the everyday chemistry of life. Metabolism involves multi-step reactions, like the Krebs cycle that you learned in school and promptly forgot. Each cycle or pathway may involve a dozen enzymes acting like an assembly line, one adding a hydrogen here, another taking away a carbon there. An example is fermentation: in a series of steps, various enzymes break down complex sugars to produce all sorts of metabolic products from alcohol to fatty acids to methane. We typically attribute these reactions to specific microbes, but the actual engineers of metabolic pathways are enzymes.

If you know what genes you have available, you know which enzymes you can make. That, in turn, tells you which metabolic reactions are possible. The microbes themselves are merely bit players, easily replaced by other microbes with similar enzymes.

New Studies

In a recent study from Eran Segal and colleagues at the Weizmann Institute of Science, a surprising number of gene swaps, additions, and deletions were found in the human microbiota.[3] Almost 10% of the genes in an ordinary microbiome are variable and over a quarter of the genes are deleted from various species. They found gene swapping in every bacterial strain they analyzed.

Segal's group found that it isn't the microbes, per se, but the genes that make a difference in our lives. The researchers found a microbe named Anaerostipes hadrus in most microbiotas, but in some people their population of A. hadrus had five deleted genes, and those people were heavier. The effect is due to the genes, not the microbes. Segal says, "We found a [genetic] region in A. hadrus that was deleted in 40% of people, and those people weighed on average 6kg more than people whose A. hadrus microbe retained this region. The region makes butyrate, a molecule known to have health benefits."

Another study from Mario Falchi and colleagues at King's College London, found that two unrelated people typically share over 80% of their metabolic pathways, but those same people only share 40% of their microbial species.[4] Again, the genes and the pathways they enable are more relevant than the actual microbes.

Because this was a twin study, the researchers were able to look at how many of our microbes and metabolic pathways are inherited. Falchi says, "The heritability of metabolic pathways is a bit higher than the heritability of species, however both of them are apparently not very highly heritable." This implies that a sizeable portion of your metabolic and microbial profile is due to your environment.

Although this finding is not in the study, Falchi says, "We also compared the functional and taxonomical composition similarities between [identical] twins, and we obtained estimates very similar to what we [found] for unrelated individuals." In other words, even twins look dissimilar when you only examine their microbes.

The Big Picture

These new studies are looking at the entire set of genes in a sample, using a technology called whole shotgun metagenomic sequencing. It is more expensive than typical methods that identify bacteria by their ribosomes, but the costs are dropping, and the finer-grained results are compelling. Expect to see a lot more such studies. John Cryan of University College Cork and a pioneer of gut-brain research, says, "Indeed the microbiome field is moving away from just cataloguing what is there, to assessing what they are doing and the functional consequences thereof."

Genes dictate which metabolic pathways are possible, but don't show which ones are actually being used. For that, researchers will have to use other techniques. "It will be important to measure the actual metabolites in various biological samples, including feces, urine, blood and even cerebrospinal fluid," says Cryan.

New Directions?

Does this mean you should quit taking probiotics? If they are working for you, fine. But keep in mind that the description of a probiotic on the jar, even down to the species level, is not enough to define the genes it contains. And, since these new studies demonstrate that the genes are the most important features of a probiotic, some skepticism is warranted.

The demotion of microbes in favor of genes and metabolites poses a problem for traditional gut-brain research, in which the Holy Grail is to find correlations between specific microbes and mood. Bacteria that improve your mood are called psychobiotics, a term coined by Cryan's colleague, psychiatrist Ted Dinan of University College Cork in 2013.

But if microbes are merely replaceable gene carriers, then those associations will be difficult to untangle. Instead, the connections between gut and brain will be easier to understand by looking at microbial genes and the enzymes they code for. The unique metabolic pathways that produce brain-enhancing chemicals like butyrate, dopamine and serotonin may hold the real keys to mental health. In fact, those metabolic end-products themselves are being investigated by Cryan and Dinan.[5],[6] As they put it, "We hypothesize that butyrate [and other metabolites] produced by microbes may be involved in regulating the impact of the microbiome on behavior including social communication."

It's a whole new way of looking at the gut-brain axis. Stay tuned for a new world of wonders.

References

[1] Rieux, Adrien, Anders Eriksson, Mingkun Li, Benjamin Sobkowiak, Lucy A. Weinert, Vera Warmuth, Andres Ruiz-Linares, Andrea Manica, and François Balloux. “Improved Calibration of the Human Mitochondrial Clock Using Ancient Genomes.” Molecular Biology and Evolution 31, no. 10 (October 1, 2014): 2780–92.

[2] Boyd, E. Fidelma. “Bacteriophage-Encoded Bacterial Virulence Factors and Phage-Pathogenicity Island Interactions.” Advances in Virus Research 82 (2012): 91–118.

[3] Zeevi, David, Tal Korem, Anastasia Godneva, Noam Bar, Alexander Kurilshikov, Maya Lotan-Pompan, Adina Weinberger, et al. “Structural Variation in the Gut Microbiome Associates with Host Health.” Nature, March 27, 2019, 1.

[4] Visconti, Alessia, Caroline I. Le Roy, Fabio Rosa, Niccolo’ Rossi, Tiphaine C. Martin, Robert P. Mohney, Li Weizhong, et al. “Interplay between the Human Gut Microbiome and Host Metabolism.” BioRxiv, February 27, 2019, 561787.

[5] Stilling, Roman M., Marcel van de Wouw, Gerard Clarke, Catherine Stanton, Timothy G. Dinan, and John F. Cryan. “The Neuropharmacology of Butyrate: The Bread and Butter of the Microbiota-Gut-Brain Axis?” Neurochemistry International 99 (2016): 110–32.

[6] Wouw, Marcel van de, Marcus Boehme, Joshua M. Lyte, Niamh Wiley, Conall Strain, Orla O’Sullivan, Gerard Clarke, Catherine Stanton, Timothy G. Dinan, and John F. Cryan. “Short-Chain Fatty Acids: Microbial Metabolites That Alleviate Stress-Induced Brain-Gut Axis Alterations.” The Journal of Physiology 596, no. 20 (October 2018): 4923–44.