Is the secret to human intelligence lurking in our guts? Recent studies suggest that it might. Together, your genes and the genes of your microbes make up the “hologenome,” a single entity that is molded and shaped by our environment. Read on to learn how microbes impact our evolutionary fitness and how they may have made our species what it is today.

hologenome

We can learn a lot from looking at paleontological evidence and studying the few remaining traditional hunter-gatherer cultures on Earth. From an ancestral or evolutionary perspective, it is increasingly clear that many modern chronic diseases are a result of a mismatch between our innate biology and our modern environment.

When we think about our biology and human evolution, though, we’re typically thinking about our genes, which carry our heritable genetic information. But what about the 99 percent of the genes associated with your body that are not even human? That’s right—while each human carries about 23,000 protein-encoding genes (1), the microbes living on and in your body have an estimated 9 million different genes (2). And these genes may be key players in determining the evolutionary trajectory of the host.

Before we go any further, though, let’s review a few basics of evolution.

Evolution 101

Every living organism has a genetic blueprint in the form of DNA. All of our physical characteristics are encoded by this DNA (and how it is expressed). When organisms pass on their genes in the form of DNA to the next generation, they are copied very precisely. On occasion, however, there will be a small change, or mutation, in the genetic code. These small changes ultimately produce genetic variation in a population of organisms. Sexual reproduction also provides a great deal of variation, with offspring receiving a mix of genes from both parents.

A particular mutation or variant of a gene can be harmful, neutral, or beneficial to an organism’s overall fitness. Those organisms that are most “fit” for their environment are more likely to survive, reproduce, and pass on their genes to the next generation. Organisms therefore tend to become more adapted to their environment over time. The various constraints of a given environment are the “selective pressures” that favor the survival and reproduction of one organism over another.

If two distinct populations of a given species migrate into different environments, they will experience different selective pressures and, over many generations, adapt to their respective habitats. If they are separated for long enough, their physiology may no longer allow them to mate with one another and produce viable offspring. When this occurs, we say that a new species has formed.

Since Charles Darwin published On the Origin of Species in 1859, abundant geological, paleontological, anthropological, molecular, and genomic evidence has provided support for his theory of natural selection. With recent knowledge about our microbial inhabitants, the picture has become a bit more complex.

The “hologenome”

In 2007, Eugene Rosenberg and Ilana Zilber-Rosenberg introduced the concept of the hologenome. Far from contradicting Darwin’s theory of natural selection, the concept of the hologenome instead adds a layer of complexity that was not previously considered in evolutionary biology. It suggests that together, the host genome and the genomes of all of its related microbes make up the “hologenome” (3).

In other words, evolution does not act solely on your 23,000 human genes. Rather, it acts on the 9.02 million genes (both host and microbial) that are present in and on your body, as a single entity. This is true for every multicellular organism on the planet, as symbiotic relationships with microbes are ubiquitous among eukaryotic organisms like animals, plants, and fungi. Every animal with a digestive tract has some form of gut microbiota that is unique to that animal. Similarly, plants are coated in bacteria and fungal microbes on their leaves and roots (4).

Did you know your body is part of a hologenome?

Microbes significantly impact host fitness

If you’ve read some of the other articles on my blog, the idea that microbes play a role in host fitness should be a no-brainer. Numerous modern chronic diseases are associated with disruption of the microbiota, such as allergies, autoimmunity, skin conditions, inflammatory bowel disease, thyroid conditions, diabetes, obesity, and others (5). The microbiota plays many roles in shaping the health of its host, including protection against pathogens, metabolism, detoxification, and immune and nervous system development (6). Microbes are also known to produce signaling molecules that influence human gene expression (7). In short, a healthy microbial composition typically results in a more “fit” individual.

In fact, microbes have been impacting host fitness for as long as multicellular organisms have been around. Mitochondria, the part of your cells responsible for producing energy, were actually once a free-living bacterium that was engulfed by a eukaryotic cell (a cell containing a nucleus) (8). This symbiotic relationship eventually became permanent. Similarly, in photosynthetic plants, the chloroplasts that are able to use light energy to make organic compounds are very closely related to cyanobacteria (9). Life as we know it would simply not exist without these microbially derived structures.

Microbes increase genetic variation

In addition to directly impacting host fitness, the microbiota provides three novel modes of introducing genetic variation (10). Variation is absolutely crucial for the emergence of new traits and ultimately new species.

  1. Horizontal gene transfer: Unlike eukaryotes, bacteria and archaea are able to link up and share genes with one another. This means that even microbes that don’t colonize your body (like those in probiotics and fermented foods) can still potentially exchange genes with your resident microbes when they encounter one another.
  2. Microbial amplification: Changes in the local environment allow some microbial populations to flourish and other microbial populations to contract. This results in a shift in the collective microbial gene pool. We see this consistently with the influence of diet on microbial composition (11).
  3. Acquisition of novel strains: Encountering new microbes in the environment may result in a few strains of microbes that are able to colonize the host. This acquisition of new strains also means the addition of new genes to the microbial gene pool.

Are some of your “human” genes microbial too?

As mentioned in the previous section, horizontal gene transfer occurs frequently between microbes (12). For example, the Japanese are able to digest agar because they traditionally eat large quantities of seaweed. The marine bacterium Zobellia galactanivorans colonizes the surface of marine plants, feeding on the agar. When the Japanese routinely ingested this marine bacterium on raw seaweed, it “shared” its genes for agar-degrading enzymes with their resident gut bacteria (13). In this way, the microbes present on the foods that we eat may very well “educate” our gut bacteria by sharing the genomic information necessary to digest it.

So microbes can share genes with each other. But what about human cells? Can microbes share genes with us? Recent studies suggest that they can, and in fact, it occurs quite frequently. A total of 145 genes commonly thought of as “human” genes can be attributed to horizontal gene transfer. Most of these genes come from bacteria, but some come from viruses or yeast (14). Considering the fact that only a small percentage of microbes on Earth have been identified (15), and an even smaller percentage have had their full genome sequenced, it’s quite plausible that many more of our genes will be shown to have microbial roots in the coming decades.

Microbes: Creators of new species

Microbes also influence the emergence of new species. In 1989, studies on fruit flies showed that splitting a fly population and raising some on a molasses medium and others on a starch medium resulted in distinct mating preferences. The flies grown on molasses preferred other “molasses flies” and the flies grown on starch preferred other “starch flies” (16). This is important because mating preference is considered to be an early event in the emergence of new species.

More recent studies followed up on this finding and found that antibiotic treatment eliminated the diet-induced mating preference. Subsequent recolonization of these antibiotic treated flies with the bacterium Lactobacillus plantarum reestablished the mating preference. The researchers found that L. plantarum was able to change the levels of sex pheromones released (17,18).

The microbiota also influences whether an offspring is viable after conception. Recall that according to the biological species definition, two groups of organisms that cannot interbreed with one another and produce viable offspring are considered to be separate species. A study on wasps found that when recently diverged wasp species were crossbred, all of the hybrids died during the larval stage. Antibiotic treatment rescued the survival of the hybrids, suggesting that their symbiotic microbes played a role in hybrid mortality (19).

Host genome shapes the microbiota

While your environment, early-life experiences, and diet all play a major role in shaping the composition of your microbiota, your genes also play a role. Across the animal kingdom, microbial community composition parallels phylogeny (20). This means that animals that share a more recent common ancestor and are more closely related to each other on the evolutionary tree of life also tend to have more similar microbiotas, even when maintained on the same diet (21).

Genetic variation can also explain differences in the microbiota within a single species. Single nucleotide polymorphisms (a change in one base molecule in the DNA) and copy number variations (the number of a certain gene that you have) can explain differences in the microbiota (22). Furthermore, in humans, identical twins have a very similar microbiota composition (23), and microbial composition tends to correlate with ethnicity (24).

So how exactly do your genes shape the community of microbes that inhabit your gut, skin, lungs, nasal passages, and other areas of your body? It turns out that hosts have developed several means of regulating which microbes can colonize and which cannot. One is encoding genes for antimicrobial peptides, which are secreted at mucosal surfaces. These small proteins inhibit the growth of certain microbes over others (25). Hosts also produce microRNA molecules that can enter bacteria and regulate bacterial gene expression, growth, and survival (26).

Expansion of diet and increased social behavior fueled human evolution

Hopefully you’re still with me, because now we get into the really interesting stuff: how the hologenome played a role in the evolution of our species, Homo sapiens. Scientists have long speculated about the forces that were responsible for the development of human intelligence. Two factors seem to stand out in relation to the hologenome: an expansion of hominid diets and an increase in social behavior. Let’s look at each separately.

Meat, starchy carbohydrates, and the advent of cooking have all been associated with expansion of the human brain (27,28). The transition to bipedalism (walking upright on two legs) allowed for the carrying of foraged materials from great distances, diversifying the diet of early hominids (29). It also made it easier for our ancestors to track and pursue large animals.

This diversification of meat and plant foods necessitated a similar diversification of microbes able to extract nutrients from these new energy sources. A study published just this month found that humans have a faster metabolic rate than any other primate, which likely fueled the evolution of larger brains (30). This increase in metabolic rate was likely at least partly due to changes in microbial composition, as microbes have been suggested to play a key role in determining host energy expenditure (31).

Social behavior in primates is also thought to be a critical factor in the evolution of human intelligence (32). Access to microbes may have been a driving force in the evolution of animal sociality, since microbes confer many benefits to the host (33). Social behaviors like grooming, kissing, and sex increased the transfer of microbes from one organism to another. Studies in social mammals have found that development of the forebrain and neocortex in social mammals depends on signals from the microbiota (34), and germ-free mice that lack a microbiota also lack social behavior and show deficits in social cognitive abilities (35).

What’s in it for the microbes?

All right, it’s clear that we benefit from the microbes in our guts. But what’s in it for the microbes? As mentioned in the previous section, increases in host social behavior allow for enhanced microbial transmission between hosts. Living in symbiosis with a host also provides microbes with an environment rich in nutrients. Recent evidence suggests that the microbiota might even shape host feeding behavior (36), making you crave the very foods that feed particular species in your gut (stay tuned for an article on that topic).

It’s also important to keep in mind that evolution does not have an end goal. Historically, Earth was completely microbial for 2 billion years before eukaryotes entered the scene. Simply put, eukaryotic evolution has never seen a period without the presence of microbes. An ancestral approach to health would be therefore be remiss without considering the role that microbes and the hologenome have played in the past and the role that they will play in shaping the future of our species.

You might be left wondering: is our modern diet and overuse of antibiotics messing with evolution? It’s certainly possible. A recent study performed in Dr. Justin Sonnenburg’s lab at Stanford showed that in mice, a diet low in fiber caused dramatic changes in the microbiota that were reversible within that generation if fiber was reintroduced. Over several generations, however, a low-fiber diet caused an irreversible loss of microbial diversity (37).

Cultivating a healthy community of microbes with a nutrient-dense diet is not only important for your own health, but might also be important for the health of your great-great-grandchildren!

Now I’d like to hear your thoughts. Had you ever heard of the hologenome? What was most surprising to you? Let us know in the comments section!

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