The difference between the old biology of you as a single-species organism versus the new biology of you as a multispecies superorganism is a powerful network of ecological interactions. Ecology is the study of interactions between organisms and their habitats or surroundings. It can involve plants, animals, and microbes, including mixtures of all three. Sounds simple! Let’s dig in.
While I was studying genetics, I had to pass a series of three-hour written exams, each going into depth on a different subject of biology. Ecology was one of those exams, and I had to prepare mightily for it since it was not a main focus of my courses or study. The university was blessed with several premier ecologists at the time. The exam question was simple enough: “What is a niche?” In discussions of evolution you often hear of how some organism prospered because it found a niche, perhaps somewhere where there was not so much competition for resources. I don’t remember my specific answer. I do remember that, thirty-nine years ago, I had thirty pages’ worth to say on the subject during the three hours. I remember waiting and waiting for the results from these exams, since they could determine whether I would be allowed to continue my PhD study. Ironically, the results never came. We were told that the two or more premier ecology professors who made up the question and were grading the exam were unable to agree on the answer. This was not a minor thing. In fact, the entire multiple-exam system for PhD qualification in that department was, at least temporarily, suspended.
There is a long tradition in science of new big ideas having to battle old big ideas. Sometimes the battle is loud; sometimes those new scientific ideas can emerge gradually and almost unseen. But perhaps most often, it is analogous to a prolonged first-pregnancy labor: uncomfortable, if not downright painful, and a bit scary. But the birthing of new scientific ideas can be a blessed event, just like the results of that physical birthing experience.
The argument for a different, more ecological understanding of humans was introduced nicely by David Relman in the opening sentences of an article titled “Microbiology: Learning About Who We Are,” published in the journal Nature. Relman begins by noting that the “dawn of the twenty-first century has seen the emergence of a major theme in biomedical research: the molecular and genetic basis of what it is to be human. Surprisingly, it turns out that we owe much of our biology and our individuality to the microbes that live on and in our bodies—a realization that promises to radically alter the principles and practice of medicine, public health and basic science.” Relman makes the case that microbes so affect our individuality that we cannot easily separate ourselves from their effects. Our biological identity and health are intertwined with that of our microbial partners.
Ecology is often represented in popular culture in ways that more resemble a soap opera or reality TV show, When Animals Attack!, but the less biting, more encompassing title When Species Interact fits more easily into my argument. Generally, when we think of species interacting, it is usually the type of interactions that are external to the organism. Things that come to mind are a cattle egret sitting on a cow, a koala up a eucalyptus tree, a bee’s encounter with a flower, or even my dog and his obsession with the doves that he is certain invade his territory each morning. Just to extend definitions, ecological interactions describe the relationships among species when they share a community space, such as your body.
Different labeling is used to describe different types of interactions among species. For example, if two species interact and there is benefit to both, this is called mutualism. If one species benefits and the other is neutral about it or unaffected, that is termed commensalism. Finally, when one species benefits at the expense of the other species, that is parasitism. Within you, the superorganism, all of these types of ecological interactions occur almost daily. Properly managing our thousands of different species is called good health. Mostly it has been accomplished unconsciously, the whole ecosystem producing us in all our inimitable complexity according to the laws of nature.
Most people are familiar with parasites from giving heartworm medications to their dogs, having heard about the effects of tapeworms on food intake and digestion, or even the alternative therapy of deliberate exposure to hookworms (called helminthic therapy) as a way to shift certain immune reactions and reduce allergies. Less well-known perhaps is that malaria is produced by a parasite that inhabits red blood cells. That parasite is a microorganism called Plasmodium. Of the hundreds of species of Plasmodium that take up residence in various animals and plants, five have the capacity to infect humans and cause malaria. Parasitism is the simplest and least interesting form of species interaction—at least for the purposes of this book. It is true that parasites can provide some benefits while overall being pernicious, but there isn’t a lot new to say about them. We knew we didn’t want them in our bodies, and we still don’t.
Two ecological concepts drive the bus for the completed self hypothesis. The first term, “commensalism,” refers to eating at the same table, and that is precisely what our thousands of co-partner microbial species do. This term refers to the majority of our microbes that live on and in us but do not normally produce infections. In fact, you will see them called commensals or commensal bacteria. Those producing infections are termed pathogens or pathogenic bacteria. The original terminology for commensal bacteria was developed during the old biology. This is important because our relationship with most of these bacteria is not what was previously thought.
In the commensal relationship terminology of our old biology, our gut bacteria were seen to benefit from the association with us since we ingest food they can use. Previously, we were thought to be unaffected by or neutral to their presence within us (a very mammalian-centric view). The interactions may be complex, but we now know virtually every microbial part of our microbiome exerts some effect on either our mammalian self or on the other microbes that are present.
Many of these relationships are not commensal but are mutualistic, the second key concept. We benefit directly by the presence of our microbes. Take, for example, the case where certain bacteria digest otherwise indigestible sugars that are present in breast milk. This bacterial digestion and the production of food metabolites provide the baby with much-needed nutrients that it cannot otherwise get. The bacteria are also getting fed. So both the bacteria and the baby’s growing mammalian cells benefit in a mutual exchange.
We, as hosts, receive benefit from the microbes through the maturing of our physiological systems. The newborn baby is essentially incomplete until the microbes take up residence and help that baby’s development. Thus my notion of the completed self. This ecology plays out over one’s lifetime.
Up until a few years ago, immunologists thought that the baby had all it needed for a well-oiled immune system at birth. That is certainly what I was taught during my immunogenetics training in graduate school. That idea came about because immunologists could count and label cells and see that all of the cells of the immune system seemed to be present at birth. But the fallacy in this thinking was the assumption that the presence of these cells meant they were well-balanced, fully mature, and functioning well together.
In reality, the numbers and markers available really told us little about what would happen when the immune system was actually challenged, such as by an infection. And that is where we as immunologists got it wrong under the old biology. If those immune cells do not encounter our microbial partners and “grow up” side by side with them in the baby, the immune system will produce dysfunctional responses at some point later in life. We are set up for immune-based dysfunction and disease if we are incomplete and lacking a full set of microbial partners. It is as simple as that.
Two well-studied ecological systems have been useful as models for how the ecology of humans should be approached. They are the tropical rain forests that circle the equatorial regions of earth and the coral reefs found in coastal areas of several continents. Learning from these examples can keep us from reinventing the wheel with our own ecology involving the microbiome.
In the 2014 documentary movie about the microbiome titled Microbirth, I used the analogy of a forest to describe mammalian humans growing in partnership with their microbiome. The type of forest I had in mind was a complex, rich tropical rain forest. Like the areas within us that are populated by our microbiome, a healthy tropical rain forest flourishes with a mind-boggling diversity of life. Such rain forests are thought to cover only about 2 percent of the earth’s total surface but contain more than 50 percent of earth’s species. Besides being important for human well-being and the planet as a whole, they are a good model for what happens among species when things change.
A large group of scientists recently catalogued the tree species of the Amazonian rain forest. They found approximately 16,000 different species of trees. However, not every species was equally represented. According to the Nature Conservancy, a four-square-mile section of a tropical rain forest can contain up to 700 different species of trees, 400 different species of birds, and 150 different species of butterflies. But these numbers don’t reflect the contribution of a rare species to the ecosystem. Rare microbes within us can provide absolutely vital functions.
Among all the rain forest birds and butterflies are some of the best sources of medicinal plants. This area of science studying indigenous cultures and their medicinal plants, ethnopharmacology, has become important enough to require its own scientific journals and multiple scientific societies. The types of drugs from these medicinal plants run the full gamut from anticancer agents to natural antimicrobials. A couple of examples are antimalarials (quinine) from the cinchona tree and antileukemia drugs from the rosy periwinkle.
During the 1990s, I was fortunate to work briefly alongside Cornell professor Tom Eisner as we were both senior fellows in the Cornell Center for the Environment. Eisner had been dubbed the father of chemical ecology and was a strong and effective advocate for chemical prospecting in the rain forests because he saw that it could both benefit humans with new drugs and simultaneously preserve biological diversity within tropical rain forests. He was not just a proponent of this strategy but actively worked with both corporations and conservation groups to make it happen. When it comes to the ecological protection of humans, my own thinking is much influenced by Eisner’s sensibility.
Think of how the rain forest is divided into layers for a moment. The tallest trees provide the scaffolding for the forest canopy, which can reach a hundred feet, and their crowns receive the largest amount of sunlight and precipitation. They are also very efficient in photosynthesis. The canopy is rich with wildlife, including monkeys, sloths, parrots, macaws, and butterflies. In a healthy rain forest, the lower-level plants receive only filtered sunlight with much less direct precipitation and fewer strong wind gusts.
The understory plants usually live with higher humidity but cooler temperatures as they normally receive more shade. These levels tend to stay moist. Most of the understory plants would be recognized as houseplants such as the philodendron. Various tree snakes, the coatimundi, and fruit bats tend to hang out at this level.
Large mammals like anteaters, along with termites, giant earthworms, scorpions, and ants, call the floor level of the forest home. Decomposition of plant material is the main theme here. Fungi in the lower levels help to recycle nutrients to support plant and animal growth in the lower levels of the tropical rain forest.
It is beautiful to imagine this layered ecosystem. But of course in the modern world there has been much disruption. Deforestation has been connected to human practices such as logging, road construction that fragments the forest into smaller sections, and the conversion of forest into farmland. The sequence of events as a forest loses its biodiversity and the overall effects of deforestation provide us with a useful model for what we can expect if our own biodiversity declines.
In the forest, when the tall canopy-topping trees become thinned out too much, everything changes, not just for those trees but also for all the wildlife living in and under those trees. Forest clearing for agriculture is an obvious change since whole sections of the tropical forest can disappear almost overnight. Less obvious changes can happen when roads intersect the forests: More trees end up on the boundaries of the forest, where wind, different levels of exposure to sun, and more dramatic changes in water levels can affect the growth and sustainability of certain species. Animals that use those trees for food and/or housing will have lost their means of sustenance and safety. The numbers and dynamics will change unless they have highly useful alternatives.
The understory plants, living at lower levels beneath the canopy, will receive what amounts to a local climate change if the protective canopy is degraded. With environmental change and canopy thinning, more direct sunlight streams into the understory in the forest. That area becomes hotter due to the increased sunlight and subsequent evaporation. The plants and animals that live there will experience changes to their housing and food sources. It is a row of dominoes, each falling in turn.
Deforestation and changes in habitat affect both the numbers of representatives within each species and the species diversity as well. There is a domino effect of changing the habitats and species diversity where alterations in one group seem to go along with changes in others. Recently, this precise type of relationship was found in studies of plant and fungal species on the boundaries of rain forest/agricultural land areas by a multicontinent research team.
A second, equally useful example of ecology and the interaction among multiple species is the living coral reef. While coral reefs are often out of sight, the postcards aren’t lying. They represent one of the world’s true treasures. Coral reefs are not only rich locations for a disproportionately high percentage of marine life per square mile, but they are also protective barriers for coastlines and water-purifying mangrove forests. The three largest are the Great Barrier Reef off the coast of Australia, the reef off the coast of Belize, and a reef associated with the Florida Keys. Coral itself is a living animal, similar to a sea anemone, that has a soft body and grows very slowly. Its limestone skeleton base provides protection and support for the delicate body of the coral.
Coral lives in a symbiotic relationship with algae known as zooxanthellae. The algae provide oxygen to the coral and energy via photosynthesis. Additionally, the algae generate sugars, which the coral needs as nutrients in an otherwise nutrient-poor environment. The coral provides inorganic carbon in the form of carbon dioxide to the algae and acidifies the local environment, facilitating photosynthesis by the algae. The different colors associated with coral are more from the algae than the animal. Millions of species live within or around a coral reef, and their survival is interlinked with the vitality of the reef. Among the most familiar animals are the seahorse, lobster, various fish, sponges, sea slugs, eels, sea snakes, starfish, sea urchins, and clams.
Like humans, coral reefs also have bacterial and viral partners. Research into the complex interactions within the coral reefs provides a useful guide for understanding how humans can work with their microbial partners, as well as the risks involved in the degradation of our internal biodiversity. The coral reef was the original source for the term “holobiont,” coined in 1992 by theoretical biologist David Mindell. A holobiont is a host organism and associated species that, as a group, serve as a unit of evolution. For the coral reef, the holobiont is all the species that participate in and are dependent upon the life of the reef.
Recently, the coral reef with its rich array of species has also been used to describe humans and their microbial partners. A human being is also a holobiont. Anything less than a fully staffed, human-microbial holobiont is a deficient organism, an incomplete self. Coral reefs can be damaged or degraded, and so can the human microbiome. The results are similar, predictable, and potentially tragic.
Coral is very sensitive to environmental changes and can be damaged by a mere touch from a snorkeling fin or boat anchor. Water pollution, infectious diseases, overfishing, fishing via dredging, tsunamis, storms, and climate changes can also affect the health of the reef. As with the tropical rain forest, the numerous species whose survival is linked with the reef interact in various ways, and effects on one can extend to others as well. Coral reefs need clear water so that their algae co-partners can get enough sunlight for photosynthesis. It is a delicate balance, teaching us about the ramifications of extremes within the ecosystem. Water pollution and increased silt associated with higher-density coastal cities and dredging can block the necessary sunlight. This increases the risk of disease and degradation of the coral reef.
Because the beneficial microalgae provide the coral’s beautiful colors, there is an easy measure for reduced algae health; the corals undergo photo bleaching. They begin to lose their vibrant colors. You mainly see the white limestone base shining through the water. Worldwide, there has been increased coral bleaching for decades.
Another type of coral destruction bears striking similarities to the human obesity epidemic. It is related to the overgrowth of a type of algae that does not support the coral animals. This particular algae (known as macroalgae) can choke out a great deal of marine life. Excessive nutrients in the water due to pollution, combined with reduced feeding by fish on the large algae, can lead to overgrowth of the harmful, weedy, large algae. In many ways this parallels obesity-associated inflammation in humans. Too much nutrient intake produces changes in our own ecosystem, bringing in microbial partners that want those specific fattening nutrients and change the environment accordingly. When the overnutrition occurs and algae overgrowth is initiated, the resiliency of the coral reef declines. If the fish that are supported by the reef can’t clear the large algae out fast enough, the reef declines.
Ironically, society recently has turned appropriate attention to the health of complex biological ecosystems like tropical rain forests and coral reefs. A better biological understanding of the risks involved with the destruction of these natural resources has permeated our thinking. Beneficial conditions that support these ecosystems, as well as harmful factors that contribute to their destruction, are better defined. The big question is: When will we apply the same level of concern and mobilize the same commitment to action toward the protection of our own human ecosystem?
As mentioned in Chapter 1, the microbiome is a collection of thousands of different species of bacteria, fungi, and viruses. They come from all three domains of life: the Eukaryota, the Archaea, and the Bacteria. Skin is thought to have approximately 1,000 different species of bacteria, with the phylum Actinobacteria the most widely represented.
The gut microbiome is composed primarily of two different phyla of bacteria: Bacteroidetes and Firmicutes (e.g., Lactobacillus found in yogurt). But a lot of the most interesting differences appear to be happening at the level of individual bacterial species, specific bacterial genes, and metabolic profiles. Like the skin, the gut is estimated to harbor approximately 1,000 different bacterial species. Beneath the species level, there is also considerable genetic variation. Gut microbial gene numbers across human populations are estimated at just fewer than ten million, but a majority of individuals share only a minority of those genes. Some bacteria species can have multiple strains each, with somewhat different copy numbers of genes and characteristics. Within gut bacteria species, some strains can vary by as much as a quarter of their genes.
Recently, a consortium of researchers presented a 3-D map of the microbiota inhabiting human skin in approximately 400 different body locations. The findings reveal the merits of an ecological approach to understanding body-location variation of inhabiting microbes. Different bacteria are prevalent on the face, back, and chest, where there are lots of oil-producing glands, than are found in the groin area, which has a local environment that is warmer with increased moisture.
The site-specific variation of microbes extends beyond the skin and is a general theme for the whole body. Body sites are different ecological regions, varying in such things as acidity, oxygen content, temperature, food availability, and moisture. These local environmental differences affect the mix of microbes that can thrive in a specific body site. For the microbes it is the difference between living in Miami, Florida, or Point Barrow, Alaska. Despite all being part of the same gastrointestinal tract, the mouth, large intestine, and small intestine differ in the profile of inhabiting microbes. If you were interested in oral health, the status of the oral microbiome would be likely to have more direct relevance than that of the small intestine or skin. Similarly, the mix of microbes in the mouth is wildly different from those inhabiting the vagina. The microbes want to be where they can have access to food and can grow and thrive, and in large part we want them to be in that specific location.
When relocated to the wrong body site, otherwise friendly microbes can cause problems. For example, gut bacteria getting into the body cavity is one of the fastest ways to induce septic shock—and death. So having each microbe in its own gated community works.
Your microbes in different body sites have an ancestral history of interacting with your mammalian cells in that specific location of your body. A cooperative synergy has been established between them across centuries. Each is tailored to match up well with the others. And, as we will cover in subsequent chapters, they have shared everything from metabolites, such as short-chain fatty acids (SCFAs), to genes.
One way to think of this is that you are cultivating a microbial garden. Each set of microbes has its own specific requirements for growth and function. Some like it hot, others prefer it cooler. Some like it acidic, others more alkaline. Some like light while others abhor it. Similarly, some want oxygen while others just want to be free of it.
The microbes you hear about the most are actually a very limited array of your total microbiome. You hear the names lactobacilli, bifidobacteria, Firmicutes, and Bacteroidetes at the forefront of probiotic discussions. But there are other microbes, and many of them aren’t even bacteria.
The same types of ecological changes that affect tropical rain forests and coral reefs can also result in our own loss of biological integrity. Donna Beales, of Lowell General Hospital, recently termed this “biome depletion.” Our own cells and tissues are affected when they are deprived of their microbial partners. You may be thinking that with the thousands of species contributing to our microbiome, what does it matter if we lose a few? We can afford it. But ecological studies tell us that maybe we can’t.
There are two weak links in the maintenance of healthy ecosystems like the human superorganism. First, predominant species may have a particular set of maintenance requirements that must be met for them to survive and maintain their status at the top of the pecking order. Species in the greatest abundance will consume the most food and certainly contribute the majority of metabolites and waste products, thereby affecting the overall environment of the ecosystem. In a way, they determine what is left for the rest of the species. Shifts in food availability and other conditions can impact their prevalence and affect the habitats of most other species as a result.
A lot of research has gone into this group of most prevalent species in diverse ecosystems such as the tropical forest and our own gut. But again, the prevalence of certain species does not always reflect their importance to the ecosystem. In fact, in highly diverse ecosystems like the rain forest and our gut, skin, airways, and reproductive tract, the rare species actually perform critical functions, such as promoting useful immune system maturation. In turn, they may be the most vulnerable when it comes to damage to the ecosystem. These are often referred to as keystone species. In such ecosystems, a lack of redundancy for supporting critical functions performed by the rare species is likely to be the tipping point in system failure.
In the tropical rain forest, 55 percent of the tree species that are involved in critical functions have only a single representation per sample. Take that single representative away and the local area is missing that critical function. Thinking locally in the gut, on the skin, and in the airways is important. Different regions of the gut harbor distinctly different microbial species that are tailored to support the specific bodily functions of that section of the gastrointestinal system (e.g., microbes of the large and small intestines are very different). The weakest link in each subsection of the gut should be made a priority when protecting the human ecosystem’s health. And there is at least one example from lab animals that illustrates why this is the case.
One comparatively rare specialized gut bacterium called Akkermansia represents only 3 to 5 percent of gut bacteria. Yet, these bacteria play an important role in communicating with cells in the gut lining and regulating mucus production. The mucus layer is critical for keeping other bacteria at a healthy distance from our gut epithelial and immune cells. If the comparatively rare Akkermansia bacteria are damaged and their numbers reduced in the gut, as appears to occur under certain environmental conditions, the critical function of gut mucus-lining maintenance is lost. Reduced Akkermansia numbers are associated with a form of obesity-promoting inflammation.
Not surprisingly, the Akkermansia bacteria were a relatively understudied type of gut microbiota until recently. Given their low profile, there was no inherent reason to suspect their importance. Yet the loss of gut Akkermansia now appears to be a tipping point for a host of inflammation-related diseases and conditions. Protecting the weakest, most critical link that promotes a healthy microbiome and effective human physiology is likely to become the highest priority.
A wealth of studies in rodents and other animals shows us what happens when the microbiome is degraded, damaged, or even lost. The storyline strikes me as a little similar to the classic Frank Capra movie It’s a Wonderful Life. We have the information to look ahead and see what the future brings for living with a damaged microbiome. It is not pretty. It is not something we would want for ourselves or our children.
When we lose our microbial partners, the path toward effective development and function is altered, and not in a useful way. The evidence supporting this has been around for a while. In fact, a comprehensive review from 1971 about the effects in lab animals when the microbiome is absent foretells exactly what happens when we are a single human mammalian species. Without those microbes, we face a life of biological deficiencies, illness, and death.
Take, for example, the forty to fifty years of producing and studying two types of mice: gnotobiotic and germ-free mice. These are mice specifically maintained in bubble-like conditions, eating sterilized food and, at least initially, delivering their babies by cesarean section. Gnotobiotic mice are completely free of bacteria, including normal microbiota. Essentially, gnotobiotic mice have to be provided with special nutritional supplements in order to survive. This is because the gut bacteria make specific nutrients that are required for a healthy life but are not produced by the mammalian cells. These include the fat-soluble micronutrient vitamin K. Levels of bacterially produced vitamins and other metabolites are critical for survival. For example, if gnotobiotic mice are fed standard rodent chow, they become sick within three days and die. Thymidine deficiency is also present, as bacterially produced thymidine is not available. Rodents completely devoid of a microbiome that are not provided with special bacterial metabolite supplements cannot survive.
There are additional issues. The cecum, part of the intestine, normally represents 6 to 10 percent of body weight in a rodent but, when lacking all gut bacteria, can swell to 20 to 25 percent of total body weight, and these complications can produce death. The heart reduces in size, and blood flow and oxygen delivery are reduced along with it. The animals have decreased motor activity as well. The immune system is defective, as are immune responses.
It is worth looking at what happens in these mice when they are deprived of a microbiome or even provided with a partial microbiome. First of all, they have to be maintained under germ-free lab conditions. If they are exposed to normal conditions, they will die of infections. According to one of the suppliers of germ-free mice (Taconic), probiotic mixes need to be supplied just to keep the mice alive. Otherwise, they are vitamin K deficient since that vitamin is made by the microbiome. Interestingly, it has been known for some time that antibiotic treatments in humans can significantly reduce the levels of vitamin K as the gut bacteria are killed off.
Just as with the tropical rain forest and coral reef, there are consequences to degrading or damaging the human microbiome garden. You need that to be whole, and you need access to a sufficient diversity of microbial partners to have a healthy and prolonged life.