I Contain Multitudes

The previous chapters talk about the concept of symbiosis. The key point about symbiosis is that it is neutral; it is the act of living together, not positive and not negative. That means that our relationship with our microbes can vary between good and bad and that we are in a constant balancing act with our own microbiome, keeping it in check to avoid negative consequences for ourselves. Our microbiome consists of organisms that have an agenda of their own: They want to live and grow in the best conditions as much as we do. Sometimes bacteria are partners, and sometimes they are parasites.

Yong provide an example of this balancing act in his favorite bacteria, Wolbachia pipientis. This bacterium is found everywhere, and during the advent of sequencing bacterial genomes, Wolbachia continually to pop up (77). A group of asexual, all-female wasps were found to reproduce by cloning themselves, and that interesting reproductive trait was found to be caused by Wolbachia. When the female wasps were treated with antibiotics, male wasps started to reappear, and typical sexual reproduction recommenced (78). Similarly, Wolbachia interfere with male hormones in a species of wood lice, resulting in the males turning into females. This bacterium was even the culprit in the killing of male embryos of the blue moon butterfly, making the females outnumber the males on a large scale.

Although those three instances involve different strains of the bacteria, all had the same goal in mind: Wolbachia  can only move to the next generation of hosts via eggs, not sperm (78). Evolution has given this bacterium many ways of sabotaging male hosts to reproduce and survive in the female hosts, whether sexually or asexually. Through this sabotaging, Wolbachia has become so common that it infects four in every 10 species of arthropods. This bacterium acts as a parasite, manipulating sexual reproduction for its own needs.

Wolbachia can be less parasitic in certain instances. Certain nematodes can’t survive without it, and it can also protect other flies and mosquitoes from viruses (79). Bed bugs rely on the bacteria for nutrition, specifically B-vitamin supplementing. Wolbachia is the perfect example of one bacterium with many strains that act in both good and bad ways.

Yong makes it clear that there are not good microbes and bad microbes: There is a continuum, or a sliding scale. Bacteria slide toward parasite or partner depending on the strain. Some bacteria act as both depending on the circumstance. Although this changing status complicates our relationship and interactions with our microbiome, it also makes it clear that we can’t label a bacterium as one thing or another.

Our gut microbiome offers an example of the sliding scale. Usually, our gut microbiome has many benefits, or, at the worst, it displays neutral activity. However, if the bacteria of our gut microbiome get past our gut barriers and into our bloodstream, they can be deadly (81). We are quick to label molecules that bacteria secrete as “virulence factors” because the context we first saw them in was disease oriented. Those molecules, however, are neutral; they are just tools and can be used for good or for bad (82). The microbes of an aphid are critical to the survival of the insect but give off molecules that attract a predator to the aphid (82). Our own bacteria can cause us to release molecules that make us more attractive to mosquitoes, especially ones that carry malaria.

H.G. Wells sums up the nature of symbiosis: “Every symbiosis is, in its degree, underlain with hostility, and only by proper regulation and often elaborate adjustment can the state of mutual benefit be maintained. Even in human affairs, the partnerships for mutual benefit are not so easily kept up, despite me being endowed with intelligence and so being able to grasp the meaning of such a relation” (83). The neutral nature of symbiosis is also visible among larger creatures. Oxpeckers are birds that pick off ticks and other blood-sucking creature from giraffes and larger animals, but they also peck at open wounds (84). The birds’ main goal is to satisfy their craving for blood, and they will use any means to do so. Pecking at wounds can bring infection and increase healing time, but this comes at the benefit of removing ticks and parasites.

Yong asks the question, “How, in other words, do I contain my multitudes?” (85). He relates managing our microbiome to managing a garden. We set boundaries for plants with fencing, feed the plants with fertilizer, and remove weeds and other harmful intruders (85). We give our plants the proper conditions to grow and meet each difficulty as it arises.

We animals can manipulate our conditions to keep our bacteria in check. Our stomachs keep most (but not all) bacteria at bay due to the highly acidic conditions (86). Animals have evolved specific locations to house bacteria, like the crypts in the luminous squids or the bacteriocytes of any insects. People don’t have these specialized cells; rather, we keep them inside of our gut, where the only thing stopping them from getting into our bodies is a layer of epithelial cells covered in mucus (88). Bacteriophages, or viruses that infect bacteria specifically, love mucus; phages are so important to controlling bacteria in our bodies that it’s possible that animals chemically change our mucus to become more attractive to certain phages to make sure only certain bacteria get through (89). This is yet another example of a symbiotic relationship, this time between us and viruses.

Considering this act of balance in the context of our immune system, it becomes clear that our immune system is more of a manager of microbes than a destroyer. If microbes get where they don’t belong, we attack to keep them in check. Our immune responses can select and manage communities of bacteria to ensure that we are being colonized with the right communities as we grow and change.

One of the first selective methods our immune system gains comes through the antibodies a mother produces in her milk. Bruce German is a scientist at the University of California, Davis, who studies mammalian milks. He calls milk “superfood” and studies the oligosaccharides (a complex sugar) within them (93). There are over 200 different human milk oligosaccharides (HMOs). They make up one-third of human milk, but babies can’t digest them (93). Because they aren’t digested, they end up in the large intestine for bacteria to eat—which suggests maybe they aren’t food for babies at all, but for bacteria.

German studies how HMOs and bacteria interact. He and other scientists have found that though HMOs aren’t a superfood for all bacteria, they do nourish specific subspecies. Specifically, B. infantis eats up these HMOs better and faster than any other bacteria, and then they release short-chain fatty acids to feed the gut cells in the stomach of the infant (94). This bacterium also helps to keep the gaps between the cells small and assists with the release of anti-inflammatory molecules to shape the immune system. Without human milk, these benefits can’t reach their full potential.

Human breast milk has many more HMOs than other mammal milks, and it’s not clear why. German’s group thinks it might have to do with our brain size in comparison. In our first year of life, our brains rapidly grow, and they depend on sialic acid to do so (95). It just so happens that B. infantis releases this while it munches on HMOs. It could be that bacteria are responsible in supporting our big growing brains. HMOs also act as a protection mechanism by acting as decoys for pathogens that are looking for sugar molecules to latch onto, deterring them from sugar on an infant’s own cells (96). On top of that, breast milk helps bacteriophages attach to mucus better, thus providing the babies their first batch of phages in their gut.

In some cases, the balance of symbiotic relationships ends in a co-dependent state, where the microbes and the host become a single being. Usually this happens when bacteria enter the cells, the same way that our mitochondria might have done originally. This does mean that both symbionts are unable to live without each other.

One example of this is the 13-year periodical cicada. They spent most of their lives as nymphs, under the ground drinking from plant roots, but after 13 years, they all emerge together, mate, and die (100). Their usual lifestyle comes with an unusual set of bacteria. The DNA sequences of the bacteria in the cicada suggested they should belong to the same bacterial genome, but none of the genomes were complete. They were just fragments of DNA that didn’t form a full genome. This is because the bacteria involved, Hodgkinia, entered the cicada and then split into two pseudo-species inside the insect. That split made them lose their original genes and become complementary. Scientists that study these bacteria see this process as a slow-moving extinction, or an “evolutionary rabbit hole” into a strange world from which there is no escape (101).

It is both apparent and backed up with evidence that our microbiome plays an important role in our well-being. There is mounting evidence that sickness or an irregularity in health might occur when we are unable to keep our microbiome in check.

One of the hallmarks of global warming has been the dying off the coral reefs. Before the shift in climate, these reefs were havens for sharks and other fish species. Sharks were a sign that the reefs were healthy, because big predators meant an abundance of smaller species to feed on. A dead or dying coral reef has no sharks, few other species, and slime-covered coral skeletons (104). Corals are soft, squishy tubes coated in tentacles. The corals build reefs out of limestone that they secrete. These mountains of limestone become massive structures that house countless marine species (104). As our climate warms up, carbon dioxide begins to warm up the ocean as well. With warmer oceans, the corals expel the algae that provide them important nutrients, and the increasingly acidic ocean lowers the minerals present, making it harder to gather them to make the reefs. Without their reefs, the corals are more susceptible to sickness and infections. Although some specific pathogens may be the cause of these infections, there is evidence that some of that illness might be caused by the corals’ own normal microbiome.

Corals are coated in microbes—10 times more on a square centimeter than on a same-size patch of human skin or soil (105). These microbes take up space and keep disease-causing bacteria from invading; this is called colonization resistance. Disrupting that regular biome makes infections more common and leaves the corals with irregular communities of bacteria. Corals also live in a delicate balance with algae, but if the number rises too much then these algae outcompete with corals for space. With climate change, we have given the algae an advantage and have let them become overgrown lawns among the reefs.

It turns out that the algae were not only outcompeting in space but also helping the corals’ own microbiome to become dangerous to their symbiotic friend (106). Algae in high numbers give off large amounts of dissolved organic carbon (DOC), which is consumed by the microbes and causes them to explode in growth and consume all the oxygen in the area (107). The corals are left depleted and unable to get any oxygen. Its turns out it wasn’t a new or pathogenic bacterium that was creating problems: The same microbes that were present when the corals were healthy just took advantage of an excess of DOC. Explosions of algae can also be traced to deposits of metal from ships acting as fertilizer. One thing is clear: Human activities have impacted the long-standing relationship between corals and their microbes (109).

As previously discussed, not every pathogen is inherently good or bad, but when the normal harmony is disturbed, the community can shift into a pathogenic state. This is known as dysbiosis. The idea of dysbiosis impacting humans has been studied since the 1990s. Utilizing germ-free mice, Jeff Gordon has been studying how humans’ bacteria may impact our health (111). Normally, these germ-free mice can eat all they want without putting on weight, but as soon as Gordon’s team gave them microbes from a normally colonized mouse colony, they started to put on weight. It wasn’t that they were eating more (they ate slightly less), but more of the food was converted into fat (113).

Though mice and humans are different, there is potential in those results to indicate that our microbes must influence what we extract from our food and, consequently, what amount of weight we put on. In humans, the ratio of major bacterial groups is different between obese people and non-obese people. If you take microbes from fat and lean mice and put them into germ-free mice, their fat or leanness is transferred as well. Moving microbes means moving obesity in these mice. These new studies don’t replace or negate previous research on obesity or its causes, but they provide another piece of the puzzle.

On the other side of obesity, microbes might also be responsible for differences in the health of malnourished children. There are two different common forms of malnourishment: marasmus and kwashiorkor. The former leaves the child very thin, almost skeletal. The latter causes fluids to leak from vessels, causing stomachs to distend and limbs to swell (116). Kwashiorkor is not well understood and is thought to be caused by protein-poor diets, even though children who show these symptoms don’t eat any less protein that kids with marasmus.

Gordon, the same scientist who conducted the obesity trials, thinks that this difference might be due to bacteria as well. After collecting stool samples from children as they aged from one to three years, his team found that kwashiorkor microbiomes don’t have the same growth pattern as the kids age (117). Their microbiomes remain stagnant and don’t diversify in the same way. Just like with the obese mice, both the food and the microbes were at fault. The microbes in kwashiorkor children make it harder to harvest energy because the microbes block chemical relations that fuel cells (117).

This theme of dysbiosis and balance can also be seen in our immune system. There is a continual balance: If responses are too low, then we might miss pathogens and get sick, but if the response is too high, there is an increase in autoimmune responses and unneeded inflammation. With the advent of antibiotics and sanitation, we have given our immune systems more reign to keep our responses at a high level (118). This means an increase in autoimmune disorders and inflammatory disorders like inflammatory bowel disease (IBD), rates of which have skyrocketed since World War II, particularly in more-developed countries (119).

There isn’t a known cause for IBD. The gut microbiomes of IBD patients are different than their peers, found to be less diverse and less stable. Rather than the normal colonies, we see more inflammatory species and invasive species. A single species can’t account for an entire disease, but if a community becomes more inflammatory then it might contribute to the disease state. Some scientists have seen that in mice with genetic mutations similar to those in people with IBD, the mice only got IBD if they had a viral infection that knocked out part of their immune system, were given an inflammatory toxin, and had a normal microbiome. All three factors were needed for an unhealthy mouse, not just one alone (120).

We can see these patterns in other autoimmune and inflammatory diseases like asthma, allergies, and multiple sclerosis (121). A trigger tips our immune system to a hyper-inflammatory state. Perhaps our hyper-clean state of living is partially to blame. People in cities are more likely to get these inflammatory diseases than indigenous or rural populations. This is the basis of the hygiene hypothesis: Developed countries have less disease and bacteria, so our immune system is not as experienced and more prone to false alarms (122). Such immune systems will react to harmless things like pollen, or even peanut dust. This is not just about our personal hygiene, but urbanization, family size, and fewer animals being around; homes with pets have more microbes than homes without. Being exposed to a larger range of microbes allows us to suppress that allergic inflammatory response, or at least, this has been shown in mice.

These disruptive changes can be seen in the case of our first microbe colonizing event: vaginal birth. Our first contact with bacteria occurs when we are born and pass through the vagina, and these bacteria are key to establishing our initial microbiome (123). Babies who are born from Cesarean section are more likely to develop inflammatory diseases or obesity late in life. Bottle feeding may also play a role, as breast milk helps colonize our initial microbiome. A Cesarean section and bottle feeding combined might drastically shift one’s microbiome (123).

Antibiotics are one of the biggest factors in disrupting our microbiome. Since the discovery of penicillin in 1928 by Alexander Fleming, we have isolated countless, increasingly potent antibiotics (125). While an incredible help to disease management, they also kill any bacteria in their path. Wiping out all bacteria means more room for the disease-causing species to jump in—for example, Salmonella or Clostridium difficile. Even small microdoses can have catastrophic effects (127).

Scientists have revealed a critical window in our early development when antibiotics can cause even more damage. A growing microbiome does not handle being wiped out very well, and the impacts can be seen even after the microbiome returns to normal. Taking antibiotics at a young age may have a role in the rise of obesity, allergies, and autoimmune diseases (127). It’s important to keep in mind that the correlations we see in mice don’t translate completely over to humans. Human studies are must less causal than mouse studies in identifying the relationships between microbes/antibiotics and obesity, but they still provide important clues as to what is going on.

Antibiotics are a real threat, and the increased use of them is putting some bacteria at risk of disappearance. Helicobacter pylori is one of those bacteria at risk. Known to be the cause of stomach ulcers and for increasing the risk of stomach cancer, this species was demonized in the scientific community for a long time (129). However, studies have revealed the bacteria has a good side, too: decreasing acid reflux and esophageal cancer. The loss of H. pylori might mean fewer ulcers, but what else might happen when the species disappears other than increased acid reflux?

B. infantis, the bacteria we feed through our breast milk, is also at risk for disappearing. The bacteria are present in 60-90% of babies in developing nations but only 30-40% in already developed nations (130). The reason for this isn’t quite clear, but the microbe seems to disappear from the gut in adulthood; if it isn’t present in the adult gut, then it wouldn’t be passed to children. It might be that kids would previously have shared the bacteria between each other, and those chains of transmissions have broken as parenting has becoming more isolated (130). In any case, the bacteria are moving towards a potential extinction.

This topic highlights an important note in the study of bacteria: We won’t know if developed countries are missing microbes if we don’t study a broader stroke of people. The nations scientists to focus on tend to be “Western, Educated, Industrialized, Rich, and Democratic” (131). The microbiomes in these places wildly differ from those in more rural or underdeveloped nations, and one of the main differences is in diversity of microbes. Pre-industrial-aged feces have also been found to have a wider variety of gut microbes than people do today (131).

It’s unclear if the lack of diversity correlates with decreased health. There’s evidence that less diversity leaves us at risk for invading or disease-causing bacteria, but our microbiome might also be shrinking as we have grown better at adapting to parasites we encounter, or as we have changed our diets. There is great worry that changing our microbes at such a rapid pace could come with great consequences. 

We must not overstate what the microbiome can do. Antibiotics are a problem, but they aren’t “extinguishing” the microbiome (133). We still have a lot to learn about what the microbiome does in our partnership. We used to hold an excessively hostile stance against bacteria, and it’s important that we don’t swing too hard in the other direction now that we are realizing the importance of bacteria.

Although Yong gives many examples of how our microbiome may be causing obesity and health issues, he also reminds us that these studies were conducted in mice. By trying to show how microbe changes lead to health-based consequences in mice, he says, we have caused confusion in making people think that there is a true cause-and-effect relationship. Things are a lot more complicated than that, not only because human systems are more complex than mice, but also because we still have much more to learn. Yong explains, “When you move away from the one-microbe-one-disease model and into the messy, multi-faceted world of dysbiosis, the lines of cause and effect become much harder to untangle” (135).

As with all scientific study, we must be critical of the results that we see. Conflicting results arise in early phases of research because of budding technology and tight budgets. There’s also an issue of contamination in bacterial studies. Many issues are being ironed out as more standards are set in this growing field and with an increase in quality and amount of data needed to show correlations. Scientists are looking at not only DNA, but also RNA, proteins, metabolites, and other chemical interactions (138). We’ve also reached a time when longer studies can be conducted to search for long-term effects microbes have on us and our health. This field is still relatively new, so there are issues to work out, but there is much to learn.