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What is a human being? How should we define “human,” the word that describes the only truly intelligent species on our planet? This is both an extremely important and an extremely contentious topic. There is no lack of writing on how we should define humans, and this definition can shift from discipline to discipline. As a microbiologist—or, more precisely, a microbial ecologist—myself, I too would like to get in on the fun and make my own contribution to this discussion.

In some sense, any discipline that takes the human being as its object must define humans from its own perspective. In terms of human characteristics, we might divide them into natural and social attributes. Accordingly, the disciplines that define humans include both the natural sciences and humanities and social sciences. One might think that since the object of research in the natural sciences is more objective, there would be less controversy in defining humans in these fields. The field of human biology, for instance, takes the anatomical structure and physiological characteristics of the human body as the object of its study. This field’s definition of human should be the clearest in terms of both content and delineation and should therefore be the least controversial. Surprisingly, it is precisely the discipline of human biology that, in recent years, has posed the most severe challenge to the way it defines humans. This challenge, spurred on by the field of microbial ecology, was brought about by advancements in the understanding of the human body’s symbiotic microbes.

The Causal Relationship Between Symbiotic Microbes and Human Diseases

The term “human symbiotic microbes” refers to the aggregate of all microbes residing in and on the human body, also known as the human microbiome. The main part of the human microbiome is located in the gut, and thus the term “gut microbiota” is also used. In 1670, the Dutch microscopist Antonie van Leeuwenhoek discovered “animalcules” swimming in his own dental plaque when he observed it under a rudimentary microscope of his own invention. This can be seen as humanity’s first realization that there are large amounts of living creatures residing in our bodies. Later, Louis Pasteur, Robert Koch, and other pioneers of microbiology developed the germ theory of disease, showing that infectious disease is caused by microbes entering the body. This triggered revolutionary changes in infectious disease prevention and treatment that vastly improved humankind’s ability to limit the harm done by infectious diseases, saving an untold number of lives as a result.

Of course, as a result of this research, most people, even today, have a fear of microbes because they believe them to be harmful, that they enter our bodies and threaten our lives by making us sick. They endeavor to avoid all microbes and try to destroy any microbes in their environment that they might come in contact with so as to avoid infection.

There was one pioneer in the field, however, the French-Russian scientist Elie Metchnikoff, who in 1908 became the first person to clearly propose that in and on the human body—and especially in the gut—there lives with us a large number of microbes. Most of these are harmless, and some are even helpful, playing crucial roles in maintaining our health. Of course, the gut also has some microbes that can produce toxic substances, and having too many of these can cause illness and accelerate aging. Metchnikoff was also the first to suggest that the secret to the long lifespan of Bulgarian farmers was their regular consumption of yogurt, which contained microbes that suppressed the toxic microorganisms in their guts, thus reducing the production of toxins.

From Metchnikoff’s theory to the early twenty-first century, related research and commercial development was carried out, but, owing to technological limitations, there was still not enough scientific evidence to demonstrate a direct causal relationship between gut microbiota and health. The mainstream medical community held out on offering widespread approval of the concept.

The twenty-first century saw major breakthroughs in demonstrating the causal relationship between gut microbiota and chronic illness, mostly thanks to the development of microbiota transplant technology. From 2004 to 2006, the lab of Jeffrey I. Gordon in the USA published a series of seminal papers using germ-free mice as a model.Footnote 1 They discovered that germ-free mice did not become obese from eating high-calorie feed. When the gut microbiota of regular mice was transplanted into germ-free mice, however, they started gaining large amounts of fat, eventually becoming obese on the same feed, despite taking fewer calories than when they were germ-free. In another experiment, they transplanted the microbiota of two identical twins—one overweight and one lean—into germ-free mice. There was a marked increase in the accumulation of fat in those mice receiving microbiota from the overweight donor. These experiments with mice verified the causal relationship between gut microbiota and obesity.

The publication of these research results was echoed by the formation and establishment of the International Human Microbiome Consortium (IHMC) from 2005 to 2008, creating a renewed wave of enthusiasm among scientists for researching gut microbiota.

In order to expand the results of the mice model to humans and thereby further demonstrate the role of human gut microbiota in causing obesity, Dutch scientists conducted a randomized double-blind microbiota transplantation experiment on obese patients in 2012. They divided the patients randomly into two groups. One group received the gut microbiota from the fecal material of a healthy, lean donor. The other group received their own microbiota. There was a marked improvement in the insulin sensitivity of the patients who received the lean donors’ microbiota.Footnote 2 Although there was no difference in the weights of the two groups, and although the improvements to insulin sensitivity disappeared after six weeks, this experiment showed the scientific community that human gut microbiota might be like that in those mice in the Gordon experiments—that it might be a factor in causing and aggravating chronic illnesses like obesity.

In 2015, our lab conducted an experiment in which we transplanted the gut microbiota of genetically obese children with Prader–Willi syndrome into germ-free mice. The recipient mice started gaining large amounts of fat; some even showed symptoms of fatty liver disease.Footnote 3 In 2018, we transplanted the gut microbiota of donors with type 2 diabetes into gene-free mice. The results of this experiment showed that the recipient mice had elevated fasting blood sugar levels, and oral glucose tolerance tests showed they had developed insulin resistance.Footnote 4 What is worth noting in these transplantation experiments is that the recipient mice had no genetic defects and were given normal feed. The recipient mice developed the same symptoms as the unhealthy human donors just from receiving their gut microbiota. These results provide convincing evidence that it only takes microbiota to trigger the symptoms of a chronic illness, and that the recipient organism’s own genes and diet do not play a role.

In 2012, our lab isolated a strain of Enterobacter cloacae from a severely obese patient. By implanting this bacterium in the gut of germ-free mice, we were able to reproduce obesity, insulin resistance, and fatty liver disease—all symptoms of obesity from the donor—in the animal. This demonstrated that there are some specific bacteria in gut microbiota with the capacity to trigger obesity and diabetes the way other bacteria trigger infectious disease.Footnote 5

Gut microbiota transplantation experiments carried out with many types of human diseases have shown that the microbiota of sick people possesses the ability to trigger corresponding symptoms in the body. Scientists have even discovered that microbiota can trigger neuropsychiatric and behavioral illnesses. For instance, in 2016, Peng Xie’s Laboratory transplanted the gut microbiota of depressed patients into germ-free mice, which subsequently exhibited symptoms of depression.Footnote 6 These results demonstrate that the relationship between gut microbiota—as a whole capable of triggering the symptoms of various illnesses in the human body—and disease is not just one of correlation but of causality.

In all of these experiments in which human microbiota was transplanted into germ-free animals, the microbiota of healthy control donors or of unhealthy donors after they underwent dietary intervention did not produce disease symptoms in germ-free mice. This shows that gut microbiota does not inherently make us sick. On the contrary, our gut microbiome is essential for keeping us healthy. It is only when its structure is, for any number of reasons, damaged that the presence of harmful microorganisms increases and they start to cause disease.

Our Gut Microbiota—a “Forgotten Organ”

These experiments, which demonstrated the causal relationship between gut microbiota and disease, all used gut microbiota transplantation technology. When one hears the word “transplant,” one naturally thinks of “organ transplants.” And indeed, quite a few scholars have pointed out that gut microbiota should be considered a type of organ. Since the mainstream medical community has long overlooked the prominent role of gut microbiota in maintaining human health and inducing pathology, this has prompted some researchers to dub gut microbiota a “forgotten organ.”Footnote 7

Could it be that human biology has advanced up to its present level while having failed to seriously discern, define, and research one of the body’s organs? Of course, the question of whether or not gut microbiota should be considered an organ is a controversial one, the reason being that this “organ” is not made up of human cells but the cells of microorganisms. From the perspective of human anatomy, this disqualifies it from consideration as one of the body’s organs. And yet more and more evidence is starting to show that even though our gut microbiota is not made up of human cells, it is no less important than the other known organs in terms of functionality and its role in human health.

Like our other organs, everybody has gut microbiota, and it is indispensable for maintaining the individual’s health.

First of all, the gut microbiota is crucial for regulating our immune system and fighting illness. Germ-free animals are extremely susceptible to infectious disease due to a naïve immune system. A normal mouse, for example, needs to be inoculated with at least 100,000 germ cells of Shigella, a bacterium that causes intestinal infection, to produce disease. In a germ-free mouse, however, the introduction of only 10 Shigella germ cells is enough to cause death by infection.Footnote 8 This is because the immune systems of germ-free mice are not fully developed. They have virtually no ability to identify and fight pathogenic bacteria. In normal mice, however, the bacteria residing in all of the ecological niches of their intestines outcompete the invading pathogenic bacteria via the competitive exclusion effect, thus helping the host ward off bacterial infection.Footnote 9

Other research has shown that after antibiotics have cleared out intestinal microbiota, mice exhibit a compromised immune response against influenza and other viral respiratory tract infections, resulting in more severe illness and higher mortality. This shows the importance of normal gut microbiota in maintaining antiviral immunity.Footnote 10 With the global spread of COVID-19, it is especially important to pay attention to the role a dysbiotic gut microbiota may play in the current and future pandemics.

Gut microbiota can “train” our immune system to identify threats, providing a level of immune tolerance to opportunistic pathogens and reducing harm done to our organs as a result of excessive immune response. For example, children who are not exposed to bacterial antigens produced by opportunistic pathogens in the gut microbiota at a young age due to excessive hygiene have a higher probability of developing type 1 diabetes and other autoimmune diseases later on.Footnote 11

Gut microbiota also influences the development of their host’s organs. Germ-free animals display incomplete development of the intestinal mucosal barrier and other organs. Their intestinal epithelial cells (especially the villus) only develop completely after they have normal microbiota.Footnote 12

Gut microbiota can even affect the activity of the central nervous system and the host’s behavior.Footnote 13 Intestinal bacteria can produce nearly all known human neurotransmitters, such as dopamine and serotonin.Footnote 14 Thus, gut microbiota may play a role in regulating the excitation and inhibition of human nerves, thereby affecting our moods. Gut microbiota can also stimulate endocrine cells in the intestines to produce peptide hormones like peptide YY, which can regulate the brain’s appetite controls.Footnote 15

In terms of nutrition and drug metabolism, it is already known that some members of the gut microbiota can produce different vitamins, and that others can influence the host’s nutrition and metabolism by competing with the host for dietary vitamins.Footnote 16 Gut microbiota carries with them large amounts of drug metabolism genes whose ability to affect drug metabolism is no weaker than the liver. Many of the personalized ways people react to drugs may not be due to genetic differences but to differences in the metabolic genes of their gut microbiota.Footnote 17

Like the body’s other organs, a variety of factors can result in damage to the structure of the gut microbiota, which will cause it to lose its ability to maintain health and possibly even lead to more severe illness. This point was already made clear in the above discussion regarding the causal relationship between gut microbiota and the development of chronic illness in humans. Just like transplantation with other organs, gut microbiota can be moved from person to person, which is known as microbiota transplantation. From the use of feces in traditional Chinese medicine in the ancient world to the treatment of Clostridium difficile-induced intractable diarrhea using fecal microbiota from healthy donors by Dutch scientists in 2012,Footnote 18 we have been able to see the indispensable role that gut microbiota plays in maintaining proper bodily function. In this regard, it is no less important than the liver, heart, kidneys, or any of the other organs. It would not be undeserved to bestow our gut microbiota with the title of “organ.”

Gut Microbiota—Challenging How We Define “Organs”

Gut microbiota also has new properties that our other organs do not. Unlike the transplantation of other organs, for example, the healthy donor’s gut microbiota does not disappear after transplantation. This is because our gut microbiota is made up of microorganisms that are all capable of reproducing on their own. As long as an appropriate method is used, a good gut microbiota can be transplanted to patients in need of an unlimited number of times, without ever “running out.”

Another way gut microbiota stands out from our other organs is that we do not genetically inherit it from our parents. We gain the microorganisms that make up our gut microbiota primarily from our parents during delivery and after we are born. The inside of a healthy fetus is essentially germ-free. At birth when passing through the birth canal and during breastfeeding, the baby’s intestines are inoculated with important bacteria. Afterward, large amounts of microorganisms from the environment continue to enter the intestines. Once the immune system develops a tolerance to them, they become “permanent residents” and settle down in the intestines as our normal gut microbiota. Our gut microbiota becomes stable by around three years old, a time that can be considered developmental maturity for the gut microbiota as an organ.Footnote 19

Since there is a level of randomness and chance to the introduction of microorganisms into the human body, no two people’s gut microbiomes are the same. Even identical twins born only several minutes apart have different gut microbiota. As we grow, the people we come in contact with may transfer some of their gut microbes to us. Our father, for instance, may have transmitted his symbiotic bacteria to our mother during intimate activities, who in turn passed it to us. In China in the past, grandmothers would sometimes chew up food in their own mouths before giving it to their grandchildren, and this too would result in a transfer of symbiotic bacteria. When we talk, also, large amounts of microorganisms are transmitted through the tiny particles in the aerosol that come out of our mouths, creating a bacterial exchange between interlocutors. Thus, the people that a child comes in contact with in the child’s early years may affect the development of the child’s gut microbiota.

Clearly, by nature of the way our gut microbiota is formed, its boundary as an organ is not clearly delineated. We might even say that this organ extends out of our body and into the bodies of the people in the environment closest to us. This is another attribute that separates gut microbiota from other organs. Should our gut microbiota—this ecological system made up of microorganisms from the environment that reside in our bodies and drastically influence nearly all of our bodily functions—be considered an organ? This is a question that challenges our definition of the word “organ.”

Redefining What It Means to be Human

Not just the definition of “organ,” but the definition of the term “human”—or at least its biological definition—is being challenged as well. When we define humans, should symbiotic microbiota, as exemplified by our gut microbiome, be included in the normal anatomical structure of the body? This is a question science and medicine must answer.

We can imagine that, if gut microbiota is included as one of the human body’s organs in medical textbooks, students will be systematically introduced to the relationship between the body’s symbiotic microbiome structure and human health when they first start learning anatomy. When these students go on to become doctors, they will consider the role of gut microbiota in diagnosing, preventing, and treating illness. This will have profound effects on the landscape of human medicine.

If the field of human biology, one of the core components of which is anatomy, includes gut microbiota as one of the normal human organs, related research of human psychology, behavior, and social characteristics must consider the position and role of symbiotic microorganisms. It is clear that all sorts of social interactions between humans involve the exchange of microbiota. Behavior in the past that was explained with purely social factors may actually be based on the biological interactions of symbiotic microbes. There is thus great value in exploring how the relationship between humans’ social networks and microbial exchange network influences people’s behavior.Footnote 20

All of these changes will eventually be reflected in new ethical norms and the establishment of new laws, subsequently affecting everybody’s right to pursue health and happiness. If, for example, it is decided that the gut microbiota is an organ, its ownership rights should certainly belong to the individual to whom it belongs. Since this organ can reproduce, however, and since the primary microorganisms that make it up can be obtained from feces, how do we delineate everybody’s individual ownership rights as they pertain to this important organ? How do we protect them? These questions pose new ethical and legal challenges.

To offer another example, given that interpersonal contact is an important avenue for the development of microbiota in newborns, if we use preventative measures like mask-wearing, social distancing, and disinfecting of the environment for long periods of time, will the post-COVID-19 generation exhibit stunted gut microbiota development? What major consequences could this have for their health? If an entire generation of people lacks important symbiotic bacteria in the gut, will this cause the extinction of these types of bacteria, an extirpation that could in turn cause irreversible ramifications for the health of future generations to come? When we change our definition of human to account for gut microbiota as an organ, these questions are not just scaremongering; they are topics that we must inevitably consider and explore.

If we stick to the view of the 1958 Nobel Prize winner Joshua Lederberg that humans are a “superorganism” composed of both human cells and the cells of symbiotic microorganisms in conjunction,Footnote 21 not only will human biology—a foundation of medicine—experience massive change, but so too will practically all natural and social sciences that concern the study of humans. It is no exaggeration to say that we are on the precipice of an academic revolution, one that all disciplines that research humankind will have to seriously confront.

This article is translated by Thomas Garbarini.