The Little Things in Life
Judging by the frequency encountered in the popular media, it’s a common belief that the human body contains ten times more bacterial cells than human cells, but is it true? Maybe yes, maybe no. The original estimate of bacterial cells in the human body came from a paper published in 1972 by Thomas Luckey, a well-respected microbiologist at the University of Missouri, who extrapolated the number from samples taken from different places in the human large intestine and from samples of feces.
That number, ten times more bacterial cells than human cells, has been repeated and repeated until no one really questions the estimate. A more recent attempt [i] to estimate bacterial numbers arrived at a very different conclusion (perhaps). Whereas the estimated number of human cells is about 30 trillion in an adult body, the new estimate puts bacterial cells at about 40 trillion (plus or minus 10 trillion).
So, despite considerable person-to-person variation, it would appear that the average human to bacterial cell ratio is about 50:50. However, about 25 trillion of the human cells are red blood cells which are short-lived (about 90 days) and non-nucleated (contain no DNA) cells whose main function is to deliver oxygen to the working cells in our bodies. Another 1.5 trillion cells are platelets that are also contained in the circulatory system. If we exclude the cells restricted to the circulatory system and consider only the remaining ~3.5 trillion body cells, the ratio of bacterial to human cells is about 10:1 and maybe even greater.[ii]
How can there be so many bacterial cells in the human body and yet we still appear to be quite human? Quite simply, it’s because bacteria are so incredibly tiny. A typical bacterial cell is a couple of microns in size (micron= one millionth of a meter) while a typical human cell is as large as 100 microns. If a human cell were a basketball, the bacteria would be the size of marbles. Also, the numbers of human cells vary with the size of the person and bacterial cells can differ considerably in abundance from one person to the next and fluctuate widely from one day to the next.
Not only are the bacteria very small, but they grow by splitting in two (fission) and can split every 20 minutes under ideal conditions (such as the conditions in your large intestine). In about 10 hours, it is possible for the descendants of a single bacterium to grow to over a trillion (assuming all of the descendants survive).
We might be somewhat dismayed at the rate of growth of bacteria, and certainly it is cause for concern when we are infected with a pathogenic bacterium, but on the other hand such growth rates are the reason yeast causes bread dough to rise so quickly (although yeast are fungi, not bacteria). In our case, the rapid rate of growth means that the bacterial community can replenish itself literally overnight and can adjust to changes in our diet very quickly.
So, what are all of those bacteria doing in us, on us, and to us? That, in fact, the focus of perhaps the greatest wave of new biomedical research in history. Those bacteria are essential, dynamic, functional, protective, problematic, and tremendously diverse. There isn’t one kind of bacteria but thousands, some very general and some with very particular roles.
The bacteria are so diverse and so interacting that the term for the assemblage of bacteria is borrowed from the ecological literature, the “microbiome”, which implies a complex ecosystem comprised of many types of species adapted to many different niches. Our understanding of the role of the microbiome in our bodies is still in its infancy, but the initial reports are that “important” is an incredible understatement.
We certainly have been aware of the intestinal microbiome for a very long time. Any injury to the large intestine that caused leakage into the body cavity (e.g., stabbing, gunshot, car accident) was considered immediately life-threatening because of the release of bacteria into what should be a sterile environment. The rupture of an appendix releases intestinal bacteria into the abdominal cavity and the threat of a rupture requires immediate emergency surgery.
Long before we had any knowledge of the cause of sepsis from appendicitis, the very earliest microbiologists were fascinated with the tiny lifeforms found on and in the human body. Indeed, Antonie van Leeuwenhoek, an early developer of microscopes, published detailed descriptions and drawings of the tiny “animacules” he discovered in his own mouth, in lake water, and many other places.[iii]
Rather importantly, Leeuwenhoek found a greater number and diversity of organisms between the teeth of people who did no dental hygiene compared to his own mouth, which he daily scrubbed with salt and a cloth. This diversity and variation among individuals established the presence of the microbiota in the human mouth, but also suggested that the diversity and abundance could be a function of the “climate” of the mouth (represented by Leeuwenhoek’s daily ministrations and his sample population’s lack of dental hygiene).
He credited his efforts at personal hygiene for the whiteness and health of his teeth and lack of bad breath, but noticed that no matter the effort, he still had dental plaque and tiny organisms in his mouth. Thus, we see early evidence that the microbiome can be manipulated by our activities, but also that it is very persistent.
Not until recently have we come to understand that disruptions to the intestinal microbiome seem to lead to physiological stress in humans. Although antibacterial drugs had been in use since the early 1900s, true antibiotics were not introduced to the public until 1945.
Broad-spectrum antibiotics, such as penicillin, were successfully used to treat generic infections because they were effective against many bacterial strains including both gram-negative and gram-positive bacteria. The resulting diarrhea and abdominal discomfort were signs that the intestinal bacteria were also susceptible to the antibiotic and somehow this affected both the balance of bacterial types in the large intestine and the passage of waste. Narrow-spectrum antibiotics are less likely to cause these disruptions, again, indicating a reduced effect on the intestinal bacterial community.
In more recent years, we are beginning to suspect (and demonstrate) much more elaborate connections between human health and the microbiome including interactions with our immune system and our resistance to infection. Indeed, the microbiome is not just a complex community of bacteria living on the indigestible portions of our food, but a symbiotic ecosystem that is integral to our health. But how to know what aspects of health are and aren’t related to the microbiome? That is, how do we separate causation from correlation? This is quite literally the multi-billion-dollar research question.
One place to start is to attempt to create a “null hypothesis” so we have something to compare our research results to. In the case of the microbiome, that starting point may well be gnotobiology (Greek for “known life”), the study of life in the absence of other organisms.
Gnotobiologists create “germ-free” organisms to study physical development and body processes without the confounding effects of microbes.
Germ-free research has been a common way to study biological processes in, for example, rats and guinea pigs for over 100 years. Perhaps more interesting than eliminating microbes to examine “pure” processes is the resulting abnormal development of the test animals as a result of being germ-free. The largest number of physical abnormalities occurs, not surprisingly, in the digestive system with an enlargement of the cecum (the pouch-like area next to the appendix) and thinning of the colon wall.
Importantly, the germ-free colon does not develop the bacterial mucus that lines the normal colon wall, osmotic balances are altered, and defense systems appear underdeveloped. These studies provide strong evidence that the normal functioning of the digestive system depends on the presence of some portion of the microbiome.
It appears that some species of bacteria assist in creating their own environment by modifying the architecture of the intestine.[iv] But also it appears that there is a shifting balance between non-pathogenic and pathogenic bacteria such that abundance and conditions may cause fluctuations in the mutualistic relationship between the host and the bacteria.[v] In other words, what we consider “good” and “bad” bacteria is a meaningless distinction unless we understand the conditions that favor one kind of behavior over another.
Two ecosystems interacting
Unfortunately, research on the human microbiome is so incredibly complex and affected by so many known and (especially) unknown variables, we will never know the full extent to which it affects humans as a species. Our microbiome is dynamic: it changes as we age, it changes with our health, it changes with our diet. The human microbiome varies with geographic region and ethnicity. It is influenced by our genetic heritage. It is affected by our personal history of disease and injury, by environmental toxins, by the drugs we take, and by the food we eat.
In other words, our microbiome is contextual. This is tremendously important. Our microbiome is not constant and its functioning depends on the behavior of the host and on interactions with the external environment of the host.
When it comes to the human microbiome, what we know is a drop; what we don’t know is an ocean. Even as we explore the meaning of the microbiome to humans, we are also exploring the microbiomes of animals and plants and those microbiomes are no less complex and challenging.
As researchers learn more, the implications expand and multiply. Of particular interest, of course, is how can we manipulate our microbiomes to our advantage? Can we manage human health by managing the microbiome and perhaps rely less on artificial drugs? Can we manage crops and livestock by managing their microbiomes and thereby rely less on chemicals such as pesticides and antibiotics? Are some of the medical problems we face today also the result of damage to our personal microbiomes in addition to the macrobiome we live in?
The number of variables that could influence the health and behavior of the human microbiome is staggering. It is difficult to manipulate more than one or two variables in an experiment of manageable size; dealing with a large number of variables is often out of the question. The more variables that are included, the more likely the “conclusions” of the study will be correlative rather than decisive. That is, the researchers will be able to say that one variable is correlated with an effect, but they won’t be able to say that it causes the effect, and such conclusions will be less than satisfying.
So, for the purposes of actually establishing causation, researchers reduce the number of variables in their experiments as much as possible to attempt to test the effect of each variable on the system. Unfortunately, such a “reductionist” approach, an experiment that manipulates only one variable, is automatically ignoring a large number of other variables that may be very important. In fact, a strong effect correlated with one variable can be misleading because it may mask a causative variable that was not included in the study.
On the other hand, research on multivariate problems is usually very slow and is often discouraging, and certainly is frustrating for consumers who would like clear answers. Ultimately, this tangle of correlated variables is why medical conditions are often referred to as “syndromes”; there are too many variables involved to say which one, IF there is only one, is responsible for the problem.
[i] Sender, Ron, Shai Fuchs, and Ron Milo. "Revised estimates for the number of human and bacteria cells in the body." PLoS Biol 14.8 (2016): e1002533. [ii] Some estimates are as high as 100 million, but the interesting thing about bacteria floating in the gut is that a large bowel movement may reduce the total by half or more since feces are about 60% bacterial biomass. [iii] A nice summary of van Leeuwenhoek’s research can be found in Theodor Rosebury’s Life on Man (Viking Press, 1969). Rosebury was one of the first to discuss the importance of the microbiome to human health. [iv] This type of response may occur in response to other organisms as well. Research on rats found that the presence of parasitic worms in newborns and their mothers stimulated the immune system and prevented developmental disorders caused by bacterial infections, and resulted in other protective changes in the digestive system. Williamson, Lauren L., et al. "Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection." Brain, behavior, and immunity 51 (2016): 14-28. [v] Falk, Per G., et al. "Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology." Microbiology and Molecular Biology Reviews 62.4 (1998): 1157-1170.
