Our immune system implements various strategies to protect us from pathogens. In general, we can summarize the various lines of defense implemented by the immune system into four categories: physical barriers, general recognition, specific recognition, and memory of the infection. Below I outline a brief description of each of these strategies. Follow up articles will dive deeper into each of these topics.
Physical barriers. The first line of defense from infection are the physical and chemical barriers presented by the body. These barriers can physically prohibit infection by blocking entry into the body (e.g., epithelial cells) or slow or kill certain microbes (e.g., the antimicrobial peptides found at mucosal surfaces). These barriers are, obviously, not always effective.
General recognition (innate immunity). The innate immune system’s role is to recognize infecting agents in a general sense. It is not specific about what it looks for, but rather it searches for those things that have made their way into the body. This tends to be the first line of defense from a pathogen that has subverted the physical barriers of the body. Because the mechanisms it invokes tend to be broad-based, it is not necessarily the most efficient means of clearing a pathogen. But, it tends to be very good at identifying that an infection is occurring, localizing or containing the infection, and recruiting the adaptive immune system to clear the infection.
Specific recognition (adaptive immunity). By contrast, the adaptive immune system provides an efficient means of clearing an infection, but isn’t always good at initially recognizing that an infection is taking place. Here, the recognition of pathogen specific antibodies induces a cascade of immune cells that target the pathogen and expedite its clearance from the body. The innate immune system usually triggers the activation of the adaptive immune system.
Memory of the infection (immunological memory). Fortunately for us, once our immune system has cleared an infection, it develops a memory of the pathogen to expedite its detection during a subsequent infection. This strategy makes it very difficult for that pathogen to successfully reinfect our bodies (though we have to watch out for evolution). When scientists develop vaccines, they are effectively hijacking this process.
One of the principle ways in which we interact with our microbiota is through our immune system. This interaction is bidirectional: our immune system influences which microorganisms live on us and various microorganisms are known to modulate immune activation. A better understanding of our immune system can improve our understanding of our microbiome.
In a continuing series, I will present brief blasts of background on the immune system. These are intended to be quick, introductory forays into the properties of the immune system, though longer and more in-depth articles may accompany these summaries from time to time. This is mostly a selfish endeavor, as I need to improve my understanding of our immune system for my research. Much of this work will stem from notes I take while reading Janeway’s Immunobiology.
Today I’ll start by highlighting the principle roles of the immune system. Our immune system does four things:
- Recognition: the presence of an infection is first recognized by the immune system.
- Containment and elimination: often referred to as effector functions, the immune system contains and attempts to eliminate a detected infection.
- Regulation: the immune system’s functions must be regulated such that it doesn’t target the host’s own tissue (i.e., immunotolerance).
- Memory: once a pathogen has been cleared, the immune system provides a long-lasting, protective immunity to the infectious agent.
Almost all immunological research pertains to at least one of these four broad categories. In future articles, we’ll dive deeper into the biology of the immune system.
Many authors, myself included, love to throw around a statistic that puts our microbiota in perspective: there are roughly ten times as many microbial cells living on our bodies than there are human cells in our bodies. But what is the basis behind this estimate? Where does it come from and is it reliable?
I did a little sleuthing to find out. I came across a 1977 Annual Reviews Microbiology manuscript (warning: paywall) written by Dan Savage that provided an early introduction to this topic. In it, Savage observes the following:
The adult human organism is said to be composed of approximately 10^13 eukaryotic animal cells (27). That statement is only an expression of a particular point of view. The various body surfaces and the gastrointestinal canals of humans may be colonized by as many as 10^14 indigenous prokaryotic and eukaryotic microbial cells (70). These microbes profoundly influence some of the physiological processes of their animal host (49, 103). From another point of view, therefore, the normal human organism can be said to be composed of over 10^14 cells, of which only about 10% are animal cells.
An interesting and insightful paragraph. But it still does not provide the basis for the estimate that there are ~10^14 prokaryotic cells, which seems to be the more difficult to measure number in the calculation of the ratio of microbial to human cells. Digging deeper, we find that reference number 70 points to a 1972 American Journal of Clinical Nutrition manuscript (warning: pdf) by Luckey:
The composition of this system is surprising. Adult man carries 10^12 microbes associated with his epidermis and 10^14 microbes in his alimentary tract (Fig. 1). The latter number is based upon 10^11 microbes/g contents of an alimentary tract with a capacity of approximately 1 liter. The 10^13 cells (2) in his body are a distinct numerical minority of the total being that we call man. If we abandon anthropomorphism for the microbic view, we must admire the efficiency of these microbes in using man as a vehicle to further their own cause.
Given what we know today, this is a seemingly prescient position. However, the critical number in question appears to be asserted here. It sounds like Luckey, or someone else, extrapolated the total number of cells in the alimentary (intestinal) tract from a tissue sample. But without a presentation of data or results, we can not be certain. Figure 1 is interesting, but no help here:
So, I dug a little deeper into Luckey’s work to see if this is something he demonstrated previously. While not particularly quantitative by today’s standards, Luckey’s ideas are creative, visionary, and insightful. I recommend reviewing his work. But, I digress.
I found this American Journal of Clinical Nutrition manuscript (warning: pdf) from 1970 which presents cell counts of fecal bacteria from mono- and diassociated (formerly gnotobiotic) mice. Some of the results look like that 10^11 microbes/g number he references in the aforementioned manuscript, but the range is substantial:
So, it could be that this data is the basis for the estimate of 10^14 microbes in the human gut. But, it seems like the variation across individual mammals is large enough that we might need to take that estimate with a grain of salt. Of course, Luckey or some other talented researcher may have conducted a similar study in a human population and found that the variation is much tighter than the data presented here.
Currently, I am somewhat skeptical about the estimate that there are 10 times as many microbes on our bodies than there are human cells in it. I will continue to dig to see if I can find a harder number than that presented above. If I find something, I’ll update this post. Either way, it appears that there are a lot of microbes in our bodies!
The term “metagenome” is frequently invoked during reports on the study of the human microbiome. Unfortunately, it seems to have different meanings to various authors, which understandably leads to some confusion.
In my mind, a metagenome refers to the genomic contents of an entire microbial community. This means that metagenomic sequencing involves the generation of whole genome sequence data from community-acquired DNA, most usually through shotgun sequencing. I do not think that sequencing DNA obtained through PCR amplification of the small subunit ribosomal RNA locus (SSU-rRNA) constitutes metagenomic sequencing. I also do not think that our microbiome is the same thing as our metagenome. Rather, the metagenome is an important component of the microbiome (see this link for more).
Other authors certainly disagree with me on these points. But, the historical literature aligns with my interpretation. The earliest reference that I can find to “metagenome” in NCBI’s PubMed is a 1998 Chemistry and Biology paper by Jo Handlesman and colleagues entitled “Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products.” In it, the authors describe a clone-library based method that enables exploration of the biological functions encoded in the genomes of the microbes that make up a soil community:
The methodology has been made possible by advances in molecular biology and eukaryotic genomics, which have laid the groundwork for cloning and functional analysis of the collective genomes of soil microflora, which we term the metagenome of the soil.
Handlesman and colleagues refer to the metagenome as the collective genome of a microbial community and point to the ability to infer the biology functions of these microbes from this data. This transcends the evaluation of a single locus whose DNA sequence was obtained via PCR amplification.
Admittedly, the SSU-rRNA locus is part of the genome. As a result, it may be fair for one to argue that an analysis of the collection of PCR-amplified SSU-rRNA sequences that have been obtained from a microbial community constitutes a metagenomic analysis. However, given that the methods needed to analyze PCR-amplified SSU-rRNA data are very different from those needed to analyze whole-genomic/shotgun sequence data obtained from a community — as are, frequently, the points of investigation — and given the rapid growth in the number of studies applying these two different sequencing strategies, I think it is important to disambiguate the term “metagenome”. Otherwise, we risk confusing readers and students of the field.
So, when you see me refer to a metagenome, it will be in regards to the sum total of the genomic information that is encompassed by all of an organisms in a community.
There are several major research consortia that focus on the study of the human microbiome. The following is a list of some of these and is not meant to be exhaustive:
- International Human Microbiome Consortium
- The Human Microbiome Project
- International Human Microbiome Standards
The study of the human microbiome requires an extensive amount of DNA sequencing. There are several major sequencing facilities involved in the study of the human microbiome, including those below:
- The Broad Institute
- The J. Craig Venter Institute
- Washington University
- Baylor College of Medicine
- CEA Genoscope
These are far from comprehensive lists and will be updated over time. If I have failed to represent an organization, please feel free to contact me.
Microorganisms are everywhere. Because of their small size, they are often difficult to see, but you will be hard pressed to find a surface or fluid in nature that is not covered by or full of microorganisms. This includes our bodies, which are covered with so many microbes that they outnumber the cells in the human body by at least a factor of ten. These organisms constitute the human microbiome and may have a profound influence on our health.
Researchers of the human microbiome use several particular terms that are worth defining. The collection of microbes that live in a given environment are referred to as microbiota. Researchers thus refer to the microorganisms that live in and on the human body, which from the perspective of a microbe is just another environment, as the human microbiota. For any given environment, a microbiome consists of the microbiota, their genomes, and their environmental interactions.
Researchers of the human microbiome evaluate which organisms live in our bodies (who is there?), how their genomes influence the environment of the human body (what are they doing?), and how the human body conversely influences its microbiota (how are they changing?). This is a highly interdisciplinary field, borrowing from ecology, evolution, molecular biology, immunology, bioinformatics, and genetics.
This research field is rapidly progressing, with important findings being released almost weekly. Many of the recent observations suggest that we can improve our understanding of and influence on human health through an improved awareness of the human microbiome. In future posts, I’ll detail these findings more specifically.