Abraham Tsoukalidis

Human Microbiome

“Ἐν πᾶσι γὰρ τοῖς φυσικοῖς ἔνεστί τι θαυμαστόν” Aristotle

I have always been awed by the fact that we host 10 times more bacteria in our organism than cells. Of course, this is still an estimate and it does not mean the same holds true for mass ratio (“prokaryotic cells (bacteria) are far smaller than eukaryotic cells (human cells). prokaryotic cells are usually 1-10 micrometers across, whereas eukaryotic cells are usually 10-100 micrometers across. Furthermore, there is a fair amount of weight that is not comprised of cells, extracellular matrix such as that in cartilage and in bone. Even when factoring in mitochondria, the vast majority of the mass of a human is strictly human, that is to say the product of our DNA.”).

Nevertheless, it is still an astounding symbiotic relationship that is now starting to be discovered and understood. The sum of all these microbes is called the Microbiome. It has been estimated that there are “10^13 human cells in a host with 10^14 microbial cells” (ref Savage DC (1977) Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 31:107–133) and for a nice illustration of this look at this article.

So 10.000.000.000.000 cells coexist with 100.000.000.000.000 microbial cells in the human body. There are more than 1,000 species per person (183 species on human arms, 44 species on forearm, 15 species behind ear) and 100 billion microbes live on our skin (from this article). There is an ongoing research project to better elucidate the nature and function of this unnatural symbiosis called Human Microbiome Project.

“Microorganisms represent the majority of life on earth, populating a wide range of niches on its surface, underground, in the oceans, in the atmosphere, and both on and inside all multicellular organisms. This ‘microbiome’ will clearly play a critical role as humans struggle to deal with society’s major challenges—health care, agriculture, energy, and the environment. As one example, the human gut microbiome contributes 36% of the small molecules that are found in human blood, and it also plays a major role in creating susceptibility to certain human diseases. In recent years, a variety of microbial communities have been characterized through such efforts as the Human Microbiome Project and the Earth Microbiome Project. But mapping these trillions upon trillions of microbes and analyzing the vast amounts of data that are accumulating will require new integrative approaches aimed at understanding how microorganisms function and are interrelated.” Leroy Hood “Tackling the Microbiome” Science 8 June 2012: Vol. 336 no. 6086 p. 1209 DOI: 10.1126/science.1225475

These microbes are called commensals, defined as “relating to, or characterized by a symbiotic relationship in which one species is benefited while the other is unaffected.” (from Latin meaning “a companion at table”, “relating to eating together, especially at the same table). Natural commensals (the bacteria and microbes living in human organism) are estimated at 65 billion bacteria per square inch of upper throat (Stipp, Fortune, Jan, 20, 2003). The high density of commensal bacteria helps to “crowd out” dangerous bacteria that could cause infection.

Although humans are remarkably similar at a genetic level between them, their microbiome differs remarkably as stated in this article: “At the phylum level, humans are remarkably similar to one another [and to other mammals], whereas at the genus, species, and strain population levels, the diversity is highly specific for each individual. A very recent study shows that even for 57 gut bacterial species present in >90% of 124 sampled persons, their estimated abundances varied by 12- to 2,000-fold.”

More studies point in the same direction: “Gut microbial communities represent one source of human genetic and metabolic diversity. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.” “Human gut microbiome viewed across age and geography” Nature (2012) doi:10.1038/nature11053

A very interesting article by Jennifer Ackerman in the June 2012 Scientific American issue, named “Your Inner Ecosystem”, presented the following interesting facts:

• Some of these commensal, possess genes that encode for beneficial compounds that the body cannot make on its own.
• Other bacteria seem to train the body not to overreact to outside threats
• Various types of microbes congregate everywhere in the and on the human body. Their presence maintains their host’s health, in part by making it hard for disease-causing germs to gain access to the body
• Advances in computing and gene sequencing are allowing investigators to create a detailed catalogue of all the bacterial genes that make up this so-called microbiome
• Unfortunately, the inadvertent destruction of beneficial microbes by the use of antibiotics, among other things, may be leading to an increase in auto-immune disorders and obesity · Here is a very interesting interactive feature.

Research into microbiome – human organism interactions continues into some unlikely paths, such as its role in metabolism and obesity: “In 2004, microbiologists showed a link between obesity and gut microbiota in mice. To find out whether that link extended to humans, microbiologist Zhao Liping adopted a regimen involving Chinese yam and bitter melon—fermented prebiotic foods that are believed to change the growth of bacteria in the digestive system—and monitored not just his weight loss but also the microbes in his gut. When he combined these prebiotics with a diet based on whole grains, he lost 20 kilograms in 2 years. His blood pressure, heart rate, and cholesterol level came down. Faecalibacterium prausnitzii—a bacterium with anti-inflammatory properties—flourished, increasing from an undetectable percentage to 14.5% of his total gut bacteria. The changes persuaded him to focus on the microbiome’s role in his transformation. He started with mice but has since expanded his research to humans.” “My Microbiome and Me” by Mara Hvistendahl Science 8 June 2012: Vol. 336 no. 6086 pp. 1248-1250

Equally important seems to be the role of the commensals for the human immune system: “The trillions of microbes associated with the human body are a key part of a comprehensive view of pharmacology. A mechanistic understanding of how the gut microbiota directly and indirectly affects drug metabolism is beginning to emerge.” “Is It Time for a Metagenomic Basis of Therapeutics?” Henry J. Haiser, Peter J. Turnbaugh Science 8 June 2012: Vol. 336 no. 6086 pp. 1253-1255 and “The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity.” “Interactions Between the Microbiota and the Immune System” Lora V. Hooper, Dan R. Littman, Andrew J. Macpherson Science 8 June 2012:Vol. 336no. 608 pp. 1268-1273

“Dynamical biological networks capture, transmit and integrate various types of information to the molecular machines inside cells that execute the functions of life and create phenotypes. The structured interactions among members of the microbiome and their interactions with the human host add complexity to these information-processing networks. A systems approach Is necessary to define these networks, see how they are interconnected and follow their dynamic with the goal of understanding how they contribute to phenotypes at all levels.” Leroy Hood In the coming years, we will be even more surprised as we try to answer how the microbiome coexists with the human organism, the role it plays in phenotypic, homeostatic and functional aspects of its host, and how the ecological interconnectedness of the microbiome might affect evolutionary pathways for the host organisms. And the more we will learn about this relationship, the more we will appreciate the connected existence of humans with nature on this planet. There sure is “grandeur in this view of life”.

It is very interesting to read the article recently published on The Economist site titled “Microbes maketh Man”, which I reproduce here below.

“People are not just people. They are an awful lot of microbes, too

POLITICAL revolutionaries turn the world upside down. Scientific ones more often turn it inside out. And that, almost literally, is happening to the idea of what, biologically speaking, a human being is.

The traditional view is that a human body is a collection of 10 trillion cells which are themselves the products of 23,000 genes. If the revolutionaries are correct, these numbers radically underestimate the truth. For in the nooks and crannies of every human being, and especially in his or her guts, dwells the microbiome: 100 trillion bacteria of several hundred species bearing 3m non-human genes. The biological Robespierres believe these should count, too; that humans are not single organisms, but superorganisms made up of lots of smaller organisms working together.

It might sound perverse to claim bacterial cells and genes as part of the body, but the revolutionary case is a good one. For the bugs are neither parasites nor passengers. They are, rather, fully paid-up members of a community of which the human “host” is but a single (if dominating) member. This view is increasingly popular: the world’s leading scientific journals,Nature and Science, have both reviewed it extensively in recent months. It is also important: it will help the science and practice of medicine (see article).

All in this together

The microbiome does many jobs in exchange for the raw materials and shelter its host provides. One is to feed people more than 10% of their daily calories. These are derived from plant carbohydrates that human enzymes are unable to break down. And not just plant carbohydrates. Mother’s milk contains carbohydrates called glycans which human enzymes cannot digest, but bacterial ones can.

This alone shows how closely host and microbiome have co-evolved over the years. But digestion is not the only nutritional service provided. The microbiome also makes vitamins, notably B2, B12 and folic acid. It is, moreover, capable of adjusting its output to its host’s needs and diet. The microbiomes of babies make more folic acid than do those of adults. And microbiomes in vitamin-hungry places like Malawi and rural Venezuela turn out more of these chemicals than do those in the guts of North Americans.

The microbiome also maintains the host’s health by keeping hostile interlopers at bay. An alien bug that causes diarrhoea, for instance, is as much an enemy of the microbiome as of the host. Both have an interest in zapping it. And both contribute to the task. Host and microbiome, then, are allies. But there is more to it than that. For the latest research shows their physiologies are linked in ways which make the idea of a human superorganism more than just a rhetorical flourish.

These links are most visible when they go wrong. A disrupted microbiome has been associated with a lengthening list of problems: obesity and its opposite, malnutrition; diabetes (both type-1 and type-2); atherosclerosis and heart disease; multiple sclerosis; asthma and eczema; liver disease; numerous diseases of the intestines, including bowel cancer; and autism. The details are often obscure, but in some cases it looks as if bugs are making molecules that help regulate the activities of human cells. If these signals go wrong, disease is the consequence. This matters because it suggests doctors have been looking in the wrong place for explanations of these diseases. It also suggests a whole new avenue for treatment. If an upset microbiome causes illness, settling it down might effect a cure.

Yogurt companies and health-food fanatics have been banging this drum for years. And in the case of at least one malady, irritable-bowel syndrome, they are right. So-called probiotics, a mixture of about half a dozen bacterial species found in yogurt, do act to calm this condition. But there is little evidence that consuming probiotics has the tonic effect on healthy people that certain adverts suggest.

A handful of doctors are taking a more fundamental approach to another microbiome-related disease, infection with Clostridium difficile. This bacterium, which causes life-threatening distension of the gut in some people who have been treated with antibiotics and thus had their microbiomes disrupted, is a bane of hospitals. It kills 14,000 people a year in America alone. But recent experiments have shown it can be eliminated by introducing, as an enema, the faeces of a healthy individual. “Stool transplants” are a pretty crude approach, to be sure, but the crucial point is that microbes are much easier to manipulate than human cells. For all the talk of superorganisms (and despite the yuck factor of what is being moved from one body to another), transplanting a microbiome is far easier than transplanting a heart or a kidney.

Disgusting but useful

Two other areas look promising. One is more sophisticated deployment of the humble antibiotic, arguably the pharma industry’s most effective invention. At the moment antibiotics are used mainly to kill infections. In the future they might have a more subtle use—to manipulate the mix of bugs within a human, so that good bugs spread at the expense of bad ones.

The other field that may be changed is genetics. Many of the diseases in which the microbiome is implicated seem to run in families. In some, such as heart disease, that is partly explained by known human genes. In a lot, though, most notably autism, the genetic link is obscure. This may be because geneticists have been looking at the wrong set of genes—the 23,000 rather than the 3m. For those 3m are still inherited. They are largely picked up from your mother during the messy process of birth. Though no clear example is yet known, it is possible that particular disease-inducing strains are being passed down the generations in this way.

As with all such upheavals, it is unclear where the microbiome revolution will end up. Doctors and biologists may truly come to think of people as superorganisms. Then again, they may not. What is clear, though, is that turning thinking inside out in this way is yielding new insights into seemingly intractable medical problems, and there is a good chance cures will follow. Vive la révolution!”