Microbiomes: We are not alone

The Amazing Human Microcosm

The microscopic world is all around us and within us. Billions of bacteria, viruses, fungi, are on every surface we touch, the food we eat, the air we breathe. They are on our skin, in our mouths, nose and eyes, and live comfortably throughout our bodies, their homes. They live inside our cells and even incorporate their DNA into ours.

In fact we are more bacteria than human! Ninety per cent of the cells in your body belong to bacteria, not you. Because they are so much smaller than our cells, bacterial cells only make up between one and three per cent of our mass, but they likely comprise over 3000 species, fewer than 750 of which have been identified and genetically sequenced(1). The typical human body contains between two and six pounds of bacteria.

This collection of alien residents is referred to as the human microbiome and comprises bacteria, viruses, and fungi and in fact anything living on or within us that is not part of our inherited genome.

For the most part these microbes don't cause us any harm. Quite the contrary they are crucial to our existence. They produce vitamins that we don't have the ability to make for ourselves. They break down the food in our intestines and supply us with nutrients that we otherwise could not obtain from our food, they assist our immune system in fighting off pathogens and are critical in training our immune system from birth.

It isn't just humans who harbor a host of microbes. Bacteria evolved on this planet over a billion years ago. They have been around throughout the evolution of all higher order species, animal and plant, and have been co-evolving with them for at least 800 million years. No higher animal has ever existed in an environment that wasn't completely filled with microbes. The higher order species have all evolved in conjunction with their predecessors on the planet and all now require their presence in order to exist.

A weeks worth of growth from the hand print of an 8 year old boy on a sterile agar Petri dish.

We are, in fact, commensual organisms. Our microbiome can't exist without us and we can exist without it!

How do you get a microbiome?

Before we are born there are few if any microbes living in our newly developing bodies. The uterus in which we are developing is relatively sterile under most circumstances and remains so at least until labor is well along. So the obvious question is where does our microbiome come from? How is it that only useful microbes come to live in our bodies while harmful bacteria are prevented from doing so? After birth microbes can and do enter our bodies constantly, where they are met and usually promptly dispatched by our immune system. How do these thousands of species that are necessary for our survival manage to occupy our bodies, evade our immune system, and establish life long residency?

Teaching the immune system.

Our immune system is a marvel of evolutionary bioengineering. It constantly examines everything it comes in contact with to determine whether it is part of us (self) or whether it is foreign (non-self). Things recognized as self are left alone while those recognized as non-self are attacked. Among those things which are recognized as non-self are cancer cells which are attacked and often eliminated by the immune system.

There are many different parts to the immune system. Some are as simple as skin which acts as a barrier to keep microbes out. Other parts of the immune system include cells which consume unrecognized substances, cells which cut unrecognized substances into pieces which they then present to other "factory" cells called B lymphocytes or B cells. These B cells then make proteins called immunoglobulins which recognize and bind to these pieces when they are encountered in the body.

Immunoglobulins are commonly called antibodies and the pieces that are presented to stimulate the productions of antibodies are called antigens (short for antibody generators). Now when these antibodies encounter their specific antigen somewhere in the body they bind to it and trigger the immune system to attack it.

When the immune systems encounters lots of antigens, as in an infection, it responds by making large numbers of antigens but each B cell has to "learn" to make the antigen. Once the B cells have learned to make a certain antibody they remember how to do it. When confronted with one of these antigens in the future the B cells begin quickly making large numbers of antibodies. This is how people become immune to some diseases (for example, chicken pox) and also how vaccines work.

When the immune system fails to identify non-self the body is more susceptible to infection and those infections are more likely to be severe and /or chronic.

When the immune system incorrectly identifies self as non-self and begins attacking parts of it's own body the result is referred to as an autoimmune disease. There are over 80 identified autoimmune diseases including type l diabetes, certain types of thyroid disease, lupus, rheumatoid arthritis, multiple sclerosis, Goodpastures syndrome, and ulcerative colitis. Autoimmune diseases are among the leading causes of death in women below 65 years of age. 6

In just the last decade we have begun to realize that the bacteria of our microbiome are actually part of our immune system. Not only do they create an environment that keeps many invasive bacteria, viruses, and yeasts in check, they play a large role in modulating, (both increasing and decreasing) our own immune inflammatory response. If those species aren't present in our bodies the result can be either insufficient immune response or excessive and chronic inflammation. 5

Failing to establish a healthy microbiome has far reaching and serious consequences. Evidence is accumulating that links many chronic diseases in humans to their microbiomes, among them type ll diabetes, metabolic syndrome, asthma, a number of autoimmune diseases, propensity to chronic infections, neurobehavioral development including autism, and even some cancers are suspected to be directly linked to the absence of an appropriate colonization of microorganisms including colorectal, pancreatic, and prostate cancers.

The nature and importance of the human microbiome is so critical that the National Institutes of Health have sponsored a Human Microbiome Project, patterned after the Human Genome Project,that seeks to identify and characterize all the the microbial fauna and flora that contribute to a healthy microbiome, the consequences of disrupting the establishment of a normal microbiome, methods for treatment of microbiome related disease, and how the microbiome is established and how it interacts with our immune system. 1

Birth is critical

While we are very early in our discovery of how microbiota become established, we do know that it is a process that begins at at birth and is completed by the age of three. There is solid information that exposure to a healthy vaginal microbiome during birth and from skin contact and breast milk in the early days to weeks after birth is critical for our immune system to learn which bacteria to leave alone and which bacteria should be destroyed.

It appears that the immune system has only one shot at becoming properly seeded, that it must occur during a very brief and narrow time frame, and that once established it can not be retrained. Once we lose the opportunity to grow within us the millions of healthy organisms required to complete us , we can never regain it. We are just beginning to accumulate evidence of what happens to human bodies that are not properly seeded at birth and the picture isn't pretty. Further more, it now seems likely that women whose microbiomes were not properly established at their own birth likely pass that impairment on to their own children.

"Scientists now believe that infants are sterile (meaning free of microbes) in the womb and receive their first inoculum of microbes from the mother during natural childbirth. This innoculum goes on to colonize the newborn and initiate a succession of events leading to the development of the child's own microbiome. The newborn relies on this maternal vaginal microbial inoculum and the additional inoculum of microbes from mother's breast milk for microbial colonization of all exposed surfaces in and on the infant's body (e.g., oral, nasal/airways, gut, urogenital, skin).2 This is a dynamic process in which microbial abundances increase from effectively zero at birth to over six orders of magnitude (that's more than a million times!) within just the first few weeks of life, with wide swings in the microbial membership of these communities until the microbiota largely stabilize in composition and numbers after approximately three years of life.3

At the same time, the newborn's gut microbiota trigger development and maturation of the newborn's immune system. Although there is still a great deal of research needed to understand precisely what happens in this developmental process, it appears the maturing immune system relies on the presence of microbial communities, and especially the presence of these early microbes, to distinguish "self" from "nonself" 4. It is these particular microbes that shape our immune systems. Once the immune system has matured, it will consult its "memory banks" if another microbe is encountered in order to determine if this microbe is considered "self" or "nonself" and to mount defenses against the microbe if it is recognized as a pathogen. 5

So the bacteria, viruses, and fungi you acquire from your mother at birth "teach" your immune system which bacteria belong there and which should be left alone.

The consequences of an improperly seeded microbiome include an increased risk of metabolic diseases including diabetes, obesity, and liver disease, asthma, various autoimmune diseases, and cardiovascular disease. There is now evidence that some cancers and even autism and other alterations in brain function are correlated with events that cause changes to the microbiome.

Microbirth

So how does our microbiome get established and what sorts of things are we doing that be impairing it?

Bacteria are everywhere. It's in our food, our water supply. It's in the air we breathe and on every surface we touch. It thrives in "sterile" operating rooms, on faucets, drinking fountains, air handling ducts. As already noted it resides throughout our bodies. In humans the largest concentrations are within our gastrointestinal tracts, our respiratory tracts, on our skin, and in women in our vaginas.

Given that bacteria are so ubiquitous it should come as no surprise that bacterial residents in your body might easily shift in response to different exposures. Changes in your diet will result in changes in your gut microbiome. Taking antibiotics may eliminate populations of beneficial bacteria in your gut, which may result in , but those populations are thought to reestablish themselves in a fairly short amount of time.

A scanning electron micrograph of e.coli (in green) in the intestines of a child. E. coli is an essential resident in the GI tract.

There is evidence that, in species that have not been domesticated, microbiota are remarkably preserved across millions of years. Examinations of the microbiota of modern whales and cows revealed that half of there gut flora are identical, yet their most recent common ancestor lived over 60 million years ago. 7

Works Cited:

1. "Human Microbiome Project / Reference Genomes Data". Data Analysis and Coordination Center (DACC) for the National Institutes of Health (NIH). Retrieved 8 March 2012.

2. Gronland, M.M., M. Gueimonde, K. Laitinen, G. Kociubinski et al. (2007). Maternal breast milk and intestinal bifidobacteria guide the compositional development of the Bifidobacterium microbiota in infants at risk of allergic diseases. Clin. Experim. Allergy 37:1764-1772.

3. Palmer, C., E. M. Bik, D.B. DiGiulio, D. A. Relman and P.O. Brown (2007). Development of the human infant intestinal microbiota. PLoS Biol. 5:e177

4. Hooper, L.V. and J.I. Gordon (2001). Commensal host-bacterial relationships in the gut. Science 292:1115-1118.

5. Round, J.L., and S. Mazmanian (2009). The gut microbiota shapes immune responses during health and disease. Nature Reviews Immunology. 9:313-323.

6. Walsh, SJ; Rau, LM (September 2000). "Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States.". American journal of public health 90 (9): 1463–6

7.Sanders JG, Beichman AC, Roman J, Scott JJ, Emerson D, McCarthy JJ, Girguis PR. Baleen whales host a unique gut microbiome with similarities to both carnivores and herbivores. Nature Communications, 2015; 6: 8285 DOI: 10.1038/ncomms9285

8. Michael C. Abt,1 Lisa C. Osborne,1 Laurel A. Monticelli,1 Travis A. Doering,1 Theresa Alenghat,1 Gregory F. Sonnenberg,1 Michael A. Paley,1 Marcelo Antenus,2 Katie L. Williams,4 Jan Erikson,4 E. John Wherry,1,* and David Artis1,3,*Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity. Immunity. 2012 Jul 27; 37(1): 158–170.

#microbiomes #immunesystem #bacteria #microbirth

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