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Our Guts, Our Bodies, Ourselves

On May 27, 2004, the scientific journal Nature released a historic publication. The special issue celebrated the culmination of the Human Genome Project, and it proudly featured what was practically the complete DNA sequence that composes the genetic makeup of humans. The decoding of the human genome was the result of nearly a decade and a half of thought and toil, and its publication was considered an enormous triumph. It was heralded by the New York Times as the “Book of Life” in 2000. Scientists anticipated that it would transform the field of medicine and lead to dramatic advances in our understanding of the relationship between genetics and physiology. In many ways, the Human Genome Project has drastically altered our approach to biology and medicine.

More recently, however, the scientific community has recognized the possibility that decoding our human genome may only be the first step in understanding human functioning. It is true that the Human Genome Project gave scientists tremendous insight into cellular physiology, human genetics, and even the ways in which our organs function cooperatively and independently. Yet, there are external factors that complicate our physiology; the interactions of our bodies with bacteria, viruses, and fungi can affect human health tremendously. Many of these interactions simply occur when the human body comes into contact with the microbes that reside in our external environment. Recent scientific data, however, indicates that intricate microbial systems reside within our bodies as integral components of every human’s lively internal environment. As it turns out, there may be a new genome that we need to sequence to fully understand human health—the one belonging to the microbiota that inhabit our bodies.

There are on the order of hundreds of trillions of bacteria, viruses, and fungi that live within, and more importantly, with humans. These bacteria and viruses form a sort of “ecosystem” of microbiota within our bodies. Rob Knight and a team of researchers are studying the human microbiome at the University of Colorado at Boulder, one of the world’s premiere institutes for research on the subject. Knight recently contributed to a comprehensive review article in Cell that explored the relationship between gut microbiota and human physiology. In it, the authors outlined the process through which these ecosystems develop within our bodies. Starting from the time a human is born (and, in fact, evidence suggests that this process may extend to the time spent in utero), microbes colonize every crevice of the body exposed to our external environment. The majority of this colonization takes place in the intestinal tract, but it also occurs in the remainder of the gastrointestinal tract and on the skin.

Just as humans develop from infancy to old age, so do our microbial ecosystems. Babies in utero can be considered to have a “blank canvas,” in the words of the Colorado research team, with respect to the presence of microbiota. When babies are born, their intestinal tracts are relatively sterile. Within the first three years of life, different bacterial and viral strains colonize and “settle down” into distinct areas of the outer lining of our guts. It’s an ecosystem within our own bodies; a careful balance ensures that no strain of bacteria or virus dominates too large an area. The process of colonization of the gut occurs gradually as an infant’s digestive tract is exposed to bacteria naturally found in breast milk and, eventually, a solid-food diet. The process through which bacteria colonize an infant’s skin, however, depends on the method of the baby’s delivery. Vaginally-delivered babies are exposed to an environment rich in the mother’s bacteria during birth, as evidenced by the robust microbiota found on the skin of these infants post-delivery. By contrast, the skin of babies delivered by caesarian section is relatively sterile. In fact, following the birth of Knight’s daughter by C-section, Knight took the precaution of swabbing her skin with a sample of his wife’s vaginal secretions to “insure a proper colonization” of microbiota.

“Clearly, there is no microbiome that is “standard” among humans; every person’s body harbors a unique and complex community of microbes.”

Clearly, there is no microbiome that is “standard” among humans; every person’s body harbors a unique and complex community of microbes. This phenomenon poses an intriguing question to the epidemiological community: what is the relationship between our bodies and the microbiota that they support? In other words, how do our own, individualized microbiota interact with our bodies? Of course, these microbes colonize distinct areas of the intestinal tract, mouth, and skin for their own benefit; unthreatened, they can proliferate and ensure that future microbe generations are well endowed with nutrients and space, like weeds dominating a particular patch of a garden. But scientists are also gaining insight into the ways that the microbiota may benefit humans—how these “weeds” can actually nurture and enrich the soil that hosts them.

What biologists have found is that a robust, diverse community of microbes in our intestinal tract (as well as on our skin and in our mouths) is extremely beneficial to human health. Loss of diversity and balance within our microbial communities, termed “dysbiosis,” is linked to consequences that range from obesity and diabetes to autoimmune disorders and inflammatory bowel disease (IBD).

Interestingly, studies have shown that C-section babies have an especially heightened susceptibility to developing asthma, allergies, and mild illness than babies delivered vaginally. Other studies have found that earlier colonization of certain bacterial species (including Lactobacillus spp, Bifidobacterium adolescentis, Clostridium difficile, and Helicobacter pylori) result in decreased likelihood of allergy development in humans. (Intriguingly, some of these bacteria can infect humans later in life with lethal outcomes.)

In a recent New York Times article, Michael Pollan, a renowned science journalist described some of the surprising ways in which our gut microbiota are known to affect our health. The growing epidemic of food allergies may be inextricably linked to the way our internal ecosystem of microbes functions. It has not escaped the notice of epidemiologists that this epidemic is, for the most part, limited to the more industrialized, developed regions of the world that includes many Western countries. How have developing countries evaded conditions like allergies and asthma?

“As it turns out, the structure of gut microbiota varies drastically from person to person.”

The answer may lie in examining the hygienic and dietary practices of these regions. Noteworthy, too, are the agricultural and industrial circumstances of a given area. As it turns out, the structure of gut microbiota varies drastically from person to person. Scientists believe that the conditions and environments humans are exposed to greatly influence our ecosystem of microbiota—our own personal “microbial genome.” Thus, it is not implausible that the microbiota vary by region. Perhaps our microbial genomes are affected by the environmental conditions, diets, and hygienic practices that we, their human hosts, are exposed to.

The “Hygiene Hypothesis” has been formulated to account for this occurrence. The Colorado research is one group of researchers that has postulated that a “lack of exposure to pathogenic and nonpathogenic microbial products early in life might result in an asthmatic phenotype due to an impaired development of the immune system.” In other words, infants and children raised in hyper-sterile environments that minimize their exposure to microbes, harmful or not, are more likely to have dysbiotic microbial communities. Catherine A. Lozupone, a microbiologist and former colleague of Knight, noted that “rural people spend a lot more time outside and have much more contact with plants and with soil.” Lozupone, who studies the global patterns of microbiota in Westernized and rural, non-Westernized regions has found that microbial diversity in the “Western gut” is significantly lower than guts of lesser-industrialized regions. Could it be possible that the hyper-sterile environments that overcautious but well-meaning parents prefer for their babies actually subject them to health difficulties later in life?

Epidemiologists and pediatricians at the University of Florence are working diligently to find out. Carlotta de Filippo is the leader of a Nutrition and Nutrigenomics research group, and she recently pioneered a study that investigated the differences in microbial communities in the guts of children from two vastly different regions: a rural village in Burkina Faso and Florence, Italy. While babies in Florence may grow up swaddled in sanitizers, germ-free environments and antibiotics, babies raised in the village in Burkina Faso have significantly less exposure to antibiotic drugs, soaps and sanitizers and heightened exposure to dirt.

Not only do the health and sterilization practices differ in these two regions, but the typical diets of humans in these two regions are nearly polar opposites. The diets of “Westernized” regions have diverged immeasurably from the diets our hunter-gatherer ancestors must have eaten. In areas such as the United States and many European countries, diets are high in fat and high in sugar. Many of the items now commonly found on the dinner table in these areas were rare (or even nonexistent) in early hunter-gatherer societies. Processed foods, bleached flours, and animal fats are staples of a Westernized diet, while produce is often pushed aside.

On the other hand, people living in more rural, less industrialized regions (like those found in rural regions of Africa, Australia, and South America) tend to subsist on diets that more closely resemble those of our ancestors. These “non-Westernized” diets typically consist of low-fat, high-fiber foods derived from plant polysaccharides. In the absence of refrigeration, fermented foods are also a staple of many non-Westernized diets.

De Filippo and her colleagues were amazed to find that the microbiota of children from Burkina Faso were also radically different from those found in children living in Italy. The 14 children studied from Burkina Faso had thriving microbiota, while the diversity of gut microbiota in the 15 European children was significantly reduced. The types of bacteria that dominated the intestinal linings in the two regions differed as well. A non-Westernized diet favored certain types of enterotypes—namely, a type of bacteria called Prevotella. Consumption of a “Western” diet tends to result in relatively low-diversity microbiota, with enterotypes dominated by Bacteroides. As Michael Pollan put it, “The ‘Westernized microbiome’ most of us now carry around is in fact an artifact of civilization, no more a wilderness today than, say, the New Jersey Meadowlands.”

” Remarkably, even temporary shifts from Western to non-Western diets result in 24-hour changes of gut microbiota.”

Remarkably, even temporary shifts from Western to non-Western diets result in 24-hour changes of gut microbiota. In mice, shifting to a high-fat, high-sugar “Western” diet from a low-fat, plant polysaccharide-rich diet can change the microbiota within a day; it becomes more dominated by the Bacteroides found in guts in Westernized regions. This change also works in the other direction; humans that shifted from a high-fat/low-fiber diet to a low-fat/high-fiber diet displayed changes in the gut microbiota within 24 hours as well, with significantly elevated levels of the Prevotella bacteria.

Drastic change can also be induced by the use of antibiotics, which decrease the size and diversity of bacterial communities populating the gut and skin. Although the microbiota diversity can, hypothetically, “bounce back,” studies have found that it’s not an entirely efficient return to previous conditions. An increasing body of evidence suggests that the structure of gut microbiota thought to be “established” after three years of life is more plastic than scientists initially anticipated. Pollan, who required treatment with the antibiotic Amoxicillin, had his microbiota composition analyzed before and after exposure to the drug. He was crushed to see that the community of microbes was nearly devastated by the invasive treatment. It “would eventually bounce back,” Pollan was reassured. But he was unnerved by a study that found that a microbial ecosystem only recovers partially after exposure to antibiotics.

It is humbling to realize that much of our body’s functioning is intertwined with our microbiome; it is almost as if a new, symbiotic organ has been discovered. After all, scientists have witnessed tangible effects of microbiota on our health, and have uncovered striking associations between our diets and our microbiota. Many are convinced that the cleanliness of our homes and communities can directly impact our microbiota. And yet, much about the microbiota is still unknown. Scientists do not fully understand the precise nature of the relationship between microbial communities and human hosts. In particular, there is limited understanding of the mechanism by which the microbiota might affect the development of conditions like asthma and allergies. This mechanism of action has puzzled scientists for years—but  a few emerging theories may give us a clue.

In 2011, researchers at Caltech led by June L. Round investigated a conundrum that had been plaguing them. In order to survive, our mucosal immune systems should have rigid defenses against threatening pathogenic bacteria. Innate immune cells and T-cells protect the body’s mucosal lining using receptors called TLRs (Toll-Like Receptors), which lie on the cell’s surface. TLRs activate an immune response upon detecting common structural features of unfamiliar, non-mammalian organisms like bacteria, viruses, and fungi. But the massive communities of non-pathogenic microbes that already live in the mucosal lining of the intestines seem impervious to such immune defenses. How do these harmless microbes avoid sounding the alarm bells and activating our immune defenses?

Round and her team of Caltech researchers discovered that one strain of bacteria, the human gut Bacteroides fragilis, has a molecular mechanism that actually suppresses the immune-activating response of TLRs during its period of colonization. Bacteroides fragilis is a commensal strain of bacteria, meaning that it can colonize the outer gut lining while maintaining a symbiotic relationship with the human digestive tract. Different species of commensal bacteria are suspected of inhibiting TLR activity during colonization periods as well. Other researchers have discovered that some bacteria even manage to manipulate the inner workings of the adaptive immune system to their benefit; the commensal bacterial strain Bacteroides thetaiotaomicron induces secretion of peptides that are bactericidal to competing microbes, but not to Bacteroides thetaiotaomicron themselves.

“Conversely, “germ free” mice (mice with sterile, microbe-free intestinal environments) have difficulty regulating an immune response.”

Conversely, “germ free” mice (mice with sterile, microbe-free intestinal environments) have difficulty regulating an immune response. As a result, they will have an overly responsive immune system. For instance, germ-free mice secreted reduced amounts of an antibody called Immunoglobulin A (IgA). IgA is secreted when the body detects the colonization of commensal bacteria in the intestinal lining. Its function is to protect mucosal surfaces while promoting mutualism between the host and the microbiota. Low levels of IgA secretion result in poor cooperation between microbes and mucosal epithelial cells. The lower the IgA levels, the more severe the immune response elicited in response to detection of microbes—pathogenic or not. Sterility, then, can be linked to an overactive immune system.

The individual mechanisms of commensal, mutualistic bacteria serve one common objective: to proliferate and colonize a host organism while suppressing an immune response. It seems that a rich, heterogeneous ecosystem of microbiota has a more stable relationship with the mucosal immune system than a more sterile, barren ecosystem, which is likely to aggravate an inflammatory response to even small provocations of microbes (independent of their pathogenicity).

Scientists are beginning to connect the dots between these isolated findings. Perhaps, common allergens like nuts, pollen, or fruits are perceived as aggravants by the immune system. Lozupone and de Filippo, proponents of the Hygiene Hypothesis, would assert that a child reared with relatively little exposure to microbes (or heightened exposure to antibiotics and sterilizers) is at risk of developing a sparse, homogeneous intestinal microbiota.  Round and her colleagues would then theorize that a frail microbial community leads to an overactive inflammatory response when aggravant substances are encountered. The Colorado research group ultimately theorized, “A reduced exposure early in life to infectious agents and human-resident mutualists could result in a weakened machinery for counter-regulation of inflammatory responses and therefore to an increase in the prevalence of allergies.”

Currently, the scientific community is hesitant to dispense advice on how to change health and dietary practices to promote microbiota health—and understandably so. To condemn antibiotics and processed foods as killers of intestinal health could lead to problematic consequences, while scientists still aren’t confident in making these claims. And while nutritionists laud probiotic yogurts and fermented foods, the scientific community still isn’t sure why there appears to be a link between microbiota and these foods. After all, we have yet to fully sequence the DNA of our body’s bacterial and viral microbiomes; as this information becomes more readily available through the Microbiome Sequencing Project, perhaps more concrete scientific recommendations will materialize. Still, existing scientific evidence is suggestive. The sanitary and hygienic practices of overly industrialized, non-rural societies have diverged from those of our ancestors in a way that may jeopardize our health. Perhaps this is enough to inspire small lifestyle changes—less hesitation to let our children play in the dirt, or just the addition of some fermented radishes to a salad—in order to preserve the integrity of our bodies and the beautiful diversity of the ecosystems found inside of them.

 

 

Works Consulted

Clemente, Jose C., Luke K. Ursell, Laura Wegener Parfrey, Rob Knight.

“The Impact of the Gut Microbiota on Human Health: An Integrative View.” Cell, Volume 148, Issue 6, 16 March 2012, Pages 1258–1270

De Filippo, Carlotta, Duccio Cavalieri, Monica Di Paola, Matteo Ramazzotti, Jean Baptiste Poullet, Sebastien Massart, Silvia Collini, Giuseppe Pieraccini, Paolo Lionetti.

“Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.” PNAS, 2 Aug 2010 ; published ahead of print August 2, 2010, doi:10.1073/pnas.1005963107

Pollan, Michael. “Some of My Best Friends Are Germs.” The New York Times 15 May 2013: n.pag. Web. <http://www.nytimes.com/2013/05/19/magazine/say-hello-to-the-100-trillion-bacteria-that-make-up-your-microbiome.html?pagewanted=1&_r=0>.

Round, June L., S. Melanie Lee, Jennifer Li, Gloria Tran, Bana Jabri, Tatal A. Chatila, and Sarkis K. Mazmanian. “The Toll-Like Receptor 2 Pathway Establishes Colonization by a Commensal of the Human Microbiota.” Science 332 (2011): 974-77. Print.

Dalia Walzer Author’s Note

Dalia Walzer is a member of the Class of 2017 majoring in biology. Her interest in both microbiology and public health nourished a fascination with the human microbiome. Dalia’s interest in the health applications of microbiome research led her to OpenBiome, the nation’s first stool bank, where she spent a wonderful and occasionally smelly summer. A New Jersey native, Dalia has yet to find a satisfactory bagel in Boston; however, she enjoys exploring the city’s many excellent ice cream shops.