The Human Microbiome

The establishment of Koch’s postulates in microbiology that links specific microorganisms to specific diseases gave rise to the concept of ‘one microbe-one disease’. Since then the thought that microbes cause disease has always overshadowed the effect of good microbes present in the body. Through the Human Genome Project (HGP) around 22,000 genes were discovered in the human body. But what about the remaining genetic material contributing to human function that is present in the human body but not associated to its genome?

Also, there was a need to understand the role played by commensal microbes in humans. Relman and Falcow in 2001 had suggested that a ‘second human genome project’ be implemented taking into consideration microbial colonization of 4 exposed sites of the body, the mouth, gut, vagina and skin.

Thus as an extension to the HGP, the Human Microbiome Project (HMP) was implemented by the United States National Institutes of Health in the year 2007.1 The primary goal of the study was to identify and characterize the microorganisms that are present in humans, their role in healthy and diseased individuals and how changes in the microbiome can affect certain disease states. It also aimed to find out if there is a core or a common microbiome that exists in most people.

The study was done in 242 healthy volunteers and at 15 (men) to 18 (women) sites in the body including the mouth, nose, skin, lower intestine (stool) and vagina. The study also evaluated the ethical, legal and social implications of microbiome research.

A new, powerful and low-cost whole genome sequencing technique was used in this study which identified the organisms from samples, as opposed to the traditional method of culturing them individually in laboratories. The study revealed the presence of around 10, 000 microbial species associated with the human body which function in several ways and also identified around 81-99 percent microsomal genera in healthy adults.2, 3, 4

Some conclusions made were that there is more variation between microbiomes present in 2 different areas within a person than there is between the same site of 2 distinct people. That is a person’s gut and skin microbiome are more different than his gut and another individual’s gut microbiome.

Also, the function performed by microbes, like digesting carbohydrates, synthesizing vitamins and breaking down toxins at a particular site is similar among individuals although there could be a difference in the makeup of their individual microbiomes. These researchers also “estimate that the human microbiome contributes some 8 million unique protein-coding genes or 360 times more bacterial genes than human genes”.2 The human body can thus be termed a “supraorganism” – one that contains a multitude of human and microbial cells and their genes.5

DEFINITION OF THE MICROBIOME

The first classic definition of microbiome was given by Joshua Lederberg in 2001. He defined it as “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space and have been all but ignored as determinants of health and disease”.6

Over the years, the term microbiome gained slightly different definitions. Microbiome is the name given to a collection of all the genes of microorganisms present in the human body, where the microorganisms themselves are called the microbiota of the human body. There is another definition of the microbiome that stems from an ecologists point of view. In ecology an ecosystem is termed a biome. Thus considering the human body as a biome, all the microorganisms living in this system is collectively called the microbiome.

Thus microorganisms or their genomes can interchangeably be called microbiome. This human microbiome consists of bacteria, fungi, viruses, archaea, protozoa and other one-celled eukaryotes of which bacteria are the most studied organisms. They live in parts of the body that are exposed to the outside world like the mouth, gut, skin, vagina, and in other places like the lungs and the stomach.

WHERE DO THEY COME FROM?

The baby’s first exposure to microbes is when it is in the mother’s womb. The placental tissue once thought to be germ-free is now said to be crawling with microbes.7 The next exposure to these microbes is when the baby comes out into the world through the birth canal. For children born due to caesarean, the infant encounters these microbes first from the skin of the mother and then from others around them. The next and crucial source of microbes the infant gets is through breast feeding.

For example, the predominant bacteria in colostrum, the breastmilk that is produced during the first 2 days of lactation are Weisella, Leuconostoc, Staphylococcus, Streptococcus, and Lactococcus.8 Thus the breastmilk is an excellent source of probiotics (microbes) and prebiotics (nutrients that are needed by the microbes to thrive) to the infant and together these two contribute a lot to the kind of microbial community getting established at a particular site in the child.

During the development of the child, other factors contribute to or influence the human microbiome. Some of them are the diet of the infant, consumption of antibiotics in early life, immunizations, host genetics, available nutrients, chemical communication, temperature, pH, moisture and oxygen. Hence the establishment of a microbiome is a ‘selection’ process influenced by the above factors. Apart from these, there is also exposure to environmental microbes and those that are shed by pets and plants around them. By the time the child is 2 years old, the microbiome that has been established is more or less equivalent to an adult one.

HOW BIG ARE THESE MICROBES?

Microbial cells were first said to outnumber human cells by ten to one.9 This was based on an estimate that there are 10 trillion cells in the body. A recent estimate suggests that there are around 37 trillion cells in the body10 thus making the microbial to human cell ratio three is to one. The total mass of all the microorganisms put together is around 1-3% of total human body mass.11 The maximum density of microbiome is in the large intestine mainly due to its large surface area. Blood and lymphatic fluids are mostly devoid of the microbes. The microbes outnumber us in genetic material too. According to the HMP project results, there are around 8 million genes compared to around 22,000 human genes.

WHY ARE THESE MICROBES IMPORTANT AND WHEN DO ABNORMALITIES ARISE?

These microbes live in a dynamic relationship in our body. They are useful in supplying us with vital vitamins, they help us churn down carbohydrates thus keeping the body metabolism in check and also help us defend pathogens (other members of their own clan). In fact disease causing microbes like E. coli, yeast, Staphylococcus aureus, and Clostridium difficile are known to live in healthy humans and cause disease only when their ecosystem is disturbed.

So when this microbiome falls out of balance, we become ill. Some of the conditions we are more prone due with a change in the microbiome are- acne, antibiotic-associated diarrhea, asthma/allergies, autism, autoimmune diseases, cancer, dental cavities, depression and anxiety, diabetes, eczema, gastric ulcers, hardening of the arteries, inflammatory bowel diseases, malnutrition and last but not the least, obesity.

Michael Fischbach of the Department of Bioengineering and Therapeutic Sciences at the University of California, San Francisco says that the microbiome helps the immune system by actually ‘talking’ to the natural killer T- cells in the body. The cells then view the healthy microbiome as an ally and attack the non-ally, invading bacteria.

Studies done on mice have revealed different types of bacteria on obese and lean mice. Lot of research has been done in this topic by Yang-Xin Fu, MD, PhD, professor of pathology at the University of Chicago.and by Jeffrey Gordon, MD, of Washington University in St. Louis. It seems like lean people have microbes that need more calories of the food we intake thus keeping the host lean. It is the opposite in the case of obese people.

Dental plaque, the sticky layer that forms on our teeth when we don’t brush, contains hundreds of species of microbes. This healthy microbiome gets imbalanced when we consume a lot of sugar and infections are thus caused. Similarly, the microbiomes of the mouth, skin, vagina, lungs, and stomach are also altered in various disease states.

Hence maintaining a healthy microbiome goes a long way in keeping us healthy.

LOCATION, LOCATION, LOCATION!

Like mentioned before, lots of factors affect the fact where the microbes choose to settle. They each find their own niche in the human body. The HMP study discovered that even in healthy individuals, microbes occupy different habitats in different individuals and each body site is home to a unique microbial community. But a very interesting fact is that although there is great variation in microbes between individuals, the functions carried out at a particular site are the same. That is, different bacteria carry out the same function in the mouth or gut of 2 different individuals. These microbial communities can also change during the course of one’s life due to factors like diet, use of antibiotics and geographical location change. A few distinct microbiomes in the human body have been outlined in the next few paragraphs.

SKIN MICROBIOME

The skin is the first line of defense to the human body. There are 2 kinds of microbes that inhabit the skin, the commensal residents (commensalism is the relationship between two organisms where one organism benefits from the other without affecting it) and the transient residents. Some bacteria like the Staphylococcus aureus, Propionibacterium acnes, and Malassezia spp., are known skin commensals that are capable of becoming pathogens under certain conditions like microbial imbalance, host genetic variation or if the immune system is compromised. Analysis of 16s ribosomal RNA gene sequences obtained from 20 distinct skin sites of healthy humans showed that similar bacteria were found in physiologically similar sites and the stability of these microbes dependent on the specific characteristics of the skin site.12

They also found that skin disorders like eczema and diabetic wound healing that were treated with antimicrobial agents had different microbiata. The same lab has shown a correlation between relative abundance of Staphylococcus spp. and the expression of cutaneous defense response genes. Other studies have shown that skin conditions like atopic dermatitis and psoriasis show differences in their microbial compositions compared to healthy skin. Since establishment of a healthy and diverse microbiome has strong influences on the immune system, the connection between skin disorders and the differences in their skin microbiome will give an insight into the treatments of those diseases.

MOUTH MICROBIOME

In pure culture approximately 280 oral microbial species have been identified and named. A recent study has identified that the genera Gemella, Granulicatella, Streptococcus, and Veillonella are common to most oral sites while some species were subject specific and others were site specific.13 Infections like tooth decay and gum disease that were associated with a single bacteria are now known to be caused by a microbial community. The Human Oral Microbiome Database (HOMD) was created to provide comprehensive information of around 700 species and their genome to better understanding the role of bacteria in tooth diseases.14

These bacteria have to live in harmony with the immune system to keep tooth diseases at bay. Human oral microbiome according to the HOMD is the collection of all the microorganisms that are found in the different microhabitats of the oral cavity (teeth, gingival sulcus, attached gingiva, tongue, cheek, lip, hard palate, and soft palate) and its contiguous extensions (the tonsils, pharynx, esophagus, Eustachian tube, middle ear, trachea, lungs, nasal passages, and sinuses). Further studies need to be done to study the understanding of the oral microbiome and disease.

VAGINAL MICROBIOME

The surface of the vagina is covered by a protective epithelial barrier that is filled with bacteria and other microorganisms. This barrier keeps the upper genital tract and the ectocervix sterile by defending against pathogens. When pathogens cross this barrier conditions like preterm labor and pelvic inflammatory disease can occur.

The vaginal microbiome that once was known to be colonised primarily by the Lactobacillus species is now showing great diversity and differences among races and ethnicity and also with different age groups. The vagina of normal women and women with the condition bacterial vaginosis (BV), an infection characterized by an odorous vaginal discharge can be similar with lesser Lactobacillus bacteria and a greater number of anaerobic bacteria.

Preterm labor, which is a growing concern that affects 10 percent of pregnancies nowadays, is linked to BV. So, can commensal bacteria play a role in preterm labor? Vaginal Microbiome Consortium at Virginia Commonwealth University is conducting an ongoing project called the Multi-Omic Microbiome Study-Pregnancy Initiative (MOMS-PI) that aims to collect samples from 2,000 women during the course of their pregnancies and for sometime after childbirth to characterize changes in the microbiomes of diverse body sites, including the vagina. This study would help us understand the relationship between the vaginal microbiome and preterm labor.

GUT MICROBIOME

The establishment of the infant gut microbiome is affected by a lot of factors that were mentioned earlier. This is an ever changing microbiome. It is first colonized primarily by aerobic organisms like enterobacteria, staphylococci, and streptococci, many of which can become pathogenic. These then change the gut environment allowing anaerobic bacteria to invade the gut.
The gut microbial community in the human body is by far the largest and the densest with the large intestine alone harbouring around 1 trillion cells per millimeter.

It helps us extract energy and nutrients from the food we eat. In fact, humans have only around 20 gut enzymes to break down carbohydrates, while a single gut bacterium could have 200 odd enzymes. Thus they have a role to play in human metabolism and in drug metabolism and in protecting us against pathogens.

When the normal gut microbial communities are disturbed, it can lead to dysbiosis. Dysbiosis is an imbalance in the gut microflora and is associated with a number of diseases like Crohn’s disease, ulcerative colitis, irritable bowel syndrome and both type 1 and type 2 diabetes. Since, the gut hosts a second immune system in the body known as the enteric nervous system (ENS), most of these conditions that result from dysbiosis are called autoimmune diseases.

In autoimmune diseases the immune system treats even the normal proteins or antigens, present in the body as pathogens and hence always stays on high alert. There could also be a genetic component in autoimmune disease or something known as a ‘leaky gut’ where proteins from food or bacteria enter our bloodstream during gut infections or stress. The body then starts reacting to this foreign body causing inflammatory conditions.

The microbiome is now known to deeply affect our immune system. A recent review paper has listed out the key points on how the health of our microbiome may be instrumental in the development of an autoimmune disease by quoting examples in type 1 diabetes mellitus and rheumatoid arthritis.15

Changes in the gut microbiome have also been implicated in several health conditions like obesity, cardiovascular diseases, and autism. Also, the metabolites that the gut bacteria secrete pass through the gut wall into the bloodstream and circulate throughout the body. The gut microbiome may thus affect sleep patterns, mood, and other brain functions. There is now strong evidence that there is a link between gut bacteria proliferation and brain function through the stimulation of the vagus nerve.

With better understanding of the connection between the gut microbiome and diseases, diagnosis and treatment of these diseases can be better established.

HOW TO MAINTAIN A HEALTHY MICROBIOME

There is a lot of advice going on regarding this. Controlling sugars and refined carbohydrates will help us maintain and strengthen our gut bacteria. The other is the consumption of foods that act as prebiotics (for example fiber, fruits, and vegetables) and foods that are termed probiotics like yogurt, cheese, and sauerkraut to increase the number of good microbes. Antibiotics have been a major boon in the last century but cutting down on long-term and repeated treatments with antibiotics that harm the good bacteria along with the bad will definitely help us maintain a healthy microbiome.

The Mayo Clinic has also performed something called a ‘fecal transplant’ in patients affected by the sometimes-deadly bacterium Clostridium difficile (C. diff), which causes recurrent episodes of diarrhea. Provided we find out which organisms do or do not drive which disease, this method can be used to treat conditions like the inflammatory bowel disease, and other immune or inflammatory diseases — including diabetes, multiple sclerosis, even arthritis.

Is this the future of medicine? Let us know what you think in the comments!

REFERENCES

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