Human Microbiome: A New Science For Our Health

From the beginning of civilization until the 1950s, major killer diseases included smallpox, measles, typhoid fever, cholera, tuberculosis, influenza, and other viral and bacterial infections. The discovery of vaccines and antibiotics has either eradicated or controlled most of these communicable diseases.

The major diseases of the 21st century are non-communicable diseases (NCDs), which include cancer, heart disease, stroke, obesity, depression, autism, allergies, Alzheimer’s, asthma, celiac disease, diabetes types 1 and 2, inflammatory bowel disease, lupus, metabolic syndrome, osteoarthritis, and many others.

According to the World Health Organization, NCDs kill almost three times as many people (68 percent of deaths) as infectious diseases (23 percent of deaths)

Almost three-quarters of the deaths due to NCDs occur in low- to middle-socioeconomic countries. However, proportionally, the rate is greater in more affluent countries, where NCDs cause up to 87 percent of all deaths.

It was rightly believed that studying the human gene could reveal the cause of disease and that gene editing could solve many health issues.

The Human Genome Project (HGP) was initiated as an international scientific research project to determine the base pairs that make up human DNA and identify, map, and sequence all of the genes of the human genome from both a physical and a functional standpoint. It started in 1990 and was completed 93 % in 2003. The balance was completed by 2022. Funding came primarily from the National Institute of Health of the USA and other countries.

Scientists were expecting 50,000 genes in the human genome. It turned out there were only approximately 22,000 genes. Not nearly the numbers estimated to account for the remarkable complexity and diversity of human biological activities. Humans barely beat the roundworm, which has approximately 20,000 genes.

Mastering our mammalian genes to cure human disease was the more significant end goal of the Human Genome Project. How can something as complex as a human be controlled, developed, survive, and even thrive with so few genes? The answer is, we don’t know!

It was hypothesized that since humans are home to microbes on our skin, mouth, urinary tracts, and the gut, a detailed study of the Microbiome should be undertaken. Over seventeen years ago, NIH started the Human Microbiome Project (HMP) to link interactions between humans and their microbiomes to health-related outcomes.

The Human Microbiome Project (HMP) had two phases. The first phase, known as HMP1, was launched in 2007. HMP1 focused on identifying and characterizing human microbiota and ran through 2013. The project aimed to build a shared community resource representing the microbiome and its role in health and disease.

The Integrative Human Microbiome Project, or HMP2, began in 2014 as the second phase. The HMP2 study ran till 2019. This second phase of the project built upon the findings of HMP1, providing a deeper understanding of the complex interactions between the microbiome and human health.

At this time, scientists are trying to find the linkages between the Human Genome, the Immune System, and the Human Microbiome to determine the cause of disease, newer diagnostics, and personalized medicine.

Clinical trials and research are moving ahead; however, it may be some time before medical professionals are provided with proven diagnostic, therapeutic, and medical tools.

techcrisp.org investigates.

Background

The Ancient Greeks did not have a modern understanding of germs as we know them today. Greek philosophers and physicians, such as Hippocrates, recognized the existence of small, invisible particles that could cause disease. They called these particles "miasmata," which translates to "bad air" or “pollution."

Ancient civilizations in Egypt, Mesopotamia, India, and China did realize that disease could be avoided if hygiene and sanitation were practiced.

Things started changing in the 17th century.

A Dutch optician, Antonie van Leeuwenhoek, was the first to observe and experiment with microbes, which he originally called “dierkens." Using a self-designed single-lensed microscope, he documented his microscopic observations of bacteria, protozoa, red blood cells, and other previously unseen organisms.

Biologists and physicians in Europe started working on microorganisms. In the 1870s, German physician Robert Koch established a set of criteria known as Koch's postulates, which are still used today to determine whether a specific microorganism causes a particular disease. The term "germ" comes from the Latin word “germen," which he used, and it became part of the microbiology parlance.

The first vaccine for smallpox was developed by Edward Jenner, an English physician and scientist, in 1796.

From the 1840s until he died in 1895, Louis Pasteur discovered that microorganisms cause fermentation and disease, which supported the germ theory of disease. Additionally, Pasteur developed the first vaccines for fowl cholera, anthrax, and rabies.?

The first antibiotic, penicillin, was accidentally discovered by Scottish bacteriologist Alexander Fleming in 1928. Fleming found that a mold called Penicillium notatum could inhibit the growth of staphylococcus bacteria.

The development of antibiotics had a slow start, and it was only by the 1944’s that Penicillin was mass-produced and used by American soldiers on D-Day. In the 1950s, a panoply of antibiotics was developed, with more than 20 classes of antibiotics in existence today.

Numerous vaccines are available. Vaccines provide protection against a wide range of pathogens, including bacteria, viruses, fungi, and parasites.

Until the mid-20th century, infectious diseases were the biggest killers worldwide. This has changed with vaccines and antibiotics. Today, the giant killers are heart disease, cancer, and strokes. All of them are Non-Communicable Diseases (NCDs).

We shall discover why this happened. For this, we must understand the human genome, immune system, and the human biome.

Human Genome Project

The Human Genome Project (HGP) was initiated as an international scientific research project to determine the base pairs that make up human DNA and identify, map, and sequence all of the genes of the human genome from both a physical and a functional standpoint. It started in 1990 and was completed 93 % in 2003. The balance was completed by 2022. Funding came primarily from the National Institute of Health of the USA and other countries.

The results were startling; humans had only 22,000 genes compared to the roundworm, which had 20,000 genes. How could a complex organism reproduce, thrive, and survive with such a limited number of genes?

Genes are units of information. They contain information for an organism to reproduce and pass on its traits, build an entire organism from a single cell, and keep it functioning.

Genes contain crucial information for the production of proteins, which are vital components of our bodies. While commonly recognized for their role in nutrition and muscle development, proteins have many functions.

Our bodies produce thousands of proteins that provide structure and strength and facilitate most essential chemical reactions that sustain life. Proteins regulate the transport of molecules in and out of cells, enable cell-to-cell communication, and are responsible for our senses, including sight, smell, touch, and the perception of heat.

Furthermore, proteins are fundamental to our nervous system, transmitting nerve signals and storing memories. They also form the basis of our immune system as antibodies and play a crucial role in synthesizing other essential molecules like fats, carbohydrates, vitamins, hormones, and genes. In essence, proteins are ubiquitous in our bodies, and each protein is synthesized following the genetic code within our genes.

How does DNA code for proteins? The section of DNA that codes for a gene is copied into an intermediate molecule called ribonucleic acid—RNA. RNA is similar to DNA but with some crucial differences. Unlike DNA, it has only one strand.

DNA is the collection of all our genes, like a library. Although the library may not lend you an expensive book to take home, it can often provide a photocopy. Similarly, RNA is a working copy of the gene that can be used by the cell. Not every piece of DNA copied to RNA codes for a protein.

Some RNAs are part of the machinery used to make proteins.

Others can control whether specific genes are turned on or off. When an RNA is made from a gene that codes for a protein, it is called messenger RNA, or mRNA, because it carries the genetic message on how to make that protein.

How is mRNA read to make proteins? The process occurs in the ribosome, a giant, ancient molecular machine in the cell with almost half a million atoms.

The ribosome carries out the process of reading mRNA to synthesize a protein. What seems miraculous is that as the newly made protein chain emerges from the ribosome, the sequence of its amino acids contains within itself the information needed for the protein chain to fold up into a particular shape so that it can carry out its function. This ability of a protein chain to fold itself up is why the one-dimensional information contained in our genes allows us to build the complex three-dimensional structures that make up a cell.

In addition to containing the blueprint for protein synthesis, genes also hold instructions that dictate the timing, duration, and rate of protein production. Environmental factors or interactions with other genes can activate or deactivate these instructions. Genes function as part of an extensive, interconnected network, constantly communicating with each other and responding to the broader cellular environment.

As a result, all cells produce specific proteins universally, while others are synthesized exclusively by particular cell types like skin cells or neurons. Additionally, the expression of specific genes varies throughout different developmental stages, enabling the transformation of a single cell into a fully formed human being. The intricate coordination of this complex genetic network is essential for sustaining life.

The process of life can be likened to a vast, self-activating program guided by the genetic information encoded in DNA. While the term "blueprint" is often used to describe this process, it can be misleading, as it suggests a rigid, predetermined outcome. In reality, DNA functions as a dynamic and responsive central hub within the cell, continuously interacting with its environment and adapting to cellular conditions.

Rather than imposing strict dictates, DNA operates within a complex network of regulatory processes that more closely resemble a democracy than a dictatorship. Just as an effective government considers the needs and circumstances of its citizens, DNA integrates cellular signals and environmental cues to modulate gene expression, ensuring that the appropriate genes are activated at the right time and in the proper context.

Mutations play a crucial role in evolution, as they introduce genetic variability that enables adaptation and the emergence of new traits. However, maintaining an optimal balance is essential, as excessive mutations can lead to cellular dysfunction and disease. Cells must tolerate some mutations to facilitate evolution while simultaneously preventing an accumulation of harmful changes.

A critical aspect of biology is maintaining control over cellular processes, as a loss of regulation can result in deterioration, death, and disease. Cancer is a stark example, wherein uncontrolled cell division and growth disrupt normal tissue and organ function. Aberrant cells are no longer inhibited by neighboring cells but instead, multiply unchecked and take over entire tissues and organs, interfering with their functioning.

Ultimately, genes govern all aspects of life, including protein synthesis, cell division, nutrient sensing, and intercellular communication. They also regulate the immune system, which must effectively respond to pathogens while avoiding chronic inflammation. Maintaining this intricate balance is essential for preserving cellular integrity and overall health.

DNA, as the carrier of genetic information, orchestrates biological processes within an organism. While it may seem reasonable to assume that understanding the complete DNA sequence would allow us to predict an organism's development, biology is only partially deterministic. Although mutations in specific genes have been linked to various diseases, our current knowledge cannot fully explain the diverse behaviors and functions of cells with identical DNA.

Several questions remain unanswered: What drives the unique genetic programs of different cell types? What mechanisms ensure cells maintain their specific identities without transforming into other cell types?

Gene regulation often operates in response to environmental stimuli and involves intricate networks of gene-gene interactions. Activated genes can subsequently activate or repress additional genes, creating a cascade of effects throughout the cellular environment. This dynamic process enables cells to adapt and respond to various external conditions while maintaining overall homeostasis.

Homeostasis is the process by which an organism maintains a stable internal environment despite changes in external conditions. It involves the body's regulatory systems working together to keep variables such as temperature, pH, glucose levels, and blood pressure within a specific range.

The famous Oxford University professor Richard Dawkins published “The Selfish Gene” in 1976. He proposed that humans are essentially “gene machines” whose biological operation is determined due to their carefully selected human genes. It was a tight argument. It was based on a general twentieth-century understanding of mammalian biology, which has turned out to be its flaw. If we are robots controlled by genes, what genes control us exactly? Some of our genes never switch on; some never switch off; some switch off for a while, then switch on again. Should we only count the ones that are on? But then, who or what is doing the switching?

We are now realizing that simply having a gene determines very little about how, when, and to what extent you may ever use that gene. The actual control is whether a gene gets switched on and when. In most cases, if it sits on a chromosome and is unused, it might not be there.

Epigenetics, the control of on-off gene switches, is one of the remarkable biological discoveries of recent decades; there is still the question of how the microbiome fits into the picture. If the environmental exposures of our cells control gene switches and the microbiome filters environmental exposures, then there is a causal relationship between the microbiome and genes.

Various factors, including age, environment, lifestyle, and disease states, can influence epigenetic modifications. These modifications can be passed down to daughter cells during cell division and sometimes even to offspring. Epigenetics plays a crucial role in many biological processes, such as development, differentiation, and the regulation of gene expression.

Recent medical initiatives remain rooted in a fundamentally flawed concept of human biology. That flaw is the premise that our mammalian genes drive our health most significantly, and much of medicine remains wedded to that premise.

Genes can predispose us to various conditions, but whether we develop them depends on our lifestyle, diet, and exposures. In short, our environment.

The human genome was supposed to be a mine of information about the causes of ill health, but searching amongst our genes has revealed fewer genetically controlled conditions than anticipated. Instead, ‘genome-wide association studies’ (GWAS) have turned up genes that affect only our predisposition to different diseases.

These gene variants are not necessarily errors but natural variations that might not lead to ill health under normal circumstances. When faced with a particular environment, though, genetic differences can make some people more likely than others to develop a specific disease. Tellingly, many genetic variants associated with twenty-first-century illnesses are genes connected to the permeability of the intestinal lining and regulation of the immune system.

CRISPR technology, which is just a decade old, allows gene editing and switching genes on/off and is used in experimental stages in hospitals and research institutes. It is one of the most remarkable scientific breakthroughs in medical science in the last decade.

Immune System

The immune system is a complex network of cells, tissues, and signaling molecules that protect the body from harmful pathogens and remove foreign substances.

Humans have two parts to their immune system: the innate and adaptive immune systems. The innate system acts as the first line of defense and works instantly in minutes. The adaptive system, on the other hand, is slower, but it creates a long-lasting immunity by forming an immunological memory. Both systems work together to fight infections.

Our body's skin and internal systems are the first lines of defense against invaders. Viruses, bacteria, parasites, and fungi must first penetrate the body's surface. The skin barrier covers approximately two square meters, while the mucous membranes lining the digestive, respiratory, and reproductive tracts measure about 400 square meters.

B Cells in the body produce antibodies. B Cells move through various parts of the body to detect invaders. Once they detect an invader, they proliferate and produce a large quantity of antibodies. These antibodies attach to the invading bacteria or virus and are then engulfed by macrophages in tissues. Macrophages also send signals using cytokines for more reinforcements.

In viral attacks, antibodies attach to viruses and prevent them from entering cells, eventually destroying them. However, if a virus enters a host cell, it will multiply dramatically, rendering antibodies ineffective. In that case, T cells are activated. T cells are part of the adaptive immune system that, once alerted, proliferate, enter the host cells, and assist in their destruction. However, they may take up to a week.

While our genes control the immune system, recent research has shown that the interaction between the immune system and the human microbiome is crucial for maintaining homeostasis. The development of gut-associated lymphoid tissue plays a vital role in immunological interactions. Immune cells within lymphoid tissues communicate, collaborate, and coordinate immune responses to defend the body. These tissues play a crucial role in developing immunological memory, ensuring a faster and more effective response upon subsequent encounters with the same pathogen.

The microbiome has a crucial role in regulating immune responses by producing various metabolites ( Molecules ) that have anti-inflammatory effects and promote the function of regulatory T cells. The immune system impacts the microbiome's composition by releasing antimicrobial amino acids. This mutually beneficial relationship between the immune system and the microbiome is essential for overall health. Any disturbance in this delicate balance can lead to chronic inflammation, autoimmune disorders, and increased susceptibility to infections.

The human gut has more immune cells than the rest of the body. Around 60 percent of the immune system’s tissue is around the intestines. Immune surveillance along the intestines is critical – every molecule and cell that passes by is assessed and quarantined if necessary.

The Human Biome

They are bacteria, archaea, fungi, protozoa, and viruses, which are infectious agents and need a host to replicate. Our body primarily comprises bacteria, but there are other microorganisms. The human body has about thirty trillion cells, while the organisms in our body are supposed to be 50 to 250 trillion. These are collectively known as the microbiome. Our skin hosts many, while the gut hosts the lion's share. Around 4,000 to 10,000 different microorganism species are available. Out of this, fewer than 100 species of bacteria cause infectious diseases in humans.

In one person with a healthy microbiome, you will likely find approximately 1,000 different gut bacterial species, with another 300 species in the mouth, 850 on the skin, and tens to hundreds in the urogenital tract. That is not counting the viruses, fungi, and parasites that also comprise our microbiome.

Their total weight is supposed to be less than one kilogram. The collective genes of the microbiome far exceed our genes, which is why some people also call the microbiome a hidden organ.

Our body’s genes, the immune system, the microbiome's collective gene pool, and the molecules they secrete, known as microbiota, influence the functioning and health of our body. Humans are not just us but also the ecosystem we house, living in symbiosis.

The bacteria in human feces tell us more about the human body than other diagnostics. These bacteria become a signature of our health and dietary status, not only as a species but as a society and personally.

The genetic wealth of the microbiome, combined with their rapid evolution and ability to respond to immediate challenges, makes them good partners. The microbiome helps digest food, releasing inaccessible nutrients and producing vitamins and minerals. They break down toxins and hazardous chemicals and protect us from diseases caused by dangerous microbes. They guide the construction of our bodies, releasing molecules and signals that steer the growth of our organs. They educate our immune system, teaching it to tell friends from foes. They affect the development of the nervous system and even influence our behavior.

Each of us has our distinctive microbiome, sculpted by the genes we inherited, the places we’ve lived in, the drugs we’ve taken, the food we’ve eaten, the years we’ve lived, the hands we’ve shaken. Microbially, we are similar but different.

The human skin microbiome is the domain of Propionibacterium, Corynebacterium, and Staphylococcus, while Bacteroides lords over the gut, Lactobacillus dominates the vagina, and Streptococcus rules the mouth.

Every organ is also variable in itself. The microbes that live at the start of the small intestine are very different from those in the rectum. Those in dental plaque vary above and below the gum line. On the skin, microbes in the oily lakes of the face and chest differ from those in the groin and armpit or those colonizing the forearms and palms—your right hand shares just a sixth of its microbial species with your left hand.

They affect our bodies so extensively that they can determine how well we respond to vaccines, how much nourishment children can extract from their food, and how well cancer patients respond to their drugs. Many conditions, including obesity, asthma, colon cancer, diabetes, and autism, are accompanied by changes in the microbiome, suggesting that these microbes are, at the very least, a sign of illness and, at most, a cause of it. If it’s the latter, we might be able to substantially improve our health by tweaking our microbial communities by adding and subtracting species, transplanting entire communities from one person to another, and engineering synthetic organisms.

This tells us that our genome lacks everything needed to create a mature immune system. It also requires input from the microbiome. Microbiomes influence the creation of entire classes of immune cells and the development of organs that make and store those cells. They are essential when the immunity machine is first constructed early in life.

How do we get our Microbiome?

It starts with the baby’s journey out of its mother’s vagina. The vagina is prepped with various microbes which smear the sterile body of the baby. The microbes the baby encounters are not enemies but friends. As it emerges from its mother, it gets another dose of microbes alongside those from the vagina.

During human labor and birth, the contraction-inducing hormones and the pressure of the descending baby cause most women to defecate. Babies tend to be born head first and facing towards their mother's bottom, pausing for a moment with their heads and mouths in prime position while their laboring mothers wait for the next contraction to help them ease the rest of the body out. After birth, the mother’s gift of a new coat of microbes, both fecal and vaginal, makes for a simple and safe birthday suit for the newborn.

These microbes help shape a baby’s immune system. Recognizing that the newborn’s immune system is neither fully matured nor balanced as the baby enters the external world is essential. These immune changes must happen for the baby to lead a healthy life.

Then comes the mother’s milk. Mother’s milk comprises an exceptional variety of material – scientists have identified over 200 human milk oligosaccharides, or HMOs, so far. They are the third-biggest part of human milk, after lactose and fats, and they should be a rich energy source for growing babies. These sugars, however, pass through the stomach and the small intestine unharmed and land in the large intestine, where most bacteria live. So, what if they aren’t food for babies - they are food for microbes!

Breast milk composition adapts to the growing baby’s needs as it ages. The initial milk, called colostrum, is thick with immune cells, antibodies, and a good four teaspoons just after birth. There are about three teaspoons of oligosaccharides in every liter of milk. Over time, as the microbiota stabilize, the oligosaccharide content of the milk decreases. By four months after birth, it has dropped to less than three teaspoons per liter; by the baby’s first birthday, it contains less than one.

Human mothers provide a microbe called B. infantis. With HMOs, it will outcompete any other gut bacterium. B. infantis devours HMOs with a cluster of 30 genes. Human milk has evolved to nourish this microbe. As it digests HMOs, B. infantis releases short-chain fatty acids that feed an infant’s gut cells – so while mothers nourish this microbe, the microbe, in turn, nourishes the baby. Through direct contact, B. infantis also encourages gut cells to make adhesive proteins that seal the gaps between them and anti-inflammatory molecules on the surface of intestinal cells. But HMOs bear a striking resemblance to these intestinal glycans, so pathogens sometimes stick to them instead. They act as decoys to draw away pathogens from a baby’s cells. They can block gut villains, including Salmonella; Listeria; Vibrio cholerae, the culprit behind cholera; Campylobacter jejuni, the most common cause of bacterial diarrhea; Entamoeba histolytica, a voracious amoeba that causes dysentery; and many virulent strains of E. coli. This helps explain why breast-fed babies have fewer gut infections than bottle-fed ones and why there are so many HMOs.

Babies fed breast milk have microbiotas dominated by lactobacilli and bifidobacteria. Unlike the human body, bifidobacteria make enzymes that can use oligosaccharides as their sole food source. As a waste product, they produce lactate (lactic acid). Microbes, known as lactic acid bacteria, include the species that convert milk into yogurt. Lactic acid creates an environment that is hostile to other bacteria, and lactobacilli produce antibiotics. Called bacteriocins, lactobacilli produce these chemicals to kill off pathogens. These feed the large intestine cells and play a crucial role in developing a baby’s immune system.

A poor diet changes the microbes within. It also impairs the child’s immune system, changing its ability to control the gut microbiome and opening the door to harmful infections that further disrupt the communities. Once these communities start wrecking the gut, they stop it from absorbing nutrients efficiently, leading to even worse malnutrition, more severe immune problems, and more distorted microbiomes.

These illnesses are caused by communities of microbes, which have shifted into configurations that harm their hosts. None is a pathogen in its own right; instead, the community as a whole has moved to a pathogenic state. This disorder involves obesity, high blood sugar, and a higher risk of diabetes and heart disease. This is a state of dysbiosis.

Dysbiosis is a condition where the balance of microorganisms in the gut, skin, or other body parts becomes disrupted, leading to potential health issues.

In the early days and weeks of life, a baby’s gut microbiota is very simple and highly unstable. Strains of bacteria go through booms and busts, leaving the community vulnerable to disaster. The entry of one pathogenic strain—Streptococcus pneumonia, for example—can wreak havoc, decimating beneficial strains.

Gut microbiota is highly unstable for the first three years of a child’s life. Populations of bacteria come and go. The most significant changes take place between nine and eighteen months of age, probably in sync with the introduction of new varieties of solid foods. Between eighteen months and three years, the gut microbiota looks more and more like that of an adult, gaining stability and diversity as the months go by. By a child’s third birthday, the microbiota starts stabilizing.

C-section babies are more likely to develop allergies, asthma, coeliac disease, and obesity later in life. Their immune system also might be compromised.

Our brains go through an intensely concentrated development period when we are babies and toddlers. At birth, we each have nearly our full allotment of around 100 billion nerve cells – neurons– in our brains. Gut microbes can influence this crucial period of brain development in early life.

The Hygiene Hypothesis

In the past few decades, there has been a phobia of protecting our bodies and environment from germs. This is the creation of various consumer product companies. Overindulgence in using antibacterial cleaning solutions and disinfectants and avoiding animals and nature, in general, hurts the diversity of our microbiome.

It is not infections that we’re lacking, but microbes.

We now know that the appendix, once widely assumed to be a pointless vestige of our evolutionary past, is a microbial safe-house, providing an education for the body’s immune system. Appendicitis, far from being an unavoidable feature of life for at least some of us, is a consequence of losing a rich microbial community.

The indigenous hunter-gatherer communities in the Amazon and Africa have a more diverse microbiome and a stronger immune system, and the incidence of Noncommunicable Diseases is very low.

Our Environment; The Food We Eat; The People We Meet

Because microbes evolve and adapt to their environments, we should expect the microbiomes of people living in cities to look different from those living in forests. Our microbiome reflects our intimate interaction with our surrounding ecosystem, including the foliage, air, water, food, and people surrounding us. All play a role in driving the microbiome's diversity within our gut and skin.

Our diet plays a significant role in the composition of our microbiome. Scientists want to find microbes that evolved with us, but many of these have since been killed off or lost.

Comparing modern-day fecal samples with ancient ones shows apparent differences. The microbiomes of today are less diverse,

Some people call it a great extinction. The decline in these microbes has been linked to an uptick in various chronic diseases.

Microbial DNA in eight samples of ancient human paleofeces, estimated to be between 1,000 and 2,000 years old, were compared with modern-day microbiome samples from people from eight different countries; significant differences were found except in cases of people living in the wild.

Modern-day samples from people living in nonindustrialized communities had much more in common with the ancient feces. The paleofeces and the Yanomami (Amazon rain forest) samples almost matched.

Evidence suggests that people living in less industrialized environments host a richer diversity of gut microbes. As industrialization takes shape in a community, its members lose this diversity. What we still don’t know is what functions we are losing.

The first step to discovering is cataloging what microbes we might have lost. Microbiologists have begun studying multiple indigenous groups to get as close to ancient microbiomes as possible. Two have received the most attention: the Yanomami of the Amazon rainforest and the Hadza in northern Tanzania.?

Researchers have already made some startling discoveries. A study found that the gut microbiomes of the Hadza appear to include microbes that aren’t seen elsewhere—around 20% of the microbe genomes identified had not been recorded in a global catalog of over 200,000 such genomes. The researchers found 8.4 million protein families in the guts of the 167 Hadza people they studied. Over half of them had not previously been identified in the human gut.

The Hadza people hunt wild animals and forage for fruit and honey. Hunters hunt in the bush for baboons, vervet monkeys, guinea fowl, kudu, porcupines, or dik-dik. Gatherers collect fruits, vegetables, and honey.

In the Yanomami community, chronic diseases are absent—including mental-health disorders. There is no depression or PTSD.

The Yanomami’s microbiomes might benefit their health, probably through their diet, which is free of sanitized and factory-processed foods. Everything they eat— monkey, capybara, or plantains—is good for their microbiome.

On the other hand, in an affluent community, there is an increased intake of a high-energy (high-fat, high-sucrose, and fructose), low-fiber diet (characterized by a lack of whole grains and vegetables) that can disrupt homeostasis. Examples of foods high in sucrose or fructose include candy, desserts, sugary soft drinks, fruit juices, and commercial cereals.

A high-fat diet containing foods with high-fat content (processed meats or animal fat) results in more than 35% of caloric intake being derived from fat.

Notably, high-energy,low-fiber food disrupts homeostasis by directly or indirectly impairing the environment of the gut microbiota. The diversity of our diet, specifically a high-fiber diet, is crucial for a more diverse and healthy microbiome.

Harboring a diverse collection of microbes is essential. People who eat healthy diets and have fewer health complaints tend to have a better mix of microbial species in their guts. The theory is that with a broader range of microbes, a person can benefit from more microbial functions and the production of more health-promoting chemicals. The more diversity, the more microbes you carry; therefore, the more genes you carry, the more biochemical work can be done.

Microbes, both viral and bacterial, are showing us that there’s more to obesity than eating too much and moving too little. The energy each of us extracts from our food and how that energy is used and stored is intricately linked with the particular community of microbes we host. To get to the heart of the obesity epidemic, we need to look inward at the microbiota and see what we are doing to alter the dynamic they established with the human body in its leanest, healthiest form.

When we meet and touch people, share a space in the office, a seat on an aircraft, or use the same toilet seat, we transfer a part of our microbiome and receive a part of the other person's microbiome. Depending on the microbes transferred, this could be good, neutral, or bad. This is another way we get our microbiome.

Indiscriminate Use of Antibiotics - Destruction of the Microbiome

While antibiotics are life-savers, indiscriminate use in children and adults has increased. Doctors prefer broad-spectrum antibiotics, which kill both good and bad bacteria.

It takes quite some time for gut microbiota to regenerate, and we may even lose out on good bacteria for a long time. It is now proven that early antibiotic exposure could increase the risk of allergies, asthma, obesity, and autoimmune diseases by altering the microbiome at a critical point.

The first step, then, is reducing unnecessary antibiotic usage. In the future, this would need the development of rapid bio-markers that can identify the source of an infection in minutes or hours and allow the doctor to prescribe focused antibiotics.

The Role of the Small and Large Intestine

The small intestine is a long, thin tube that leads off the stomach, where human digestion happens. Enzymes pumped in from the stomach, pancreas, and small intestine break down the large food molecules into smaller ones capable of crossing through the gut lining cells into the bloodstream. Proteins, like twisted and folded pearl necklaces, are cut into single beads, called amino acids, and shorter chains of these building blocks.

Complex carbohydrates are sliced into more manageable chunks called simple sugars, such as glucose and fructose. Fats are pruned into their parts: glycerols and fatty acids. These smaller units do their business in the body, making energy, building flesh, and being repurposed for our use.

But many food molecules, mainly the ‘indigestible,’ are left over. These go on to the large intestine, where they meet a large colony of microbes, ready to break them down using their own enzymes.

In the process of feeding themselves, the microbiota release another set of leftovers. These molecules are absorbed into the blood.

For a persistent effect, we need to provide an environment where beneficial microbes thrive, day after day, without needing outside intervention to replenish their numbers.

So, we come to prebiotics. These are not live bacteria but bacteria food designed to enhance entire populations of the healthiest strains. The science of prebiotics is still developing.

Effect of the Microbiome on Health

Dysbiosis, or the breakdown in the balance of the microbiome, affects our health, especially the illnesses of the twenty-first century.

In short, we have damaged our microbiotas. Simply pushing our microbial communities, particularly those in the gut, out of balance causes inflammation, which in turn causes chronic disease.

According to the World Health Organization, NCDs kill almost three times as many people (68 percent of deaths) as infectious diseases (23 percent of deaths). Yet NCDs tend to be a hidden epidemic. The NCD epidemic is not restricted to one culture, socioeconomic class, or geographic area. Almost three-quarters of the deaths due to NCDs occur in low- to middle-socioeconomic countries. However, proportionally, the rate is greater in more affluent countries, where NCDs cause up to 87 percent of all deaths.

Of the approximately four billion prescriptions that were filled in the USA recently, the most common were statins, used to treat metabolic issues and cardiovascular diseases. They were followed by antidepressants, antidiabetic drugs, sleep medications, antihistamines, and drugs for respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD). Just in looking at the medicines, the prevalent NCDs of cardiovascular disease, depression, type 2 diabetes, insomnia, allergies, and asthma were dramatically apparent.

Evidence shows that microbiome dysbiosis is predictive of specific NCDs. Different NCDs can have their particular microbiome profile and a type of fingerprint associated with them. But does dysfunction within the microbiome directly cause NCDs, or does it help lock them into your physiology, making corrective therapies very difficult?

Changes in the composition of gut-associated microbial communities are linked to a broad spectrum of human diseases, such as cancer, obesity, IBD, and neurological disorders. Should we consider it a gut–microbiota–brain connection instead?

The microbiome can influence virtually every physiological system and tissue in the body, including the brain, through the production of specific metabolites like propionic acid, butyrate, vitamins B3 (niacin), B5, B6 (active form), B12, and K, serotonin, dopamine, and countless other microbial by-products.

Depression doesn’t seem to be the only neurological outcome of this immune bellicosity. People suffering from many other mental health disorders also show signs of immune overactivity. ADHD, OCD, bipolar disorder, schizophrenia, and even Parkinson’s disease and dementia appear to involve an immune overreaction.

People with allergies rarely see themselves as having an immune dysfunction, but that is precisely what it is. What they need, though, is not a ‘boost’ but quite the opposite. Allergies result from an overeager immune system, acting to destroy substances that pose no real threat to the body. Treating them often involves calming the immune system down through steroids or antihistamines.

Six prime factors led the way to this pivotal point in health and medicine: Birth delivery mode, antibiotic overreach, the food revolution and diet, urbanization, misguided efforts at human hygiene, and mammalian-only human medicine.

What Is The Way Forward?

For an individual, there is a unique human genome, immune system, human biome comprising trillions of cells and genes secreting trillions of metabolites, as well as individual disease and environment.

What would be the ideal microbiome to maintain a healthy life?

How does one repair a damaged microbiome?

As you can see, we have defined a problem with trillions of variables, and finding an optimal solution would seem impossible. Researchers are facing this challenge.

Human microbiome studies share technical and conceptual similarities with genome-wide association studies and genetic epidemiology. The microbiome has many features that differ from genomes, such as its temporal and spatial variability, highly distinct genetic architecture, and person-to-person variation. Moreover, various potential mechanisms exist by which different aspects of the human microbiome can relate to health outcomes.

Recent advances, including next-generation sequencing and the proliferation of multi-omic data types, have enabled the exploration of the mechanisms that connect microbial communities to human health.

Developing science of ‘omics has made the following tools available.

These include, Genomics: the study of an organism's entire genetic material, including its genes, their functions, and interactions. Proteomics: The large-scale analysis of proteins, their structures, functions, and interactions within an organism. Metabolomics: The comprehensive analysis of metabolites, small molecules produced during metabolism, and their roles in cellular processes.Transcriptomics: the study of the complete set of RNA transcripts in a cell or organism, including gene expression patterns and regulation.?

Omics approaches often involve high-throughput technologies, such as next-generation sequencing and mass spectrometry, enabling simultaneous analysis of many biomolecules. By integrating data from different omics disciplines, researchers can gain a more holistic understanding of biological systems and discover novel insights into health and disease. IT solutions in big data, visualization, machine learning, and AI support these sciences.

Another issue is about moving from correlation to causation.

Researchers have gathered more evidence in the last two or three years to prove causality vs. correlation.

Based on omics and causality, researchers can narrow down the list of potential disease drivers in the microbiome and study their possible functions in the human genome.

Looking at this data, we can predict who these are and to whom they're related, as well as what they're doing, what they're making, and what their functions might be. The net sum of all these effector molecules that microbes are making and using to talk to each other becomes the basis for the functioning of a true community.

It is now also possible to measure microbiome status using biomarkers. These can measure the microbes themselves or specific microbial functions (such as the production of certain vitamins and other microbial chemicals).

In this new era of the microbiome, there is, however, a massive gap between what we know about human biology and how human health is managed in Westernized medicine.

Metagenomic sequencing allows researchers to study the entire genetic makeup of these communities via whole genome sequencing of the samples without distinguishing which gene belongs to each microbial species within a community.

A considerable percentage—around 30-50% of the protein families known so far has no known function. Yet, after almost 20 years of metagenomic data and metagenomic analysis, there has been no real analysis of protein families from metagenomes per se.

Taxonomic analysis found that most of these protein families belonged to bacteria and viruses, though 6 million of the sequences evaded classification. Researchers also tried to hone in on the function of the genes via 3D modeling and comparing structures of the unknown to those of the known – similar structure equates to a high likelihood of similar function. Researchers also identified protein families with completely novel structures.

This is the first time protein structures have been used to help characterize the vast array of microbial dark matter. The study took roughly two years, with only about 20,000 metagenomes sequenced, then increasing to 60,000. 70-80% of known microbial diversity still needs to be captured genomically. That diversity holds many new secrets in terms of functional diversity.

It is still impossible to define homeostasis or dysbiosis by the presence or absence of specific microorganisms. Limited information on the ecological causes of dysbiosis and its causative effects on disease makes it difficult to translate research into medical interventions.

Therefore, understanding factors influencing microbiota composition and function is a fundamental goal of microbiome research.

To approach this problem, most researchers probe the microbiota to ask what is there, what could they do, or what are they doing. However, microbial communities show high diversity between individuals, making it challenging to define what constitutes a balanced microbial community in a healthy state by simply cataloging bacterial taxa.

As a result, homeostasis cannot be explained by the presence or absence of specific microbial species, which also challenges the validity of defining dysbiosis using this approach. This gulf in understanding and the complexity of microbial communities make it impossible to translate microbiota analysis into a measurement unit that could quantify homeostasis or dysbiosis.

Researchers have evaluated whether the concept that the host controls the environment to ensure a microbiota composition that sustains health could provide a way of moving past the current impasse on quantifying homeostasis.

This viewpoint suggests that, besides measuring microbiota composition and gene expression, the host environment needs to be measured to understand what constitutes a healthy microbiome. The available evidence indicates that the host controls the microbiota's environment.

Based on the above, microbiome-based therapeutics can be divided into various initiatives.

Probiotics / Prebiotics / Synbiotics

Probiotics have been used for centuries in fermented foods and pickles.

Over-the-counter sales of Probiotics are estimated to be around US$85 billion. Since they are not classified as Drugs, various companies sell their unique formulations. Some companies do a fecal analysis before concocting a mixture of microorganisms unique to the consumer. While Probiotics are here to stay, many doctors feel that the quantity of bacteria dispensed in one dose is so minuscule that it may not have the desired effect even if taken for a long time. In contrast, others argue that probiotics are not focused on an identified microbe and may only provide temporary relief. There is substantial public awareness of probiotics, with many self-help books available.

Prebiotics are more focused as they provide food for certain microbes only. These are considered more effective, provided the microbes are identified and prebiotics designed for them. Synbiotics are a combination of probiotics and prebiotics.

Then there is the emerging field of Postbiotics, which are metabolic byproducts produced by probiotics, and Parabiotics, which are dead microbial cells modified to influence host health.

Another emerging area is skincare. Companies like L’Oreal, Johnson and Johnson, and Unilever use microorganisms to control skin diseases such as dermatitis and acne. A 20-ml bottle of skin elixir sells for around US$50.

Fecal Transplant

A fecal transplant is similar to a probiotic: both aim to deliver beneficial microbes to the gut. A donor with the correct biome is selected, and fecal matter is inserted into the patient's stomach by endoscopy or colonoscopy. The donor’s microbiome is evaluated based on the patient's requirements.

Researchers are working on a capsule that delivers its contents to the correct location in the gut, to the same community of fecal microbes, and is swallowed with a glass of water.

Phage Therapy

Phage therapy is a type of treatment that uses viruses called bacteriophages to target and destroy harmful bacteria in the body without harming the beneficial bacteria in the microbiome. This treatment has the potential to be especially useful in treating infections caused by antibiotic-resistant bacteria by altering the composition of the gut microbiome.

Additionally, phages can affect the immune system by regulating the host's inflammatory response and encouraging the production of anti-inflammatory cytokines. As a result, phage therapy offers a promising approach to managing microbiome-related diseases like gastrointestinal infections, inflammatory bowel disease, and colorectal cancer. Ongoing research focuses on the potential of phage therapy as a personalized treatment option and examines its long-term effects on the gut microbiome and human health.

It is tough to procure Phage-Virus and produce it in bulk due to regulatory issues.

Microbiome Mimetics

Microbiome mimetics are interventions that imitate the interaction between the microbiome and the host, resulting in beneficial outcomes. These interventions can include products derived from bacteria, small molecules, conventional therapeutics, or products derived from the host. Microbiome mimetics aims to utilize the advantageous effects of the microbiome without relying solely on live microorganisms like probiotics or fecal microbiota transplantation.

Live Biotherapeutics

Live biotherapeutic products (LBPs) are medicines that contain live microorganisms, like bacteria or yeast. These microorganisms are purposely given to humans to cure, prevent, or treat medical conditions or diseases. LBPs aim to exploit the microbiome's therapeutic potential by altering the microbial community's composition or function and modulating host physiology.

LBPs have some essential characteristics, including well-characterized specific strains and live microorganisms chosen for their safety and beneficial properties. They have a targeted impact as they are designed to exert their therapeutic effects through various mechanisms, such as inhibiting pathogens, improving gut barrier function, or modulating the immune system.

CRISPR Technology

Jennifer Doudna, the 2020 Nobel Prize winner for co-inventing Crispr, is now working on identifying and modifying the gene responsible for producing an inflammatory molecule that causes asthma. Her team has already discovered the microbes that produce this molecule, and she hopes to modify its gene without affecting the microbiome.

Personalized Medicine and Nutrition

Understanding and controlling an individual's microbiota to improve drug outcomes is the next step in personalized medicine. Two new medical initiatives transforming the landscape are "personalized medicine" and "precision medicine.” Personalized medicine refers to tailoring medical treatment to the individual characteristics of each patient, including their genetic makeup, environment, and lifestyle. This approach aims to optimize treatment outcomes by providing therapies most suitable for a patient rather than using a one-size-fits-all approach.?

Precision medicine goes a step further by focusing not only on a patient's individual characteristics but also on the specific molecular mechanisms that underlie their disease. This allows for more precise therapy targeting and the identification of subgroups of patients who may benefit from specific treatments.?

In summary, personalized medicine involves customizing treatment based on a patient's unique characteristics. In contrast, precision medicine adds an extra layer of specificity by targeting the underlying molecular mechanisms of a disease. Both approaches aim to improve patient outcomes by providing more effective and individualized therapies.

These initiatives emphasize using massive amounts of data, also known as "data-intensive biology,” to identify trends in diseases and treatments and understand how all the pieces fit together in a particular patient.

By analyzing microbiome data and other clinical data, researchers can accurately predict how an individual may respond to specific foods, which opens up the possibility of personalizing dietary approaches.

Precision medicine is currently focused on one specific disease category: cancer. It is particularly interested in identifying human mammalian genes that drive tumor development.?

Start Up’s and Big Pharma

Currently, numerous startups in the USA and Europe are involved in the research and development of microbiome therapeutics. The USA is leading the research in this area, with an estimated 250 clinical trials in progress. However, since the science is relatively new and unproven, investor interest in these startups has been limited. In 2023, venture capital funding of around US$ 1 billion was invested in these startups. Recently, big pharmaceutical companies like Boehringer, Pfizer, and Merck have entered the field, with Boehringer investing US$ 500 million in a startup. The market size for this industry has yet to be discovered, as credible data is not available at this time.

Challenges and Opportunities

As a nascent industry with science yet to crystallize and the introduction of a new element (the Microbiome) in human biology, regulators, health providers, and patients still need to be convinced of the efficacy and safety of the offerings.

Before microbiome-based therapeutics become mainstream, significant time and investment will be required in R&D, evidence collection, therapeutic development, clinical trials, delivery mechanisms, and education.

As science on the working human biome matures in the coming years, we shall see a significant change in the way we view health and disease treatment.

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