The Human Microbiome: Health and Disease

TL;DR: The Human Microbiome – Your Inner Ecosystem

The human microbiome is the intricate community of microorganisms (bacteria, fungi, viruses, archaea) and their genes living within and on us, often called our "second genome." It plays a crucial role in metabolism, nutrient processing, immune system development, and acts as a natural barrier against pathogens. Modern research, including the groundbreaking Human Microbiome Project, uses advanced sequencing techniques to understand its diversity and stability across body sites, populations, and lifespans. Imbalances in the microbiome are increasingly linked to a range of health issues, from obesity and inflammatory bowel diseases to various forms of cancer, highlighting its profound impact on human health and disease.

The Human Microbiome: Health, Disease & Research Explained

Have you ever considered that you're not just a single organism, but a "superorganism" teeming with life? This fascinating concept lies at the heart of understanding The Human Microbiome: Health and Disease. It refers to the vast collection of all microorganisms and their genes that reside on the surface and inside the human body – from the deep layers of your skin and oral cavity to your gastrointestinal and urogenital tracts. Sometimes dubbed the "second human genome," this intricate ecosystem includes bacteria, fungi, molds, viruses, and even archaea.

This article aims to provide a comprehensive overview for students, explaining what the microbiome is, why it's so vital, how it's studied, and its significant connections to both health and various pathological conditions.

Your Inner Universe: What is the Human Microbiome?

As defined, the human microbiome encompasses all the microbial residents and their genetic material within and on us. These tiny inhabitants are found almost everywhere: in saliva, oral mucosa, conjunctiva, and extensively throughout the gastrointestinal and urogenital tracts. Far from being passive passengers, these microorganisms form dynamic communities crucial for our existence.

They represent a diverse biological landscape, with countless species working together in complex ways. Understanding this inner universe is key to unlocking new perspectives on human biology and medicine.

Why is the Microbiome So Important for Your Well-being?

The importance of the human microbiome cannot be overstated. These microorganisms are actively involved in numerous bodily functions, making them indispensable to our health. Their contributions span several critical areas:

• Metabolism: They produce essential enzymes for processing complex substances like xyloglucans (major plant polysaccharides). They metabolize foreign substances, including some medical drugs, and de novo synthesize vital metabolites like amino acids, vitamins, and steroids. Crucially, they extract metabolites from food and generate energy sources such as butyrate and methane.
• Nutrient Processing and Synthesis: Microbiome members are instrumental in processing nutrients from our diet and synthesizing essential vitamins that our bodies cannot produce on their own.
• Epithelial Renewal: They stimulate the renewal of the intestinal epithelium, maintaining the integrity of our gut lining.
• Immune System Stimulation: The microbiome plays a pivotal role in stimulating and maturing the immune system. It increases the body's resistance to infections by influencing the expression of mucin, immunoglobulin A, and anti-microbial peptides.
• Natural Barrier Against Pathogens: A healthy microbiome acts as a robust defense mechanism. It outcompetes pathogenic microorganisms for resources and space, and produces antimicrobial substances to directly combat invaders.
• Pre-natal Development: The maternal microbiome can even influence pre-natal development, impacting the nourishment and development of the fetus, and the length and course of the pregnancy.

Unlocking the Microbiome's Secrets: Research Methods

Studying the human microbiome presents unique challenges. Traditional microbiology, which often focuses on culturing individual bacterial species, can only grow less than 1% of the bacterial species present in the human body under contemporary laboratory conditions.

To overcome this limitation, modern microbiome research relies heavily on advanced genetic analysis techniques:

• Bacterial Genome Analysis and Sequencing: Researchers analyze the genetic material of microorganisms directly.
• Metagenomics: This involves studying the genomes of entire communities of organisms directly from environmental samples, bypassing the need for individual culturing.
• 16S rRNA Sequencing: This technique sequences the 16S ribosomal RNA gene, which is specific to prokaryotes (bacteria and archaea). It's widely used to identify different species and determine their relative frequencies within a sample.
• 18S rRNA Sequencing or Whole Genome Sequencing (WGS): These methods are employed to study eukaryotic components of the microbiome, such as fungi (mycobiome).
• Metabolomics: This field analyzes the complete set of small-molecule metabolites (the metabolome) within a biological sample. Techniques like MALDI (Matrix-Assisted Laser Desorption/Ionization) and mass spectrometry are used to identify and quantify these metabolites, providing insights into the metabolic activities of the microbial community.

These techniques allow scientists to answer crucial questions like: Which organisms are present? What are their functions? What are the metabolic pathways of the entire community? And what variants and polymorphisms exist among microbes?

The Human Microbiome Project (HMP): A Landmark Initiative

The Human Microbiome Project (HMP), launched in 2007 by the National Institute of Health (NIH) in the USA, was a monumental 5-year, $173 million endeavor to characterize the human microbiome. It involved 4 major sequencing centers and sampled 15 body sites in men and 18 in women from 242 healthy individuals aged 18 to 40, collecting a total of 5298 samples.

Objectives of the HMP included:

• Characterizing microbial communities at various human body sites.
• Determining microbiome stability and variation over time.
• Defining a "basic" microbiome common to all people and understanding its acquisition and maintenance.
• Identifying factors influencing microbiome diversity.
• Creating a collection of referential microbial genomes.
• Developing new techniques for data processing and analysis.
• Clarifying links between microbiome changes and diseases.

Key Findings and Understanding Microbiome Dynamics

The HMP yielded profound insights. While the specific species might differ among healthy individuals, the basic metabolic pathways and overall metabolic activity of the microbial community at a given site tend to remain consistent within a healthy population.

Microbiomes from different body sites significantly vary in composition and the frequencies of genera/species. For example, microbial communities primarily cluster by body area; nasal microbes bridge skin and oral populations, while gastrointestinal tract microbes largely remain within the GIT. The intestine and oral cavity exhibit high microbial diversity, whereas the vagina shows low diversity. The epidermal microbiome is rich in species but differs significantly among individuals, while the saliva microbiome is rich in species but strikingly similar across individuals.

Each healthy person generally possesses a relatively unique microbiome, and its composition tends to be stable over time, though continuous variability occurs throughout the lifespan.

Diet, Geography, and Lifespan: Factors Shaping Your Microbiome

Many factors influence the composition of the human intestinal microbiome:

• Age: The microbiome evolves rapidly until about 3 years of age, then stabilizes and persists through adulthood. Bacterial diversity generally increases with age.
• Geographic Location: Significant differences in microbiome composition are observed across individuals from different geographic locations, particularly between industrialized and non-industrialized populations. For instance, the diversity of the gut microbiome in the USA is much lower compared to rural populations in Malawi or village Amerindians in Venezuela.
• Diet: Diet has a crucial influence. A fiber-rich diet (fruits, vegetables) promotes beneficial bacteria like Ruminococcus bromii, Roseburia sp., Eubacterium rectale, and Bifidobacteria. Conversely, a "Western-type" diet, rich in animal fats and carbohydrates, fosters different communities including Alistipes shahii, Bacteroides sp., and Bilophila sp..
• Host Factors: An individual's genotype and metabolism also play a role.
• Environmental Factors: The outer environment and exposure to bacterial species.
• Lifestyle: Regular bodily exercise is a factor.
• Medical Factors: Diseases and medications can significantly alter microbiome composition.

These influences contribute to the existence of 3-4 globally distinguishable "enterotypes" or types of gut microbiomes. Research has also identified individuals with "low gene count" (LGC) microbiomes (fewer species) and "high gene count" (HGC) microbiomes (richer in species), with LGC linked to obesity.

Beyond Bacteria: Fungi, Viruses, and Archaea in Your Microbiome

While bacteria often dominate the conversation, the human microbiome is a complex web that includes other microbial domains:

• Mycobiome (Fungi): This fungal community is studied using 18S rRNA or WGS. Candida species are among the most common members of the human mycobiome.
• Virome (Viruses): The human body harbors various viruses, including bacteriophages (viruses that infect bacteria), herpesviruses, papillomaviruses, and other single-stranded (ssDNA) and double-stranded (dsDNA) viruses. On average, most people carry about 4 viral genomes. Viral communities differ across body sites and show more variation between individuals than bacterial communities, potentially useful in criminology. They are relatively stable within an individual for periods like six months.
• Archaea: These single-celled organisms, distinct from bacteria, are also part of our microbiome. A notable example is Methanobrevibacter smithii, an archaeon that produces methane by metabolizing gases like H2 and CO2, as well as acetate, formate, and methanol. This prevents the accumulation of H2, which would inhibit NADH dehydrogenases and reduce ATP yield, thereby improving fermentation efficiency.

The Microbiome in Health and Pathologic Conditions

Characterizing the microbiome of healthy individuals has opened doors to studying its profound relations with various diseases across different organ systems:

• Skin: Psoriasis, acne, atopic dermatitis.
• Digestive Tract: Obesity, Crohn disease, esophageal adenocarcinoma, necrotizing enterocolitis, ulcerative colitis, irritable bowel syndrome.
• Urogenital Tract: Bacterial vaginosis, sexually transmitted diseases.
• Systemic Disorders: Immune deficiencies, febrile conditions.

Microbiome and Obesity: A Global Challenge

Obesity has become a global epidemic. Research indicates that the microbiomes of obese individuals are structurally and functionally distinct from those of healthier counterparts. This strong correlation suggests the microbiome as a potential target for obesity therapeutics.

One significant finding is the link between antibiotic use and obesity. The intensity of prescribing antibiotics correlates with obesity rates, as antibiotics can disrupt the delicate balance of the intestinal microbiome.

Individuals with an intestinal microbiome containing a low number of genes (and thus fewer microorganism species) are more frequently obese, resistant to insulin, and suffer from dyslipidemia (abnormal amounts of lipids in the blood).

A striking example is American Samoa, which has some of the highest obesity rates globally (75-80% of adults). This is attributed to a "perfect storm" of factors:

1. Cultural and Nutritional Transition: Traditional diets have been replaced by imported, highly processed, high-caloric foods.
2. Genetic Predisposition: A specific genetic variant (rs373863828) linked to efficient fat storage, an evolutionary advantage for Polynesian ancestors.
3. Economic and Geographic Factors: Limited agriculture, reliance on high-fat imports.
4. Cultural Norms: A perception that "big is beautiful."

These factors combined with microbiome changes contribute to increased prevalence of diseases like diabetes, cancer, and kidney failure.

Inflammatory Bowel Disease (IBD) and the Microbiome

Inflammatory bowel disease (IBD) encompasses autoimmune chronic inflammations affecting the gastrointestinal tract from the esophagus to the rectum. Globally, IBD incidence is increasing, particularly in developed countries. Patients with IBD have a significantly altered microbial metagenome, containing about 25% fewer genes compared to healthy populations, impacting metabolic functions.

Specific shifts in microbial communities are observed:

• Ulcerative Colitis: Often characterized by an explosion of Proteobacteria.
• Colonic Crohn Disease: Can show high levels of Archaea, a collapse of Bacteroidetes, and an explosion of Actinobacteria.

Causative agents possibly linked to IBD include M. avium sp. paratuberculosis, Helicobacter, Campylobacter, and certain E. coli strains.

The Microbiome's Role in Carcinogenesis

The human microbiome can significantly influence carcinogenesis (cancer development) through various mechanisms:

• Oncoviruses: Human oncoviruses, such as human papillomaviruses (HPV), can integrate oncogenes into host cells or block tumor suppressor proteins (e.g., HPV E6 and E7 blocking p53 and RB proteins), driving tumor formation.
• Genome Stability and Proliferative Signaling: Microbes can affect the stability of human cell genomes, their resistance to cell death, and proliferative signaling pathways.
• Microbial Defense Factors Causing DNA Damage: Some microbial factors can directly cause mutations in human cellular DNA, contributing to carcinogenesis. Examples include:
• Colibactin: Expressed by B2 group Escherichia coli and other Enterobacteriaceae, causes double-stranded DNA damage at adenine nucleotides, leading to specific single-base substitutions (SBS-pks) and insertion/deletion mutations (ID-pks).
• Cytolethal Distending Toxin (CDT): Produced by several Escherichia coli and other epsilon- and gamma-proteobacteria, also causes double-stranded DNA damage.
• Cytotoxic Necrotizing Factor (CNF) and Cycle Inhibiting Factor (Cif): Produced by certain Escherichia coli strains.
• Bacteroides fragilis Toxin (BFT): Produced by enterotoxigenic B. fragilis, acts indirectly by eliciting high levels of reactive oxygen species (oxygen radicals), which then damage host cell DNA.

Studies have found that specific DNA mutations induced by bacteria like colibactin are indeed present in human colorectal cancer (CRC) tumors. Colorectal cancer incidence is growing steadily in developed countries, including the Czech Republic, where around 7,700 patients are diagnosed annually.

Athletes and the Microbiome

Intriguingly, the microbiome can also influence athletic performance. Studies have shown that athletes often have a different microbiome composition compared to the regular population. Their microbiomes may be enriched for genera like Prevotella and archaea such as Methanobrevibacter smithii. These organisms are capable of metabolizing waste products in the human intestine into other resources and nutrients, and thus energy, leading to higher performance.

M. smithii specifically produces methane by metabolizing H2 and CO2 gases, acetate, formate, and methanol. By removing H2 through archaeal methanogenesis, it prevents H2 accumulation that would inhibit NADH dehydrogenases, thus improving fermentation efficiency and increasing nutrient and energy yield from food for the high-performing athlete.

Future Horizons: Other Microbiome Projects

The study of the human microbiome is a continuously expanding field. Beyond the HMP, several other significant initiatives are exploring its facets:

• MetaHIT: Focused on studying the human intestinal microbiome.
• Home Microbiome Project: Investigates the microbial communities within our living spaces.
• Hospital Microbiome Project: Examines the microbiome in hospital environments, with implications for infection control and patient health.

These projects underscore the widespread recognition of the microbiome's pervasive influence on human life, from our bodies to our immediate surroundings.

Frequently Asked Questions

What is the primary function of the human microbiome?

The primary function of the human microbiome is to support host health through diverse metabolic activities, nutrient processing, immune system development and stimulation, and by acting as a natural barrier against pathogenic microorganisms. It helps synthesize vitamins, extract energy from food, and protect against infections.

How is the human microbiome studied?

The human microbiome is primarily studied using advanced genetic sequencing techniques like metagenomics and 16S rRNA sequencing, which analyze the DNA of entire microbial communities without needing to culture individual species. Whole Genome Sequencing (WGS) and 18S rRNA sequencing are used for fungi, and metabolomics helps understand the biochemical output of the microbial communities.

What factors influence the composition of my gut microbiome?

Many factors influence your gut microbiome composition, including your age, geographic location, diet (e.g., fiber-rich vs. Western), host genotype and metabolism, exposure to environmental bacteria, lifestyle choices like exercise, and medical conditions or medications.

Can the microbiome influence diseases like obesity or cancer?

Yes, the microbiome has a significant influence on diseases. Imbalances are linked to obesity (e.g., low gene count microbiomes), inflammatory bowel diseases (e.g., altered microbial populations), and even carcinogenesis, where certain microbial toxins can cause DNA damage in human cells, contributing to cancer development.

Is everyone's microbiome the same?

No, everyone's microbiome is relatively unique, akin to a fingerprint. While certain metabolic functions might be consistent in healthy individuals, the specific species and their proportions vary significantly between people and across different body sites within a single individual. Factors like diet, geography, and genetics contribute to this diversity.