Understanding the Human Microbiome

TL;DR: Understanding the Human Microbiome

The human microbiome is the collection of all microorganisms (bacteria, fungi, viruses, archaea) living on and in our bodies, along with their genes. Often called a "second human genome," it plays crucial roles in metabolism, immune system development, and acts as a barrier against pathogens. Research, notably the Human Microbiome Project, uses advanced sequencing to study its diversity and links to diseases like obesity, inflammatory bowel disease, and cancer. Factors like diet, age, geography, and lifestyle significantly influence its unique and dynamic composition.

Welcome, students, to the incredible world residing within and on us – the human microbiome! Far from being just a sterile vessel, each human body is a bustling ecosystem, teeming with trillions of microorganisms. Understanding the human microbiome is key to unlocking new insights into health, disease, and even human identity. This comprehensive guide will explore what the microbiome is, why it's so important, how scientists study it, and its profound impact on our well-being.

What is the Human Microbiome? A Definition

The human microbiome is defined as the entire collection of microorganisms and their genes that reside on the surface and inside the human body. These microscopic inhabitants are found everywhere, from the deep layers of our skin, saliva, and oral mucosa, to the conjunctiva, gastrointestinal tract, and urogenital tract. Think of your body as a "superorganism" containing both eukaryotic (human) and prokaryotic (microbial) genes.

Sometimes, the microbiome is even referred to as a "second human genome" due to the sheer volume and diversity of its genetic material. It comprises a wide array of life forms, including bacteria, fungi, moulds, viruses, and even archaea. These tiny tenants are not mere passengers; they are active participants in our biology.

The Vital Importance of the Human Microbiome

The microorganisms within our bodies are far from passive; they are constantly at work, performing essential functions critical for our health. Their importance spans several key areas:

• Metabolism: Microbes are metabolic powerhouses. They produce enzymes that help process complex carbohydrates like xyloglucans (a major plant polysaccharide). They also metabolize foreign substances, including some medical drugs, and synthesize vital metabolites such as amino acids, vitamins, and steroids. Furthermore, they excel at extracting energy from foodstuffs, producing important compounds like butyrate and methane.
• Natural Barrier Against Pathogens: Our microbiome acts as a frontline defense. It outcompetes pathogenic microorganisms for resources and space, and some microbes even produce anti-microbial substances directly.
• Immune System Development and Maturation: The microbiome is a crucial stimulator of our immune system, helping to increase body resistance to infections. It influences the expression of important immune components like mucin, immunoglobulin A, and anti-microbial peptides.
• Pre-natal Development and Health: The maternal microbiome can influence the nourishment and development of the fetus, as well as the length and course of pregnancy.

How Scientists Study the Microbiome: Methods and Key Projects

Traditional microbiology often focuses on studying individual bacterial species, but this approach has limitations when it comes to the complex microbiome. Using standard laboratory and cell culture conditions, scientists are only able to culture less than 1% of bacterial species. This means that to understand the full scope of the microbiome, we need advanced techniques.

• Bacterial Genome Analysis: The microbiome is primarily studied using genetic techniques.
• Sequencing Techniques: Directly reading the DNA sequences of microbes.
• Metagenomics: This involves studying the genomes of entire communities of organisms directly from environmental samples, bypassing the need for culture.
• 16S rRNA Sequencing: This technique focuses on sequencing the 16S ribosomal RNA gene, which is specific to prokaryotes (bacteria and archaea). It's used to identify individual taxonomic species and their relative frequencies within a sample.
• Whole Genome Sequencing (WGS): This method sequences all the DNA in a sample, allowing for the identification of genes and metabolic pathways to understand the functions of the microbial community.

The Human Microbiome Project (HMP)

The Human Microbiome Project (HMP), funded by the National Institute of Health (NIH) in the USA, was a landmark initiative that began in 2007 and lasted five years, costing 173 million dollars. It involved four major sequencing centers across the USA.

Objectives of the HMP: The project aimed to:

• Characterize microbial communities at various sites of the human body.
• Determine the microbiome's stability and variation over a human lifespan.
• Define a 'basic' microbiome common to all people, and understand how it's acquired and maintained.
• Identify factors influencing microbiome diversity.
• Create a reference collection of microbial genomes.
• Develop new techniques and software for data processing and analysis.
• Clarify links between microbiome changes and diseases.

HMP Participants and Samples: The HMP involved 242 healthy individuals aged 18 to 40. A total of 5298 samples were examined from various body sites: 15 in men and 18 in women. Sampled sites included:

• Oral cavity: Gingiva, subgingival/supragingival dental plaque, buccal mucosa, hard palate, tonsils, saliva, tongue, throat.
• Epidermis: Inner elbow (both arms), behind the ear (both sides).
• Gastrointestinal tract: Stool.
• Urogenital tract (women): Mid-vagina, vaginal introitus, posterior fornix.
• Nasal cavity: Anterior nares (nostrils).

Key Results of the HMP: The project yielded significant insights:

• Body Area Specificity: The primary clustering of microbes is by body area. For instance, gastrointestinal tract microbes tend to stay within the GIT, while nasal microbes bridge skin and oral populations.
• Unique and Stable Microbiome: Each healthy person has a relatively unique microbiome whose composition is generally stable over time.
• Site-Specific Diversity: Microbiomes from different body sites vary significantly in their composition and the frequency of genera/species, both within an individual and among different individuals.
• High microbial diversity is found in the intestine and oral cavity.
• Low microbial diversity is observed in the vagina.
• Human epidermal microbiome is rich in species and highly diverse among individuals.
• Saliva microbiome is rich in species but remarkably similar among individuals.
• Pathogens in Healthy Individuals: Pathogens are often present in the microbiomes of healthy people but typically do not cause disease when the microbiome is balanced.

Factors Influencing Human Microbiome Composition

The composition of an individual's microbiome is not static; it's a dynamic community shaped by numerous internal and external factors.

• Diet: This has a crucial influence, especially on the intestinal microbiome.
• A diet rich in fiber from fruits and vegetables promotes beneficial bacteria like Ruminococcus bromii, Roseburia sp., Eubacterium rectale, and Bifidobacteria.
• A "Western-type" diet, high in animal fats and carbohydrates, leads to a different gut microbiome composition, favoring species like Alistipes shahii, Bacteroides sp., and Bilophila sp.
• Enterotypes: Studies have identified 3-4 globally distinguishable enterotypes, which are types of significantly different gut microbiomes. These often feature predominating Bacteroides, Prevotella, or Ruminococci.
• Host Environment: Inner factors like an individual's genotype and metabolism play a role.
• Life Style: Regular bodily exercise is another influencing factor.
• Diseases and Medication: These can drastically alter microbiome composition.
• Age: Microbiome composition evolves rapidly until around 3 years of age, then stabilizes throughout adulthood. Bacterial diversity (the number of microbe species) generally increases with age.
• Geographic Location: Individuals from different geographic locations, such as metropolitan areas in the USA, rural Malawi, or village Amerindians in Venezuela, exhibit distinct microbiome compositions and differing levels of microbial diversity. For instance, the diversity of the gut microbiome in the USA is often lower compared to non-industrialized populations.

Beyond Bacteria: The Human Mycobiome and Virome

While bacteria often take center stage in microbiome discussions, our bodies also host vast communities of other microorganisms.

The Mycobiome (Fungi)

The mycobiome refers to the fungal component of the human microbiome. It is studied using sequencing of 18S rRNA or Whole Genome Sequencing (WGS). Candida species are among the most common members of the human mycobiome.

The Virome (Viruses)

The virome encompasses all the viruses that reside in and on the human body, including bacteriophages (viruses that infect bacteria), herpesviruses, and papillomaviruses.

• The body of most healthy people contains about 4 viral genomes on average.
• Viral communities differ significantly between body sites, as diverse types of viruses infect specific tissues.
• Intriguingly, there are more differences in virome composition between individuals than for bacterial communities, making viral genetic information potentially useful in criminology.
• The virome in a given individual remains relatively stable over periods, for example, 6 months.

The Microbiome in Health and Pathologic Conditions

Characterizing the microbiome of healthy individuals is paving the way for understanding its intricate relations with various diseases. Changes in the microbiome, known as dysbiosis, are increasingly linked to numerous health issues.

Skin Conditions

• Psoriasis
• Acne
• Atopic dermatitis

Digestive Tract Disorders

• Obesity:
• Obesity has become a global epidemic, with a threefold increase in prevalence since 1975, and is a major public health crisis, particularly in the Western World.
• High-caloric diets and sedentary lifestyles are key contributors.
• The microbiomes of obese individuals are structurally and functionally distinct from those of healthier counterparts, suggesting the microbiome as a potential therapeutic target.
• Individuals with a "low gene count" (LGC) microbiome, meaning fewer species, are more frequently obese, resistant to insulin, and suffer from dyslipidemia (abnormal lipid levels in blood).
• There is a correlation between the intensity of prescribing antibiotics in the US and the occurrence of obesity, suggesting adverse effects of antibiotics on the intestinal microbiome.
• The example of American Samoa highlights a "perfect storm" of factors contributing to the world's highest obesity rates (75-80% of adults): cultural and nutritional transition (processed foods replacing traditional diets), genetic predisposition (a "thrifty gene" variant for efficient fat storage), economic/geographic factors, and cultural norms ("big is beautiful"). This leads to high rates of diabetes, cancer, and kidney failure.
• Crohn's Disease
• Ulcerative Colitis: These are autoimmune chronic inflammations affecting the digestive tract, collectively known as inflammatory bowel disease (IBD).
• Patients with IBD have a microbial metagenome containing 25% fewer genes compared to healthy individuals, impacting metabolic functions.
• Causative agents like M. avium sp. paratuberculosis, Helicobacter, Campylobacter, and E. coli are implicated.
• In ulcerative colitis, there is often an explosion of Proteobacteria, while in typical ileal Crohn's disease, Proteobacteria explode and Bacteroidetes collapse. Colonic Crohn's disease can show high levels of Archaea.
• The global incidence of IBD varies, with higher rates in developed countries.
• Oesophageal adenocarcinoma
• Necrotizing enterocolitis
• Irritable Bowel Syndrome (IBS)

Urogenital Tract Disorders

• Bacterial vaginosis
• Sexually transmitted diseases

Systemic Disorders

• Immune deficiencies: Such as Common Variable Immunodeficiency (CVID), an immune disorder affecting 1 in 25,000 to 1 in 50,000 people worldwide, characterized by recurrent infections, low antibody levels (IgG, IgM, IgA), chronic lung disease, and GI inflammation. It is often linked to deletions in genes encoding cell surface proteins.
• Febriles (feverish conditions)

Human Microbiome and Carcinogenesis (Cancer)

The microbiome can play a significant role in the development of cancer, particularly colorectal cancer (CRC).

• Genome Instability: Microbes can affect the genome stability of human cells, their resistance to cell death, and proliferative signaling.
• Some microbial defense factors lead to mutations in human cell DNA. Examples include:
• Colibactin: Expressed by B2 group Escherichia coli (pks+ E. coli) and other Enterobacteriaceae. It modifies DNA at adenine nucleotides, causing damage and leading to specific single-base substitutions (SBS-pks, typically T replaced) and insertion/deletion mutations (ID-pks, deletion of T in thymine strings). These specific mutations are also observed in human colorectal cancer.
• Cytolethal distending toxin (CDT): Produced by several Escherichia coli and other ε- and γ-proteobacteria, it causes double-stranded DNA damage.
• Cytotoxic necrotizing factor (CNF): Produced by several Escherichia coli.
• Cycle inhibiting factor (Cif): Produced by EPEC and EHEC.
• Bacteroides fragilis toxin (BFT): Produced by enterotoxigenic B. fragilis, acts indirectly by eliciting reactive oxygen species that damage host cell DNA.
• Inflammation and Tumorigenesis: Pks+ E. coli can promote tumorigenesis in an inflamed environment. In a healthy intestine, obligate anaerobes dominate, and intestinal epithelial cells (IECs) maintain epithelial hypoxia (low O2). In an inflamed intestine, nuclear factor kappa B (NF-κB) induces interleukin 6 (IL-6), which promotes IEC proliferation and inhibits apoptosis, contributing to pro-tumorigenic pathways.
• Oncoviruses: Human oncoviruses can drive carcinogenesis by integrating oncogenes into host cells or blocking tumor suppressor proteins (e.g., HPV E6/E7 blocking p53/RB).
• Colorectal Cancer Incidence: CRC is one of the most commonly diagnosed cancers globally, with incidence rates steadily growing in developed countries. In the Czech Republic, for instance, about 7,700 patients are diagnosed with CRC annually, with almost 3,400 deaths.

Metabolic Activity and the Unique Functions of the Microbiome

While the species composition of the human microbiome can vary significantly among healthy individuals within a population, the underlying metabolic pathways and the overall metabolic activity of the microbial community at a given body site often remain remarkably similar in a healthy population. This suggests a functional redundancy where different species can perform similar metabolic roles. The metabolome, which includes all the small-molecule metabolites, reflects and interacts with the activity of the genome, transcriptome, and proteome.

Athlete Microbiome

Interestingly, athletes have been found to possess a different microbiome composition compared to the general population. Their microbiomes are often enriched for genera like Prevotella and species like Methanobrevibacter smithii.

• Methanobrevibacter smithii: This archaeon plays a crucial role in metabolizing waste products, such as H2 and CO2 gases, acetate, formate, and methanol, in the human intestine. By removing H2, M. smithii prevents its accumulation, which would otherwise inhibit NADH dehydrogenases and reduce ATP yield, thereby improving fermentation efficiency. This enhanced metabolic efficiency by M. smithii can lead to more nutrients and energy extraction from food, potentially contributing to the higher performance seen in athletes.

Future Directions and Other Microbiome Studies

Research into the microbiome is a rapidly expanding field, moving beyond just the human body. Several large-scale projects are exploring new frontiers:

• Study of intestinal microbiome: Projects like MetaHIT are dedicated to mapping the genes of the human gut microbiome and understanding its role in health and disease.
• Study of home microbiome: This investigates the microbial communities found in our living environments.
• Study of hospital microbiome: This focuses on the microbes present in hospital settings, which is crucial for understanding healthcare-associated infections and environmental health.

Frequently Asked Questions About the Human Microbiome

What is the human microbiome definition?

The human microbiome is the collective community of all microorganisms (bacteria, fungi, viruses, archaea) and their genes that live in and on the human body, influencing various bodily functions and overall health.

Why is the human microbiome important for health?

The human microbiome is vital for health because it assists in metabolism (e.g., nutrient processing, vitamin synthesis), acts as a natural barrier against pathogens, and helps develop and stimulate the immune system, increasing resistance to infections.

How does diet influence the human gut microbiome?

Diet significantly influences the gut microbiome. A diet rich in fiber from fruits and vegetables promotes beneficial bacteria, while a "Western-type" diet high in fats and carbohydrates can lead to a different composition and may be linked to conditions like obesity.

What is the Human Microbiome Project?

The Human Microbiome Project (HMP) was a large-scale, NIH-funded research initiative from 2007-2012 that aimed to characterize microbial communities across various human body sites, understand their stability, identify influencing factors, and link microbiome changes to diseases.

Can the microbiome affect diseases like obesity and cancer?

Yes, the microbiome is strongly linked to diseases. Imbalances can contribute to obesity (e.g., low gene count microbiomes, antibiotic effects), inflammatory bowel disease, and even carcinogenesis through microbial toxins (e.g., colibactin) that can damage host DNA and promote inflammation.