Microbial Symbioses with Humans

All sites on a human that contain microorganisms are part of a microbiome.
A microbiome is a functional collection of different microbes in a particular environmental system (e.g., the human microbiome).
Microbiota describes all the microbes in a microhabitat (e.g., skin microbiota).
Different microhabitats support different microbes (e.g., skin vs. mouth).

Microbial Habitats of the Human Body

There are $10^{13}$ microbial cells in the human microbiome living in complex communities.

Overview of the Human Microbiome

Future benefits of knowing the human microbiome:
- Development of biomarkers for predicting predisposition to diseases.
- Designing targeted therapies.
- Personalized drug therapies and probiotics.
Early studies:
- Most Bacteria cannot be cultured.
- Advanced sequencing techniques allow for identification of different microbiota at different body sites.
- Reveal that there are complex interactions between host and its microbiota.

Major Human Microbiome Research Programs

MetaGenoPolis (France): Demonstrate the impact of the human gut microbiota on health and disease using metagenomics technology.
International Human Microbiome Standards (European Commission): Optimize methods for the assessment of the effects of the gut microbiome on human health through the standardization of procedures and protocols.
Korean Twin Cohort Project (Korea): Characterize microbiota associated with epithelial tissue in a twin cohort study group, with the goal of identifying targets for early disease diagnosis and prevention.
NIH Human Microbiome Project (HMP) (USA): Characterize the microbes that live in and on the human body, and assess the ability to demonstrate correlations of changes of the human microbiome with health.
Canadian Human Microbiome Initiative (Canada): Characterize the microorganisms colonizing the human body. Evaluate their relationship to health and examine compositional changes associated with chronic disease.
NIH Jumpstart Program (USA): Generate the complete genome sequences of 200 bacterial strains isolated from the human body; recruit donors for securing samples from five body regions, and perform 16S rRNA and metagenomics sequence analysis of the sampled body regions.
American Gut: An Open Platform for Citizen Science Microbiome Research (USA): Crowdsourcing model to secure fecal samples for comparative 16S rRNA, metagenomic, and metabolomic analyses.

Overview of Major Microbial Populations in the Body Sites Sampled by Human Microbiome Projects

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Skin flora

Transient microorganisms:
- On skin due to daily activities.
- Unable to multiply on dry, acidic skin.
Resident microorganisms:
- Reside and multiply on skin
- Mostly bacteria; some fungi & yeast.

Human skin

Microorganisms are associated with warm, moist places like the sebaceous and apocrine sweat glands in your skin.

Public Health: Smelly Sweat

Body odor (bromhidrosis) is due to bacterial species on the skin giving off smelly odors.
- $brom$ = "stench"
- $hidro$ = "sweat"
- $sis$ = "the act of"
Bacterial cells on the skin multiply in the sweat, they break down some of the proteins in the sweat.
Propionibacteria in the sebaceous glands break down amino acids into propionic acid which has a pungent vinegar-like smell.
Staphylococcus epidermidis on the skin degrades the amino acid leucine into isovaleric acid, which has the typical "locker room" smell.
The typical human has 3 to 4 million sweat glands and the sweat or perspiration from these glands is most likely to occur on face, armpits, palms, and the soles of the feet.
The apocrine glands, found in the genital area, breasts, armpits, and eyelids, become active with puberty and contribute to apocrine bromhidrosis through the breakdown of fatty sweat; bacterial breakdown of apocrine sweat is the major cause of body odor.
Maintain good hygiene: take regular showers or baths and use a deodorant (designed to eliminate odor by turning the skin pH acidic, making for a more hostile environment for bacterial growth) or antiperspirant (designed to prevent odor and reduce sweat production by blocking the sweat pores).

Factors Influencing Skin Flora

Temperature and moisture of skin (weather).
Age of host.
Personal hygiene.

Distributions of Staphylococcus, Propionibacterium, and Corynebacterium on the Human Skin

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Skin Microbiome of the Human Back

There are variations in a person’s skin flora.
Propionibacterium is the predominant organism on these individual’s back skin.

Oral Cavity and Airways

Microenvironments of the Respiratory Tract:
- Upper respiratory tract:
  - Microbes thrive.
  - Bacteria continually enter from the air during breathing.
  - Most are trapped in the mucus of the nasal and oral passages and expelled with nasal secretions or swallowed and killed in the stomach.
- Lower respiratory tract:
  - No normal microbiota in healthy adults.
  - Only particles smaller than about $10µm$ in diameter reach the lungs.
  - These include some pathogenic microbes, most notably certain bacteria and viruses that cause pneumonia.

Oral Cavity

Saliva contains antimicrobial enzymes such as lysozyme.
High concentrations of nutrients near surfaces in the mouth promote localized microbial growth.
The tooth serves as a surface for the formation of biofilms (dental plaque).

Bacterial Diversity of Saliva

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Structured Microbial Community of Dental Plaque

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The Respiratory Tract

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Upper respiratory tract

Microorganisms enter during breathing, become trapped in nasal passages and expelled with nasal secretions.
Moist mucous membranes harbor microorganisms.

Resident Microflora for the Upper Respiratory Tract

Staphylococcus
Streptococcus
Cornyebacterium
Neisseria
Opportunistic pathogens
- Staphylococcus aureus
- Streptococcus pneumoniae

Lower Respiratory Tract

Cilia lining the walls of the respiratory tract beat upward pushing bacteria and particulates up to be expelled in saliva and nasal secretions.

Microflora of the Lungs

Along with various bacteria shown here, there are also a common set of 19 bacteriophages present.

Gastrointestinal Microbiota

Microbes in gut affect early development, health, and predisposition to disease.

Biochemical/Metabolic Contributions of Intestinal Microorganisms

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Vitamin synthesis: Thiamine, riboflavin, pyridoxine, B12, K
Amino acid synthesis: Asparagine, glutamate, methionine, tryptophan, lysine, and others
Gas production: $CO<em>2$ , $CH</em>4$ , $H_2$
Odor production: $H<em>2S$ , $NH</em>3$ , amines, indole, skatole, butyric acid
Organic acid production: Acetic, propionic, butyric acids
Glycosidase reactions: β-Glucuronidase, β-galactosidase, β-glucosidase, α- glucosidase, α-galactosidase
Steroid metabolism (bile acids): Esterified, dehydroxylated, oxidized, or reduced steroids

Small Bioactive Molecules Produced by Bacteria in the Large Intestine

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RiPPa (lantibiotic): Ruminococcin A, Ruminococcus gnavus, Antibiotic
RiPPa (bacteriocin): Ruminococcin C, Ruminococcus gnavus, Antibiotic
Amino acid metabolite: Indolepropionic acid, Clostridium sporogenes, Protective antioxidant
Amino acid metabolite: 4- Ethylphenylsulfate, Undefined, Neuromodulatory
Amino acid metabolite: Tryptamine, Ruminococcus gnavus, Neurotransmitter
Volatile fatty acid: Propionic acid, Bacteroides spp., Immunomodulatory
Oligosaccharide: Polysaccharide A, Bacteroides fragilis, Immunomodulatory

The Human Gastrointestinal Tract and Major Members of Its Microbiota

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Different Microenvironments in the Large Intestine

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Gut Enterotypes

While individuals vary in their gut microbiota, each individual has a relatively stable gut microbiota until impacted by diet or drug therapy.
Two basic enterotypes:
- #1 is enriched in Bacteroides
- #2 is in Prevotella, each is functionally and phylogenetically distinct
A person’s enterotype is influenced by what they eat.
A person’s enterotype influences the response to diet and drug therapy and may contribute to health or disease status in yet unknown ways.

Fecal Transplants

Persons suffering from Clostridium difficile infection benefit from a fecal transplant.

Gut Microorganisms and Weight Gain

Obese individuals (mice and humans) have more methanogenic Archaea and Bacteroidetes.
Pregnant women’s gut diversity decreases, enrichment of Proteobacteria and Actinobacteria.

Constant Replacement of Intestinal Microflora

Growth rate of bacteria is 1-2 doublings/day in the intestinal tract.
Bacteria make up 1/3 of feces.
Necessitates sanitation for clean drinking water.

Urogenital Tract

Microflora varies, bacteria and yeast present.
Urethra (male & female):
- Urination regularly eliminates microbes
Vagina:
- Ethnicity and age.
- Lactobacillus acidophilus - predominant bacteria between puberty and menopause that ferments glycogen to lactic acid
Penis:
- Circumcision lessens amount and composition.

Immune Defense Mechanisms of the Human Vagina

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Questions to be answered About the Human Microbiome

Do individuals share a core human microbiome?
Is there a correlation between the composition of microbiota colonizing a body site and host genotype?
Do differences in the human microbiome correlate with differences in human health?
Are differences in the relative abundance of specific bacterial populations important to either health or disease?
When are we colonized by our human microbiome?

The Human Virome

A healthy human is teeming with viruses—not just animal viruses but also bacteriophages and possibly even some plant viruses.
Some cause severe diseases such as hepatitis and severe acute respiratory syndrome, some cause milder acute infections such as influenza and viruses of the common cold, and some are completely benign.
The most abundant viruses in all body sites are not animal viruses but instead are bacteriophages.

Examples of the Human Virome

Anellovirus
Papillomavirus
Polyomavirus
Adenovirus
Circovirus
Pepper mild mottle virus
Bacteriophage

Bacteriophages

Bacteriophages likely play a protective role in human health.
- Can be a first line of defense against certain pathogens, especially within mucosal surfaces where bacteriophages accumulate. It has been estimated that 20 times more bacteriophages than bacteria exist in the mucosa of our lungs and intestines.
Can be considered to have a symbiotic relationship with the human host and provide a form of host- independent immunity.

Microflora Colonization

Sterile prior to birth?
- Oral bacteria from mother are found in the placenta
- Amniotic fluid and fetal meconium have microbes
Further colonized by microorganisms in the days after birth
- Air
- Food and water (milk)
- People
Competition
- those most fit for a microenvironment become resident flora

Gut Microflora and Diet

Microbes that colonize your gut depend on what you eat
Nursing Infant Microflora
Formula Fed Infant Microflora

Impact of Birth Mode on the Young Infant’s Gut Community

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Changing Microbiota

Stability of the Adult Microbiome and Transitions with Age
- Early experiences determine gut microbiome
- Aging and frailty are associated with decreased microbial diversity