The Dynamic Human Microbiome

• Human Microbiome refers to the collective genetic material of microorganisms in a particular environment.
• Microbiota consists of all microorganisms living in/on an organism.
• Holobionts describes hosts and microbes evolving and living together.
• Microbial niches are impacted by body location, age, sex, diet, and environment.

Microbiome Development

• The microbiota community is dynamic, changing with age and development.
• Microbiome development begins at birth and stabilizes by age 3.
• A diverse microbiome is essential for health.

Early Colonization

• Newborn colonization is important for establishing a healthy microbiome.
• Vaginal birth exposes newborns to beneficial microbes from the mother.
• Cesarean delivery exposes newborns to microbes from the initial caretakers.
• Bifidobacteria transport polymeric sugars from breast milk across their plasma membrane.
• Fermentation of these sugars provides calories and lowers gut pH, inhibiting pathogen growth.

Adult Microbiota

• Adult human microbiota is generally stable but can change due to physical or lifestyle factors.
• Microbiota varies among individuals and body sites.
• Common bacterial phyla on human skin, intestinal tract, and other mucosal surfaces:
  • Actinobacteriota
  • Bacteroidota
  • Firmicutes
  • Fusobacteriota
  • Proteobacteria
  • Verrucomicrobiota
• Archaea, fungi, and viruses are also present in the microbiota.

Microbiota Variation

• Internal organs and tissues are usually microorganism-free.
• Surface tissues like skin and mucous membranes are colonized by diverse microbes due to constant environmental interaction.

Skin Microbiome

• Skin has a slightly acidic pH and high NaCl concentration.
• The skin environment can be dry or oily, impacting microbe presence.
• Three main environmental niches on the skin are dry, moist, and sebaceous.
• Dry skin has the greatest microbial diversity.

Staphylococcus Epidermidis

• Colonizes skin and is generally nonpathogenic.
• Essential component of healthy skin.
• It stimulates antimicrobial peptide release by modulating keratinocyte gene expression.
• Products of fermentation secreted by S. epidermidis are short-chain fatty acids.
• S. epidermidis binds to the pattern recognition receptor TLR-2.
• Has bacterial interference which inhibits pathogen growth.

Respiratory Tract

• The upper respiratory tract includes nostrils, sinuses, pharynx, and oropharynx, and is colonized by various microbes.
• Lower respiratory tract includes the larynx, trachea, bronchi, and lungs, not previously thought to be sterile.

Upper Respiratory Tract

• Areas nearest to the environment are colonized by Staphylococcus, Corynebacterium, and Cutibacterium (Gram-positive, lipophilic).
• Deeper nasal cavity hosts Streptococcus, Dolosigranulum, Moraxella, and Haemophilus spp.
• The oropharynx is the most diverse, with Neisseria, Rothia, Veillonella, Prevotella, and Leptotrichia.
• Home to viruses, including human pathogens.

Lower Respiratory Tract

• Lungs have resident microbes, difficult to sample without contamination from the upper respiratory tract.
• Lower respiratory tract microbes are primarily from the oropharynx.
• Lower respiratory tract microbes are temporary, expelled and replaced by new transients.

Eye and External Ear

• Small bacteria numbers found on the conjunctiva.
• Staphylococcus epidermidis is the predominant bacterium in the eye.
• The external ear hosts skin flora, including staphylococci and Corynebacterium spp.

Mouth Microbiome

• After birth, the mouth is colonized by environmental microorganisms.
• Anaerobes like Porphyromonas, Prevotella, and Fusobacterium spp. become dominant due to the space between teeth and gums.
• Streptococcus parasanguinis and S. mutans attach to enamel surfaces as teeth grow, while S. salivarius attaches to the buccal and gum surfaces.
• The mouth microbes produce glycocalyx and adherence factors for oral surface attachment.
• The mouth microbes contribute to dental plaque, caries, gingivitis, and periodontal disease.

Stomach Microbiome

• Acidic conditions kill most microbes in the stomach.
• Streptococcus, Staphylococcus, Lactobacillus, Peptostreptococcus spp., and yeasts such as Candida spp. may survive.
• Survival can occur if microbes pass quickly or are ingested with acid-resistant food particles.

Small Intestine Microbiome

• Divided into three areas: Duodenum, Jejunum, and Ileum.
• Duodenum contains few organisms due to stomach acid, bile and pancreatic secretions; mostly Gram-positive bacteria.
• Jejunum contains Enterococcus faecalis, lactobacilli, diphtheroids, and Candida albicans.
• Ileum has flora similar to the colon, increasing in pH with Gram-negative bacteria and Enterobacteriaceae.

Large Intestine (Colon) Microbiome

• Densely packed microbial ecosystem.
• People in industrialized nations differ in core microbiome compared to those consuming plant-based diets.
• Has metabolic, immunological, and endocrine roles.

Genitourinary Tract

• Kidneys, ureter, and bladder are typically free of microbes.
• Distal urethra contains a few microbes like S. epidermidis, Enterococcus faecalis, and Corynebacterium spp.
• The female genital tract has a complex microbiota that changes with the menstrual cycle.
• Acid-tolerant lactobacilli predominate in the female genital tract.

Functional Core Microbiome

• Functional Core Microbiome provides activities required for health and homeostasis.
• Provision of vitamin K is provided by E. coli.
• Emerging role of gut microbiota in human behavior is a rapidly advancing field.

Host Metabolism

• Gut microbiota converts food into usable calories.
• Overweight individuals show high concentrations of Firmicutes relative to Bacteroidota.
• Attention has shifted from individual species to the metabolome.

Germ-Free Mice

• Germ-Free mice are born by cesarean section and raised in sterility.
• Germ-Free mice are used to study effects of microbes on animal health.
• Germ-Free mice can eat more but gain less weight than beconventional mice.
• Following fecal microbiome transplant, a Germ-Free mice will likely become obese, independent of exercise or diet.

Immunity

• Antibiotics can disrupt the gut microbial community.
• People are at higher risk of GI tract infections following antibiotics.
• Colonization resistance is based on competitive exclusion.
• The microbiome releases toxic peptides to target pathogens.

Immune Cell Function

• Germ-free mice have limited development of white blood cells.

Gut Microbiota

• Mucosal tolerance describes how microbes reside in the gut without overwhelming inflammation.
• There is a balance between pro-inflammatory cells and anti-inflammatory IL-10.

Secretory IgA

• Secretory IgA requires ILC3 and microbial stimulation.

Central Nervous System

• Behavioral traits and feelings differ between GF and conventional mice.
• Microbiome influence is heritable.
• Microbiomes influence the CNS by:
  • Impacting the immune system
  • Direct pathway from gut to brain through nerves in GI tract
  • Soluble microbial products crossing the blood brain barrier.

Dysbiosis

• Metabolic syndrome, the metabolic endotoxemia hypothesis, diet high in red meat and atherosclerosis and the relationship with cancer are diseases that all have a connection with dysbiosis.

Metabolic Syndrome

• Characterized by large waist circumference, high blood triglyceride level, high blood pressure, elevated low-density lipoprotein, and high fasting blood glucose levels.
• Is associated with chronic, low-level inflammation.
• Is linked to the microbiome via metabolic endotoxemia.

Metabolic Endotoxemia

• A high-fat diet leads to a less diverse microbiome.
• This is followed by tight junctions loosening, which results in LPS crossing the mucosal barrier called leaky gut.
• LPS then enters host circulation.
• Which leads to fat and other cells releasing pro-inflammatory cytokines promoting chronic inflammation and disease.

Cardiovascular Disease

• Associated with diets high in red meat and fat, resulting in less fiber for gut microbes to produce anti-inflammatory SCFAs.
• Such diets promote "meat-eating" microbial populations, which metabolize L-carnitine and phosphatidylcholine to produce trimethylamine (TMA).
• TMA is absorbed in the blood streamm traveling to the liver causing enyzmatic oxidization by liver cells
• The final result that leads to acceleration of atherosclerosis is trimethylamine N-oxide or TMAO.

Cancer

• Microbes contributing to about 20% of malignancies.
• Certain viruses causing host cells to become cancerous
• Helicobacter pylori dysregulating host cell cycling.
• Bacteria can cause metastasis of tumors to distant sites.
• Many cancers are linked to the dysbiosis-associated inflammatory state.

Probiotics

• Described as a live microorganism, which, when administered in adequate amounts, confer a health benefit to the host
• The U.S.F.D.A does not regulate probiotic foods and supplements, so claimed health benefits have not been rigorously tested.
• Synbiotics is the combination of both a prebiotic and a probiotic.
• Prebiotics are a compound added to boost colonization and positive health benefits of probiotic microbes.

Probiotic Product

• Is more difficult to control uniformity and effectiveness of microbes as therapeutic agents when compared to drugs with unique chemical structures.
• *Lactobacillus acidophilus is a species of probiotic
  • Lactobacillus acidophilus aids cattle who consume feed containing this microbe as appears to carry less E. coli.
• Facilitates easier bee production that meets industry quality standards.

Take Home Message

• Understanding microbe/organism interactions and the more specific interactions between humans and the microbes in or on us
• Explain main concepts and terms of the different types of relationships.
• Extrapolate that understanding forward to the normal human microbiome.
• Finally, think about what might occur in the different human body areas if the normal microbiome was disrupted or removed.