KS

Biology of the Human Microbiota – Key Vocabulary

Learning Outcomes

  • LO1: Describe roles of the human microbiota and key terminology

  • LO2: Discuss impacts of changes (dysbiosis) on health & disease states

  • LO3: Evaluate approaches to identify pathogens as causative agents of disease

Core Definitions & Key Terminology

  • Microbiota – the community of microorganisms (Bacteria, Archaea, yeasts, protists, viruses) that live on or within the human host.

  • Microbiome – collective genomes/genes of those organisms.

  • Dysbiosis – imbalance in composition/structure of a microbiota that disrupts homeostasis.

  • Colonisation resistance – ability of resident commensals to prevent pathogen establishment.

  • Volatile Fatty Acids (VFAs) – short-chain fatty acids (e.g. acetate, propionate, butyrate) derived from bacterial fermentation.

  • Opportunistic vs. obligate pathogen – (mentioned as concept check; ensure student can define for exam).

Gut Microbiota – Metabolic Roles

  • Enzymatic conversion of complex carbohydrates → monosaccharides & VFAs.

  • Nitrogen metabolism: complete set of 20 amino acids; humans cannot synthesise 10 ‘essential’ ones.

  • Folate-producing enzymes – enriched in infant gut to compensate for dietary lack.

  • Synthesis of vitamin K & several B-vitamins (vital for prothrombin formation & blood clotting).

  • Modulate host gene expression → ↑ nutrient uptake & altered energy harvest.

  • Germ-free mouse data: microbiota composition tightly linked to body-fat proportion.
    • Shift: ↓ Bacteroidetes, ↑ Firmicutes + methanogenic Archaea correlates with ↑ adiposity.

  • Human observations: ↑ prevalence of Bacteroidetes genus Prevotella and methanogenic Archaea in obesity.

  • Pregnancy: 1st → 3rd trimester marked by ↓ gut diversity, ↑ Proteobacteria & Actinobacteria, mirrored by ↑ body-fat.

Gut Microbiota – Immunity & Colonisation Resistance

(Buffie & Pamer 2013, Nature Rev Immunol 13:790–801)

  • Commensals compete with pathogens for physical space & nutrients; secrete bacteriocins/antimicrobial peptides.

  • Specific examples:
    • Bifidobacterium spp. → organic acids & peptides that ↓ adhesion of pathogenic E. coli to enterocytes.
    • Bacillus thuringiensis bacteriocin inhibits spore-formers (C. difficile, Bacilli).
    • Bacteroides thetaiotaomicron competes for carbs utilised by Citrobacter rodentium (murine enteric pathogen).

  • Immune-stimulation:
    • B. thetaiotaomicron ↑ expression of C-type-lectin REGIIIγ – kills Gram-positive bacteria incl. vancomycin-resistant Enterococcus spp.
    • Segmented filamentous bacteria (SFB) – Gram-positive, spore-forming, non-culturable Clostridia-related organisms – provoke Th17 responses that also curb pathogens.

Dysbiosis & Gut-Associated Disease

  • Antibiotic-associated diarrhoea – broad-spectrum drugs (e.g. Clindamycin) disrupt community → overgrowth of Clostridioides difficile (endospore-former, produces up to 3 toxins).
    • Clinical spectrum: mild diarrhoea → pseudomembranous colitis & toxic megacolon.
    • Tx: vancomycin; recurrent cases → faecal microbiota transplant (FMT) to restore flora.

  • Inflammatory Bowel Disease (IBD) – chronic GI inflammation.
    • iHMP2 followed 132 pts × 1 yr; captured periods of dysbiosis.
    • Identified 2900 microbe–host molecular interactions involving fatty acids, taxa (↓ Faecalibacterium, Subdoligranulum, Roseburia, Alistipes; ↑ Escherichia), and cytokines (interleukins).

Oral Microbiota – Composition & Ecology

  • ~750 species; dominant genera: Streptococcus, Haemophilus, Veillonella, Actinomyces, Fusobacterium (+ Archaea & yeasts).

  • Distinct habitats:
    • Tongue – Streptococcus
    • Buccal mucosa – Haemophilus
    • Supragingival plaque – Actinomyces
    • Subgingival plaque – Prevotella

  • Environmental drivers: O$_2$ gradient, pH, nutrient availability, oral hygiene.

  • Intra-individual strain variability example: Streptococcus mitis B6 (genomic islands, V-type H$^+$-ATPase genes, choline-binding proteins).
    • Study of 127 tongue-dorsum samples showed wide spread in Streptococcus species abundance.

Oral Microbiota – Disease Links

  • Dental caries – diet & hygiene drive early vs. late coloniser succession; global burden 2.3\times10^9 adults & 5.3\times10^8 children.

  • Periodontitis – chronic gum inflammation; Gram-negative pathogens induce TNF-α, ↓ IL-10, ↑ C-reactive protein.
    • Multifactorial: poor hygiene, tobacco, stress, diabetes (I/II), CVD, osteoporosis.
    • Affects 35{-}50\% of global population.

  • Systemic spread – ~1000 ml saliva/day can disseminate microbes/molecules via bloodstream or GI tract.
    • CVD risk 25{-}50\% higher with periodontitis.
    • Porphyromonas gingivalis associated with oesophageal & pancreatic cancers.

Skin Microbiota

  • Surface area ≈ 2\,\text{m}^2; low pH & moisture.

  • Major phyla: Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes (total 19 phyla recorded).

  • Site-specific profiles:
    • Moist (armpit) – Corynebacteria, Staphylococci.
    • Dry (palms) – Betaproteobacteria.
    • Oily/sebaceous (side of nose) – Staphylococci, Propionibacterium.

  • Ageing: cellular senescence → ↓ commensal Cutibacterium, ↑ opportunists/pathogens.

Human Virome – Overview

  • Aggregate of all viruses in/on body; ≈ 10^{13} particles per individual.
    • Includes eukaryotic, bacterial (phage) & archaeal viruses.

  • Phage genome size range: smallest 2435\,\text{bp} (Leuconostoc phage L5) → jumbo >200\,\text{kbp} (e.g. >540\,\text{kbp} Prevotella phages).

  • Structural diversity: tailed, polyhedral, filamentous, pleomorphic; no universal gene marker for detection.

Site-Specific Virome Snapshots (Liang & Bushman 2021)

  • Saliva: 10^8 VLP mL$^{-1}$; dominant phage families Siphoviridae, Podoviridae, Myoviridae; eukaryotic Herpesviridae, Anelloviridae, Papillomaviridae.

  • Faeces: 10^9 VLP g$^{-1}$; phage-rich, eukaryotic fraction relatively low.

  • Cerebrospinal fluid: 10^4 VLP mL$^{-1}$; low diversity.

  • Urine: 10^7 VLP mL$^{-1}$; mix of phage & eukaryotic (Polyomaviridae, Papillomaviridae).

Gut Virome Specifics

  • crAssphage (cross-assembly podovirus)
    • Infects Bacteroides intestinalis.
    • Accounts for ≈90\% of gut virome reads; present in ≈50\% of humans; global distribution.

  • Acquisition: early life mostly phages from pioneer bacterial genomes; crAssphage detected by 4 months.

  • Modulators: diet (breast-milk contains antiviral molecules), age, geography, medication, host genetics & disease.

  • Virome structure correlations emerging with IBD, diabetes, hypertension, cancers.

Microbiota–Organ Axes (Systemic Crosstalk)

  • Gut–Lung Axis: Mesenteric lymphatics transport microbes/metabolites (e.g. SCFAs) → modulate pulmonary immunity; implicated in asthma, COPD, cystic fibrosis, susceptibility to influenza/pneumonia.

  • Gut–Skin Axis: Dysbiosis + leaky gut ↓ antimicrobial peptides in skin → acne, atopic dermatitis, psoriasis.

  • Gut–Brain Axis: Correlative data linking microbiota to neuro- & psychiatric conditions: Huntington’s, multiple sclerosis, schizophrenia, major depressive disorder, ASD, ADHD.

Investigative & Diagnostic Approaches

  • Sequencing (NGS, 16S/shotgun metagenomics) – accelerates identification of uncultured taxa & disease associations; beware biases (Boers et al 2019).

  • Fluorescent in situ hybridisation (FiSH) – fluorophore-labelled probes bind rRNA; has visualised ‘hedgehog’ dental plaque structures (Corynebacteria core with layers of Streptococcus, Haemophilus, Porphyromonas, Neisseria, Fusobacterium, Leptotrichia, Actinomyces).

  • Gnotobiotic/Germ-free animal models – dissect microbe–microbe & microbe–host interactions.

  • Revisiting Koch’s postulates – essential for causal attribution but adapted for fastidious, unculturable or polymicrobial pathogens (sequence-based criteria, animal surrogates, etc.).

Summary & Take-Home Points

  • Human body hosts dynamic, site-specific ecosystems; core members underpin stability & health.

  • Metabolic, immunological & structural functions of commensals are integral to host physiology.

  • Dysbiosis can trigger local disease (IBD, periodontitis) and systemic sequelae via body-wide axes.

  • Virome is vast, understudied; phage–bacteria interactions likely shape bacterial community & immune tone.

  • Modern molecular tools (NGS, FiSH, gnotobiotics) are redefining our ability to study microbiota and satisfy causal criteria for disease agents.

  • Maintaining/ restoring eubiosis (e.g. FMT, diet, targeted probiotics) represents an emerging therapeutic frontier.

Concept Check & Exam Preparation

  • Define: obligate vs. opportunistic pathogen; microbiota vs. microbiome; colonisation resistance; dysbiosis.

  • Explain how gut, oral, skin microbiota influence health & provide concrete examples (metabolism, immunity, disease links, systemic axes).

  • Describe experimental/diagnostic methods (culturing challenges, sequencing, FiSH, Koch’s postulate revisions).

  • Be able to outline pathways by which dysbiosis contributes to extra-intestinal diseases (lung, skin, brain).