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Module 7 · Host & Disease

Microbiome & Pathogenesis

A human body carries roughly as many bacterial cells as human cells (~3 × 1013 each, by Sender & Milo’s 2016 recount). The vast majority are commensal — or, more accurately, mutualistic — and assemble into the microbiome. A small minority causes disease, and the molecular machinery they deploy is among the most refined in biology.

1. The Human Microbiome

Major sites and dominant phyla in healthy adults:

  • Gut — ~1011 cells/g, ~1000 species. Dominated by Firmicutes and Bacteroidetes; ratio shifts in obesity, diabetes, IBD.
  • Skin — Actinobacteria (Cutibacterium acnes), Firmicutes, Proteobacteria. Site-dependent (oily vs dry vs moist).
  • Oral cavity — Streptococcus, Veillonella, Neisseria; the dental plaque biofilm is the most-studied biofilm in biology.
  • Vagina — Lactobacillus dominance (lactic-acid producing, low pH). Disruption (bacterial vaginosis) sets up Gardnerella, Mobiluncus.

The Human Microbiome Project (2007–2016, NIH) and HMP2 catalogued these communities by 16S rRNA and shotgun metagenomics. The microbiome contributes digestion (especially complex polysaccharides), vitamin synthesis (K, B12, folate), immune education, colonisation resistance against pathogens, and modulates host metabolism, neurodevelopment (gut–brain axis), and drug metabolism.

2. Dysbiosis

Disturbance of the microbial community — typically by antibiotics, infection, or diet — can produce a stable alternative state with reduced diversity and altered ratios. Inflammatory bowel disease (Crohn’s, ulcerative colitis), Clostridioides difficile overgrowth, type 2 diabetes, and even depression correlate with characteristic dysbiotic signatures. Faecal microbiota transplant (FMT) is the only approved “ecological” therapy — rescuing recurrent C. difficile infection in >90% of cases.

3. Routes of Pathogenesis

A pathogenic bacterium typically:

  1. Adheres to a host surface using pili, adhesins, or surface lectins.
  2. Invades tissue (intracellular) or remains extracellular.
  3. Acquires nutrients — especially iron, sequestered by host transferrin/ferritin (hence the elaborate siderophore systems).
  4. Evades immune clearance — capsule, antigenic variation, intracellular hiding, secreted modulators.
  5. Damages the host — toxins, immune-mediated pathology, biofilm-related obstruction.
  6. Transmits to a new host.

4. Type III & IV Secretion Systems

Gram-negative pathogens build remarkable molecular machines to inject effector proteins directly into host cells:

  • Type III Secretion System (T3SS) — the “injectisome”, evolutionarily related to the flagellum (sharing core components). Used by Salmonella, Shigella, Yersinia, EPEC E. coli. The T3SS spans both bacterial membranes and the host plasma membrane, delivering 20+ effectors that subvert host actin, vesicle traffic, and innate immunity.
  • Type IV Secretion System (T4SS) — descended from conjugative pili. Used by Helicobacter pylori (CagA), Legionella (300+ effectors via Dot/Icm), Bordetella pertussis (pertussis toxin export).
  • Type VI Secretion System (T6SS) — a phage-tail-spike-like nano-harpoon used in inter-bacterial competition; contributes to gut microbial-community sculpting.

5. Bacterial Toxins

Toxins fall into three broad classes:

  • AB toxins — A subunit catalytic, B subunit binding/translocation. Cholera toxin (ADP-ribosylates Gαs, locks adenylyl cyclase ON, raises cAMP, opens CFTR, voluminous watery diarrhoea); diphtheria toxin (ADP-ribosylates EF-2, halts translation); botulinum toxin (cleaves SNAREs at neuromuscular junction, flaccid paralysis).
  • Pore-forming toxins — α-haemolysin (S. aureus), perfringolysin (Clostridium); insert into host membranes and lyse the cell.
  • Superantigens — staphylococcal toxic-shock-syndrome toxin (TSST-1), streptococcal pyrogenic exotoxins; cross-link MHC II to T-cell receptor irrespective of antigen, activating up to 20% of T cells — cytokine storm.

The Gram-negative endotoxin (lipid A of LPS) is not actively secreted — it’s a structural component released on lysis. TLR4-MD2 recognition triggers massive cytokine release; hence the lethality of septic shock.

6. Famous Pathogens

  • Mycobacterium tuberculosis — ~1.5 million deaths/year. Intracellular in macrophages, evades phagolysosomal killing, induces granuloma. Multi-drug therapy (isoniazid, rifampin, pyrazinamide, ethambutol) for 6–9 months. MDR-TB and XDR-TB now widespread.
  • Streptococcus pneumoniae — pneumonia, meningitis, otitis. Polysaccharide-conjugate vaccines (PCV13/PCV20) work brilliantly.
  • Helicobacter pylori — gastric ulcers and gastric cancer. Marshall & Warren’s 1982 culture (Marshall self-infected to prove Koch’s postulates) earned the 2005 Nobel Prize.
  • Vibrio cholerae — pandemic cholera; cholera toxin and TCP pilus on the CTXφ phage-borne element.
  • Yersinia pestis — bubonic plague. T3SS-delivered Yops paralyse phagocytes; 2014 Lassa-style fleas + reservoir rodents drove three pandemics.
  • Clostridioides difficile — antibiotic-associated diarrhoea. Produces toxins A and B; FMT is the most effective therapy for recurrent disease.

7. The Microbiome and the Future

The next decade of bacterial biology will be dominated by the microbiome — its causal contribution to disease, its rational manipulation (next-generation probiotics, defined consortia, engineered strains for cancer immunotherapy), and the bioactive small molecules it produces (the gut microbiome is, by mass, the largest endocrine organ in the body). Bacteria remain the most abundant, most diverse, and most metabolically inventive cellular life on Earth. The graduate microbiologist will not run out of work.

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