Human Microbiota and Infectious Diseases: Structure, Function, and Pathogenesis

Microbial Symbioses with Humans

Definition and Overview

• Microbiome: All sites on a human that contain microorganisms are part of the microbiome.

• Microbiota: Refers to all the microbes in a specific microhabitat (e.g., skin microbiota).

• Microbiome (genetic): The collective genes of the host and its microbiota.

• Different microhabitats (skin, mouth, gut) support distinct microbial communities.

Examples of Symbiosis

• Vibrio fischeri and the Hawaiian bobtail squid: A model for studying beneficial host-microbe interactions.

• Microbiota can influence regeneration in organisms such as flatworms.

I. Structure and Function of the Healthy Adult Human Microbiome

Overview of the Human Microbiome

• There are approximately $10^{13}$ microbes in the human microbiome, living in complex communities.

• Most Bacteria cannot be cultured; advanced sequencing techniques are used to identify microbiota at different body sites.

24.2 Gastrointestinal Microbiota

Gut Enterotypes

• Each individual has a relatively stable gut microbiota, but composition varies between people.

• Three basic enterotypes:

  • #1: Enriched in Bacteroides

  • #2: Enriched in Prevotella

  • #3: Enriched in Ruminococcus

• Enterotypes are functionally and phylogenetically distinct.

Products of Intestinal Microbiota and Immune Education

• Microbial metabolites and transformation products influence host physiology, including:

  • Vitamin production

  • Modification of steroids

  • Amino acid biosynthesis

Process	Product or Enzyme
Vitamin synthesis	Thiamine, riboflavin, pyridoxine, B12, K
Amino acid synthesis	Asparagine, glutamate, methionine, tryptophan, lysine, others
Gas production	CO2, CH4, H2
Odor production	H2S, NH3, amines, indole, skatole, butyric acid
Organic acid production	Acetic, propionic, butyric acids
Glycosidase reactions	β-Glucuronidase, β-galactosidase, α-glucosidase, α-galactosidase
Steroid metabolism (bile acids)	Esterified, dehydroxylated, oxidized, or reduced steroids

II. From Birth to Death: Development of the Human Microbiome

Colonization, Succession, and Stability of the Gut Microbiota

• Colonization begins at birth, with microbes transferred from mother to infant.

• Early colonizers are often facultative anaerobes and provide vitamins.

• Vaginally born infants have microbiomes more similar to their mothers than those born via Cesarean section.

• Breastfed infants have more commensal bacteria due to oligosaccharides in breast milk.

• Early experiences shape the gut microbiome; aging and frailty are associated with decreased microbial diversity.

III. Disorders Attributed to the Human Microbiome

Disorders Attributed to the Gut Microbiota

• Inflammatory Bowel Disease (IBD):

  • Chronic gut inflammation and disruption of homeostasis (dysbiosis).

  • Antibiotic use increases IBD risk; IBD may be transmissible between family members.

  • Individuals with IBD have lower gut microbiome diversity.

• Obesity:

  • Normal mice have 40% more fat than germ-free mice on the same diet; germ-free mice gain weight after microbiota transplant.

  • Obese mice and humans have more Firmicutes than lean counterparts.

  • Gut microbiota composition is influenced by both diet and genetics.

Disorders Attributed to the Oral, Skin, and Vaginal Microbiota

• Dental Caries and Periodontitis:

  • Dental plaque is a biofilm containing Streptococcus and other fermenters.

  • Fermenters produce acid, eroding tooth enamel.

  • Periodontal disease is linked to systemic conditions, including cardiovascular disease and arthritis.

IV. Modulation of the Human Microbiome

Antibiotics and the Human Microbiome

• Oral antibiotics decrease all gut microbes, both target and non-target.

• Early-life antibiotic use increases risk of IBD and other dysbiosis-related disorders.

• Clostridium difficile infections are associated with antibiotic use; this bacterium is a spore-former and generally antibiotic resistant.

• Fecal transplant is a newer therapy for C. difficile infection.

Probiotics and Prebiotics

• Probiotics: Live organisms (e.g., Bifidobacterium, Lactobacillus) that confer health benefits, often by occupying niches and limiting pathogen colonization.

• Prebiotics: Indigestible carbohydrates that nourish fermentative gut bacteria.

V. Human-Microbial Interactions

Infection, Pathogens, and Pathogenicity

• Infection: Establishment and growth of a microorganism in a host, regardless of harm.

• Pathogens: Microbial parasites that cause disease or tissue damage.

• Pathogenicity: The ability of a parasite to inflict damage on the host.

Microbial Adherence

• Adherence is the enhanced ability of microbes to attach to host tissues; it is necessary but not sufficient for disease initiation.

• Many different receptors on both pathogens and host tissues mediate binding.

• Adhesins: Glycoproteins or lipoproteins on the pathogen surface that enable binding to host cells.

Adherence Structures

• Capsules: Sticky, receptor-containing coatings that facilitate attachment and protect bacteria from phagocytosis (e.g., Streptococcus pneumoniae).

• Fimbriae, Pili, Flagella: Surface protein structures that function in attachment.

Colonization and Invasion

• Colonization is the growth of microorganisms after gaining access to host tissues, typically starting at mucous membranes.

• Mucous membranes are composed of tightly packed epithelial cells coated in mucus (glycoproteins).

Invasion and Systemic Infection

• Invasiveness: The ability of a pathogen to grow in host tissue at densities that inhibit host function.

• Bacteremia: Presence of bacteria in the bloodstream.

• Septicemia: Bloodborne systemic infection, which may lead to massive inflammation, septic shock, and death.

Pathogenicity, Virulence, and Attenuation

• Virulence: The relative ability of a pathogen to cause disease.

• Virulence can be estimated by the LD50 (lethal dose50), the amount of agent that kills 50% of a test group.

  • Highly virulent pathogens show little difference in the number of cells required to kill 100% vs. 50% of the population.

• Attenuation: Decrease or loss of virulence; attenuated strains are used in vaccine production.

• Compromised Host: Host-pathogen interaction depends on both parties; medical procedures or underlying conditions can predispose to disease (e.g., nosocomial infections, HIV).

• Opportunistic Infections: Caused by organisms that do not cause disease in healthy hosts.

VI. Enzymes and Toxins of Pathogenesis

Enzymes as Virulence Factors

• Pathogens often produce enzymes to break down host tissues and facilitate invasion.

• Hyaluronidase: Breaks down host connective tissue.

• Coagulase: Forms clots to protect pathogens from immune cells.

• Streptokinase: Dissolves clots, allowing pathogen spread.

AB-Type Exotoxins

• Toxicity: The ability to cause disease via toxins that inhibit host cell function or kill host cells.

• Exotoxins: Proteins released from the pathogen cell as it grows; three categories:

  • Cytolytic toxins

  • AB toxins

  • Superantigen toxins

Organism	Disease	Toxin	Activity
Bacillus anthracis	Antrax	Lethal factor, Edema factor, Protective antigen (AB)	Combine to cause cell death
Bordetella pertussis	Whooping cough	Pertussis toxin (AB)	Blocks G-protein function
Clostridium botulinum	Botulism	Botulinum toxin (AB)	Blocks acetylcholine release, causes flaccid paralysis
Clostridium tetani	Tetanus	Tetanus toxin (AB)	Blocks glycine release, causes spastic paralysis
Corynebacterium diphtheriae	Diphtheria	Diphtheria toxin (AB)	Inhibits protein synthesis
Vibrio cholerae	Cholera	Cholera toxin (AB)	Induces fluid loss from intestine

Diphtheria Exotoxin

• AB toxin composed of an Active (A) domain and a Binding (B) domain.

• The A domain adds an ADP-ribosyl group to EF-TU, blocking protein synthesis in host cells.

Neurological Exotoxins

• Clostridium tetani and Clostridium botulinum produce potent AB exotoxins affecting nervous tissue.

• Botulinum toxin blocks acetylcholine release, causing flaccid paralysis.

• Tetanus toxin blocks glycine release, causing spastic paralysis.

Enterotoxins

• AB-type exotoxins that affect the small intestine, causing massive fluid secretion, vomiting, and diarrhea.

Cytolytic and Superantigen Exotoxins

• Cytolytic exotoxins: Degrade cytoplasmic membrane integrity, causing cell lysis and death (e.g., hemolysins, staphylococcal α-toxin).

• Superantigens: Overstimulate the immune system, leading to shock and death; systemic effects can result from localized infections.

Endotoxins

• Endotoxins are the lipopolysaccharide (LPS) portion of the outer membrane of Gram-negative bacteria.

• They are generally less toxic than exotoxins but can cause fever, inflammation, and shock when released into the bloodstream.

• Detection: The Limulus amoebocyte lysate (LAL) assay is used to detect endotoxins, but overharvesting horseshoe crabs for this assay is an environmental concern.