Lecture 6 - host-microbiota interactions at mucosal surfaces

What types of signalling molecules are shared between host and microbes for interkingdom communication?

Neurotransmitters (e.g., dopamine, serotonin, acetylcholine, GABA) and hormones (e.g., cortisol, epinephrine, norepinephrine).

Which microorganisms respond to norepinephrine, and how?

• Campylobacter jejuni, Citrobacter freundii

• Show increased growth and virulence in response to norepinephrine.

How does acetylcholine affect Candida albicans?

Decreases biofilm formation and virulence.

What is microbial endocrinology?

The study of how microbes respond to or produce human signalling molecules like neurotransmitters and hormones.

Which microbial receptors detect host signalling molecules?

• QseC and QseE/F in E. coli detect epinephrine/norepinephrine.

• GBP in Pseudomonas fluorescens detects GABA.

• CpxA in E. coli (EHEC) responds to serotonin.

What is the microbiota–gut–brain axis?

A bidirectional communication system between the gut microbiota and the central nervous system, influencing mood, immunity, and neurodevelopment.

What are cortisol’s effects on immune cells?

• ↓ Neutrophil and macrophage activation

• ↓ T helper cytokines (e.g., IL-1, IL-8, TNF)

• ↑ IL-10

• Inhibits IgG, may promote IgE

• Enhances DC antigen uptake but blocks maturation

How can chronic cortisol exposure affect immune responses?

Leads to glucocorticoid receptor (GR) desensitisation → paradoxical proinflammatory response.

Which cells synthesize acetylcholine (ACh)?

Bacteria, fungi, mammalian epithelial and immune cells, keratinocytes, and neurons.

What is the cholinergic anti-inflammatory pathway (CAP)?

A neuroimmune mechanism where ACh released by ChAT⁺ T cells suppresses inflammation via α7nAChR activation on immune cells.

What is α7nAChR and which cells express it?

A nicotinic acetylcholine receptor that suppresses inflammation.
Expressed by:

• Macrophages

• Dendritic cells

• Keratinocytes

• Oral fibroblasts

What are the intracellular effects of α7nAChR activation?

• Inhibits IκB phosphorylation → blocks NF-κB

• Activates JAK2–STAT3 signalling → ↓ proinflammatory cytokines

Which method confirmed α7nAChR expression in oral mucosa?

Real-time PCR and immunohistochemistry (Macpherson et al., 2014).

How do muscarinic cholinergic receptors influence immunity?

• GPCRs (M1–M5)

• Promote Th2 responses

• Regulate epithelial integrity

• Activate mast cells → wound healing and anti-inflammation

How do nicotinic receptors modulate immune responses?

• Ligand-gated ion channels

• Suppress cytokine production

• Inhibit mast cell degranulation

• Modulate fibroblasts, B cells, Tregs

How does P. gingivalis influence host cholinergic signalling?

Its LPS stimulates ACh synthesis in keratinocytes, which in turn modulates immune cell activity via α7nAChR.

Which commensal bacteria are known to produce acetylcholine?

Some strains of Lactobacilli.

How does acetylcholine act as a cross-kingdom signalling molecule?

Synthesized by both microbes and host cells, ACh modulates immune responses and microbial behaviour (e.g., motility, virulence).

What is the functional significance of ACh in epithelial cells?

Modulates cell–cell contact, ciliary motility, proliferation, angiogenesis, and cytokine secretion.

What term describes the two-way biochemical communication between microbiota and host using shared signalling molecules?

Microbial endocrinology — the ability of microbes to both respond to and produce neurotransmitters and hormones traditionally associated with the host.

How does serotonin affect the virulence of E. coli (EHEC)?

It reduces virulence by interacting with microbial serotonin-responsive systems like the CpxA receptor.

What type of receptor is α7nAChR and what is its ligand?

It is a nicotinic acetylcholine receptor, a ligand-gated ion channel, and its ligand is acetylcholine (ACh).

How do pathogens exploit host signalling pathways for immune evasion?

They sense host hormones (e.g., cortisol) or neurotransmitters to modulate their gene expression, increase virulence, suppress immune detection, or enhance motility and biofilm formation.

What is the significance of JAK2–STAT3 signalling in cholinergic anti-inflammatory responses?

It mediates anti-inflammatory effects downstream of α7nAChR activation by inhibiting expression of proinflammatory cytokines.

Which stress hormone modulates both immunity and microbiota–brain signalling?

Cortisol — a glucocorticoid that suppresses immune responses but can lead to inflammation when chronically elevated.

What does CAP stand for and what is its function?

Cholinergic Anti-inflammatory Pathway (CAP) — a vagus nerve-mediated response that reduces systemic inflammation via ACh release and α7nAChR activation on immune cells.

Which immune functions are suppressed by glucocorticoids like cortisol?

• Neutrophil migration

• Macrophage pro-inflammatory responses

• T cell cytokine production

• B cell-mediated IgG responses

• DC maturation

What are the therapeutic implications of α7nAChR modulation in inflammatory diseases?

Targeting α7nAChR could reduce chronic inflammation (e.g., in periodontitis, IBD, sepsis, or autoimmunity) by dampening excessive cytokine responses.

What’s the role of epithelial cells in cholinergic immune regulation?

They can synthesize and respond to ACh, contributing to immune signalling, barrier integrity, cytokine regulation, and interactions with underlying immune cells.

Which cellular and microbial processes are altered by ACh in interkingdom communication?

• Microbial: virulence, motility, biofilm formation

• Host: immune signalling, cytokine expression, mucosal barrier integrity

Which muscarinic receptors are involved in Th2 polarization and mast cell activation?

Muscarinic GPCRs (M1–M5) — they bias toward Th2 responses, promoting wound healing and anti-inflammatory outcomes.

What immune-related role does the myenteric plexus play in the gut?

It produces ACh, which modulates antigen-presenting cells (APCs) and contributes to mucosal immune regulation through the cholinergic pathway.

What evidence supports ACh production in oral epithelial cells in response to microbial signals?

Macpherson et al. (2014): P. gingivalis LPS stimulates keratinocytes to produce ACh, modulating immune responses.

Why is ACh considered an evolutionarily conserved signalling molecule?

Because it’s synthesized by bacteria, fungi, and human cells, enabling cross-kingdom communication that regulates both microbial behaviour and host immunity.