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Role of Endocrine System in Host-Microbial Cross-Talk - Coggle Diagram
Role of Endocrine System in Host-Microbial Cross-Talk
List the most important gut hormones and describe their key roles
GLP-1 (Glucagon like peptide-1):
Proglucagon gene codes for Glucagon in pancreas and GLP-1 in L cells
Prohormone converts (1/3) is expressed in L cells that forms GLP-1
Incretin hormone - mediates insulin release in response to oral glucose intake
Acts through GLP-1 receptor on insulin producing beta cells
Incretin function altered in T2DM, therefore successful drug target
GIP (Gastric Inhibitory Polypeptide):
Secreted in upper gut
Acts through GIP-receptor on insulin producing beta cells
Reduced efficacy of GIP related drugs in humans and potential obesogenic effects
CCK (Cholecystokinin):
Responsive to fat digestion and induces satiety
Action of CCK:
Gall bladder contraction, sphincter of Oddi relaxation
Increased pancreatic enzyme secretion
Augment effect of secretin in producing alkaline pancreatic juice
Slow down gastric emptying
Induced satiety by acting through hypothalamus
Mechanism of action:
CCK bind to receptor activate phospholipase C --> IP3, DAG
Increased intracellular Ca --> activate protein kinase
Release of granule (pancreatic enzyme)
PYY (Petide YY):
Co-secreted with GLP-1
Acts through many receptors --> PYY (3-36) acts through Y2 receptor
Secreted in response to food intake and stay elevated for hours
Regulates appetite, intestinal motility and energy expenditure
NTS (Neurotensin)
:
Coexpressed and consecrated with GLP-1 and PYY
Involved in regulation of appetite as well as learning and memory
Peripheral functions include regulation of fat absorption, insulin secretion and bile acid secretion
5-HT (Serotonin):
Monoamine neurotransmitter
Produced from amino acid tryptophan by rate limiting enzyme, tryptophan hydroxylase
There are 2 pools of serotonin (brain derived and gut derived)
Stored and released from specialised enterochromaffin cells
Once activated, serotonin is released that interacts with enteric nerves
Then in the recovery phase, serotonin is transproted to enterocytes where it is degraded or it is taken up by platelets
Main function is to regulate gastrointestinal motility
Explain how diet-microbiota interactions relate to enteroendocrine cells
Chemosensing and Action Potential:
Nutrient sensing –
Receptor mediated or nutrient absorption Na+ ion induced – generate action potential K+ channel closure
GPCR sensing – through G-protein coupled receptors
Describe GPCR-mediated signaling in enteroendocrine cells and nutrient sensing
Nutrient sensing - glucose:
The best characterised glucose sensor in the body is the pancreatic beta-cell. It employs metabolism-dependent closure of Katp channels to sense changes in the ambient glucose concentration.
SGLT1 is the apical glucose cotransporter responsible for glucose absorption across the intestinal brush border. It achieves glucose transport against its concentration gradient by coupling the uptake of each glucose molecule to the influx of two Na+ ions.
SGLT1-dependent mechanism appears to underlie the early elevation of plasma GLP-1 and GIP levels following carbohydrate ingestion.
EECs also express SGLT1
Entry of Na+ ions promotes action potential and Ca2+ entry through voltage gated calcium channels leading to hormone release
Glucose sensing and absorption from apical side is required to stimulate hormone release
Consistent with the incretin effect, glucose absorption is required for hormone release
Nutrient Sensing - Fat:
Long chain fatty acid and monoacyl glycerol are assembled into chylomicrons and absorbed through enterocytes
They activate receptors such as GPR119 and free fatty acids receptor 1 on the basolateral side of the enteroendocrine cells (EEC)
Ablation of lipid absorption also diminish the release of gut hormones
The G protein–coupled bile acid receptor GPBAR1 (TGR5) is a membrane receptor coupling to Gαs signaling pathways and results in the elevation of cAMP in target cells. GPBAR1 is highly expressed in EECs, particularly those of the distal gut, and provides an effective link between bile acid concentrations and GLP-1 secretion
Nutrient Sensing - Protein:
Protein ingestion stimulates the secretion of SST in the stomach and the secretion of a range of gut hormones in the small intestine (i.e. CCK)
PEPT1 (Peptide transporter 1) transports one peptide and one H+ ions
Proton-coupled peptide transporters and Na+ coupled amino acid transporters potentially provide a pathway for EEC activation
Entry of H+ ions promotes action potential and opening of voltage gated Ca2+ channels promoting Ca2+ ions entry leading to hormone release
Na+ dependent glutamine transport and H+coupled di/tripeptide transport trigger GLP-1 release in vitro
EECs can directly detect fluctuations in luminal nutrient concentrations. Direct applications of sugars, amino acids and bile acids can trigger release of hormones such as GLP-1, GIP, CCK etc.
Provide examples of microbial metabolites important for gut hormone regulation
The most common microbial metabolites are SCFAs, bile acids, LPS, indole, hydrogen sulfide
SCFAs:
Primary metabolites: Acetate, propionate and butyrate
Butyrate mainly serves as fuel to the colonocytes
All excess SCFAs are absorbed into the portal vein that collects blood from whole intestine to the liver
About 5% of SCFAs are excreted in faeces
SCFAs are
ligands
for two GPCRs: GPCR 43 (FFAR) and GPCR41 (FFAR3)
FFAR2 is Gq coupled and promote intracellular Ca2+ levels to stimulate hormone release
FFAR3 (and FFAR2) are also Gi coupled and may inhibit hormone release by decreasing cAMP levels.
In human colonic cultures, propionate exposure increases both PYY and GLP-1 however, another group could only show an increase in PYY transcription and release but not in GLP-1.
Indole
:
Produced by bacterial catabolism of dietary tryptophan and is now recognised as a signalling molecule to improved epithelial barrier and intestinal inflammation.
Indole acutely stimulates GLP-1 secretion; in contrast long-term exposure to indole attenuated GLP-1 secretion in L cell cultures
Acute exposure along with glucose promotes GLP-1 secretion in 0-5 min – promotes intracellular Ca2+ accumulation
LPS:
Lipopolysaccharide is the by product of membranes of gram negative bacteria in the gut
LPS induces low grade inflammation often called "metabolic endotoxemia"
Systemic LPS levels are higher in obesity and T2DM
LPS binds to Toll like receptors on the gut epithelium to
induce inflammatory signals
Administration of LPS abrogates intestinal barrier integrity that makes L cells accessible to LPS thus promoting GLP-1 secretion in Toll-like receptor 4 (TLR-4)-dependent mechanism
Bile acids:
Farnesoid X receptor (FXR) is a nuclear receptor expressed in liver and intestine
Primary bile acid Chenodeoxycholic acid is the ligand of FXR.
Secondary bile acids also show weak affinity with FXR
FXR activation by chemical agonist GW4064 decreases GLP-1 expression in vitro
Takeda G-protein coupled receptor 5 (TGR5) is expressed in L-cells
TGR5 couples with Gs thus stimulating cAMP levels and
promoting hormone release from cells
Perfusion of small intestinal regions has further revealed that bile acid administration stimulates the release of not only GLP-1 but also PYY and neurotensin
TGR5 is expressed toward the basolateral side of EECs and inhibition of the ideal bile acid transporter (IBAT), which mediates intestinal absorption of conjugated bile acids from the gut lumen diminishes GLP-1 secretion in ileal segments.