1
Nutrition & Infectious Disease
AM_470816, January 2022.
Biological mechanisms
Zinc
Mechanisms of action of zinc in acute diarrhea, Canani et al. 2011
Zinc supplementation:
+ ↓ mean duration of acute diarrhea with 20% and persistent diarrhea with 15-30%.
+ ↓ diarrhea mortality with 23%.
+ ↓ diarrhea prevalence.
+ ↑ oral rehydration solution (ORS).
+ ↓ use of necessary antibiotics.
+ ↓ need for medical visits for acute diarrhea.
Mechanisms of zinc in acute diarrhea:
Zinc is not stored in the body, its level is determined by the balance of dietary intake, absorption and
losses.
The positive action by zinc in acute diarrhea:
1. Zinc regulates intestinal fluid (ion) transport and mucosal integrity.
a. Reduces intestinal permeability.
2. Zinc plays a substantive role in immunity.
3. Zinc can modify expression of genes encoding several zinc-dependent enzymes
(metalloproteases, cytokines and uroguanylin).
4. Zinc may modulate positively oxidative stress and inflammation.
5. Zinc is able to resist its potential loss in diarrhea.
6. Zinc stimulates red blood cell growth and differentiation.
The intestine is the first tissue confronted with zinc. Sufficient absorption of zinc from the small
intestine is essential for body health, but high levels of zinc are harmful. Zinc homeostasis is
coordinated via regulation by proteins involved in uptake, excretion and intracellular storage or
trafficking.
● Proteins = metallothioneins and transmembrane transporters.
○ Zinc regulated transporter (ZRT).
○ Iron-regulated transporter (RT)-like protein (ZIP).
■ Zinc uptake and transport into the cytoplasm.
■ Mobilize stored zinc by transporting the metal from an intracellular
compartment into the cytoplasm.
○ Cation diffusion facilitator (CDF) families.
, 2
■ Promotes zinc efflux by pumping zinc from the cytoplasm out of the cell into
the lumen of an organelle.
■ Zinc transporter proteins (ZnT); transport zinc out of cells.
Metallothioneins:
- Cysteine-rich intracellular proteins that bind zinc.
- Detoxification of harmful metals and homeostasis of essential metals.
During acute inflammation monocytes secrete proinflammatory chemokines that stimulate ZIP3 in
the hepatocytes, thereby zinc is holded and stored by fusing it with metallothioneins. But, circulating
zinc ions also have the ability to decrease hyperfunctional monocytes and thus reduce a sharp
decline of zinc ions in the circulation.
Effects of zinc on intestinal transepithelial ion transport:
Zinc induces ion absorption in red blood cells in basal conditions, this is a direct pro-absorptive effect
on transepithelial ion transport in the intestine.
A number of organisms cause diarrhea by producing and secreting enterotoxins that affect the
absorption and/or of the enterocytes (cell in the intestinal lining) without causing acute
inflammation or mucosal destruction.
The enterotoxins trigger signaling molecules as cycling AMP and GMP (cAMP, cGMP) → activate
apical Cl- channels → secretion of Cl- ↑ and consequently of water.
In patients with HIV infection during zinc supplementation, zinc could act also in Ca2+-mediated
diarrhea.
Main intracellular pathways of intestinal ion secretion modulated by zinc:
Nutrition & Infectious Disease
AM_470816, January 2022.
Biological mechanisms
Zinc
Mechanisms of action of zinc in acute diarrhea, Canani et al. 2011
Zinc supplementation:
+ ↓ mean duration of acute diarrhea with 20% and persistent diarrhea with 15-30%.
+ ↓ diarrhea mortality with 23%.
+ ↓ diarrhea prevalence.
+ ↑ oral rehydration solution (ORS).
+ ↓ use of necessary antibiotics.
+ ↓ need for medical visits for acute diarrhea.
Mechanisms of zinc in acute diarrhea:
Zinc is not stored in the body, its level is determined by the balance of dietary intake, absorption and
losses.
The positive action by zinc in acute diarrhea:
1. Zinc regulates intestinal fluid (ion) transport and mucosal integrity.
a. Reduces intestinal permeability.
2. Zinc plays a substantive role in immunity.
3. Zinc can modify expression of genes encoding several zinc-dependent enzymes
(metalloproteases, cytokines and uroguanylin).
4. Zinc may modulate positively oxidative stress and inflammation.
5. Zinc is able to resist its potential loss in diarrhea.
6. Zinc stimulates red blood cell growth and differentiation.
The intestine is the first tissue confronted with zinc. Sufficient absorption of zinc from the small
intestine is essential for body health, but high levels of zinc are harmful. Zinc homeostasis is
coordinated via regulation by proteins involved in uptake, excretion and intracellular storage or
trafficking.
● Proteins = metallothioneins and transmembrane transporters.
○ Zinc regulated transporter (ZRT).
○ Iron-regulated transporter (RT)-like protein (ZIP).
■ Zinc uptake and transport into the cytoplasm.
■ Mobilize stored zinc by transporting the metal from an intracellular
compartment into the cytoplasm.
○ Cation diffusion facilitator (CDF) families.
, 2
■ Promotes zinc efflux by pumping zinc from the cytoplasm out of the cell into
the lumen of an organelle.
■ Zinc transporter proteins (ZnT); transport zinc out of cells.
Metallothioneins:
- Cysteine-rich intracellular proteins that bind zinc.
- Detoxification of harmful metals and homeostasis of essential metals.
During acute inflammation monocytes secrete proinflammatory chemokines that stimulate ZIP3 in
the hepatocytes, thereby zinc is holded and stored by fusing it with metallothioneins. But, circulating
zinc ions also have the ability to decrease hyperfunctional monocytes and thus reduce a sharp
decline of zinc ions in the circulation.
Effects of zinc on intestinal transepithelial ion transport:
Zinc induces ion absorption in red blood cells in basal conditions, this is a direct pro-absorptive effect
on transepithelial ion transport in the intestine.
A number of organisms cause diarrhea by producing and secreting enterotoxins that affect the
absorption and/or of the enterocytes (cell in the intestinal lining) without causing acute
inflammation or mucosal destruction.
The enterotoxins trigger signaling molecules as cycling AMP and GMP (cAMP, cGMP) → activate
apical Cl- channels → secretion of Cl- ↑ and consequently of water.
In patients with HIV infection during zinc supplementation, zinc could act also in Ca2+-mediated
diarrhea.
Main intracellular pathways of intestinal ion secretion modulated by zinc:
