Mechanism and Regulation of Transport of
Water-Soluble Vitamins: Cellular and Molecular Aspects
Hamid M. Said
University of California School of Medicine, Irvine
&
VA Medical Center, Long Beach
USA
Hamid Said has nothing to disclose
THANK YOU!
Acknowledgements
Current and Previous Postdocs
P Srinivasan, PhD
W Tipton, MD
A Ghosal, PhD
S Khorchid, MD
A Biswas, PhD
D Dunning, MD
S Senthilkumar, PhD
D Dyer, PhD
S Subramanya, PhD
E McCloud, MD
T Sekar, PhD
K Balamurugan, PhD
F Bukhari, MD
J Redling, PhD
L Vogeley, MD
V Subramanian, PhD
L Mee, PhD
C Kumar, PhD
Z Mohammed, MD
N Chatterjee, PhD
A Balasubramanien, PhD
R Ul-Haq, MD
S Nabokina, PhD
T Nguyen, PhD
”We thank the NIH and the DVA for their kind support”
THANK YOU!
Acknowledgements
Collaborators
W Strum (Scripps)
D Hollander (UCI)
C Wagner (Vanderbilt)
D Horne (Vanderbilt)
F Ghishan (Vanderbilt)
I Parker (UCI)
J Marchant (U Minn)
T Ma (UNM)
P Dudeja (UIC)
N Vaziri (UCI)
N Yanagawa UCLA)
C Halsted (UCD)
J Sze (Albert Einstein U)
K Maedler (U Bremen)
G Hecht (UIC)
V Subramanian (UCI)
S Pandol (UCLA)
H Tsukamoto (USC)
”We thank the NIH and the DVA for their kind support”
Molecular/C
ellular
Biology
Nutrition
Mechanism
of Disease
Physiology of
Vitamin
Transport
Microbiology
Toxicology/
Pharmacolog
y
*Water – Soluble Vitamins: An Introduction*
1) Water-soluble vitamins are structurally and functionally unrelated organic
compounds that share the common features of being essential for normal cellular
function, growth and development.
O
O
H
O
O
Cl
N
N
N
Pyridoxin
e
N
N
O
N
H
H
HOO
C
N
O
Biotin
Folic acid
O
N
OH
H
N
HOOC
H
O
N
O
O
S
O
N
H
N
OH
O H 3C
N
CH 3
O
Cl
N
N
O
O
N
O
N
O
S
N
N
O
Pantothenic acid
Riboflavi
n
Thiamin
O
O
O
O
O
O
O
N
O
Ascorbic Acid
Niacin
*Water-soluble vitamins: An introduction* -----continues
2)
Humans cannot synthesize water-soluble vitamins (exception:
some endogenous synthesis of niacin), and thus, must obtain these
micronutrients from exogenous sources.
3)
Deficiency of water-soluble vitamins leads to a variety of clinical
abnormalities that range from anemia, growth retardation, congenital
deformities, and neurological disorders.
-Vitamin deficiency is of two types:
i) Systemic (global) deficiency
ii) Tissue-specific (localized) deficiency (e. g., ThiaminResponsive Megaloblastic Anemia)
4) Optimizing body homeostasis of water-soluble vitamins, on the
other hand, brings about positive health benefits
*Folate:
-Prevention of neural-tube defects
-Decrease risk of Alzheimer Disease
-Decrease risk of the development of certain types of
cancer (e.g. cervical cancer)
*Thiamin:
-Has the potential of preventing diabeticretinopathy, nephropathy, and vascular damage
Why study transport of water-soluble vitamins?
The case for the intestine
The case for the intestine---continues
1) The human body cannot synthesize these micronutrients nor
can it store them in significant quantities; it relies on uninterrupted
absorption in the gut.
2) Water-soluble vitamins exist in minute quantities in the diet, and thus,
efficient mechanisms are needed for their extraction from the moving
food digest in gut lumen.
3) A variety of conditions interfere with normal intestinal absorption of
water-soluble vitamins.
Examples of the conditions that are associated
with impairment in intestinal absorption of
water-soluble vitamins
• Congenital defect in the specific uptake system (e.g., mutations in
PCFT leading to Hereditary Folate Malabsorption Syndrome)
• Congenital defects in the enzyme that hydrolyzes non-absorbable
dietary forms of the vitamin into the absorbable form (e.g.,
Biotinidase - deficiency)
• Chronic alcohol consumption
• Bacterial infection (enteropathogenic E. coli, EPEC)
• Drug-interaction
• G.I. diseases (e.g., IBD); intestinal resection
Why study transport of water-soluble vitamins?
The case for the intestine----continues
4) Optimization of water-soluble vitamin bioavailability and body
homeostasis via optimized absorption improves health and prevents
certain diseases.
Sources of water- soluble vitamins
Two sources are available to the human gut:
1) Dietary
2) Bacterial (i. e., the normal microflora of the large intestine)
Sources of water- soluble vitamins----dietary source
-
This is where we were in the early 1980s
-Early studies on the mechanisms involved in the intestinal absorption of
(many) water-soluble vitamins have concluded that these events occur via
simple diffusion.
-This came out as a result of the use of non-physiological/non-optimal
experimental conditions. Further, when evidence for the existence of a specific
mechanism was observed, e. g., saturability, it was attributed to intracellular
metabolism, limited solubility of the vitamin (due to existence of an acidic
microclimate at the surface of the small intestine), etc.
-The above erroneous belief has significantly delayed progress in the field.
Thus, very limited studies were attempted to investigate if and how these
absorptive events are regulated, whether they are affected by certain disease
conditions or by drug interaction, and whether certain human genetic diseases
are due to defects in vitamin transporters.
This is where we are in 2012
Involvement of specific, carrier-mediated and highly regulated transport systems in the
absorption of dietary water-soluble vitamins in the human small intestine
Lumen
Ascorbic Acid
Riboflavin Pyridoxine
Thiamine
Biotin/
Pantothanate
Folate
THTR2
SVCT 1
SVCT 2
Blood
RFT2
RFT1
??
THTR1
THTR-1
SMVT
??
PCFT
MDR-3
Niacin
Sources of water- soluble vitamins----dietary source
Absorption of certain dietary water-soluble vitamins in the small intestine is sitespecific; However adaptation (induction) occur following resection
Sham-operated
Resected
Am J Clin Nutr 47:75-9, 1988
Sources of water- soluble vitamins
1)
Dietary source
1) Bacterial source, i. e., the normal microflora of the large
intestine.
Humans have more bacteria in their GI tract
than they have cells
Human Body
1012
Cells
1014
Bacteria
GI Tract
* There are over 1,800 different species of bacteria in our GI tract identified so far.
Microbial distribution in the GI tract
Aerobes
Stomach
Small Intestine
Duodenum
<102 cfu/mL
pH, 1-2
101-3 cfu/mL
pH, 6-7
Jejunum
103-4 cfu/mL
pH, 6-7
Ileum
107-9 cfu/mL
pH, 6-7
Colon
<1010-12 cfu/mL
pH, 5-7
Anaerobes
According to Mayo Clin Proc 2008; 83:460-469
Happy VS unhappy intestinal microflora
vitamin
vitamin
Adopted from Gastroenterology 2009;136:2015-2031
-Bacterial source-----continues
Enterotypes of the human gut microbiome
Arumugam et al, Nature 473:174-180, May 2011
*Human microbiota can be functionally classified into three distinct
enterotypes:
-Enterotype A:
Has an over-represented Biotin (vitamin B7; vitamin H)
biosynthetic pathway
-Enterotype B:
Has an over-represented Thiamin (vitamin B1) biosynthetic
pathway
-Enterotype C:
Has an over-represented Haem biosynthetic pathway
Functional differences between enterotypes (Nature 473:174-80, 2011)
a.
b.
c.
Four enzymes in the biotin biosynthesis pathway are overrepresented in enterotype 1.
Four enzymes in thiamine biosynthesis pathway are overrepresented enterotype 2.
Six enzymes in the haem biosynthesis pathway are overrepresented in enterotype 3.
Arumugam M, Raes J, Pelletier E, Ehrlich DS , Bork P et. al. “Enterotypes of the human nature in microbiome.” Nature. 2011 A473(7346):174-80pr 20. Doi: 10.1038.
Science
Bacteria Divide People Into 3
Types, Scientists Say
By Carl Zimmer
Published: April 20, 2011
“The ability of the microbiota to synthesize vitamins has been
known for many years, but this was considered unimportant for
nutritional health, because it was assumed they were
malabsorbed and lost in stools. However, the recent
demonstration of specific transporters for folate (24), biotin (25),
thiamine (26), riboflavin (27), and pyridoxine (28) in the colonic
mucosa has forced us to reconsider our view.”
O”Keefe et al, J. Nutr. 139: 2044-2048, 2009
Identification of carrier-mediated transport systems for water-soluble
vitamins in the human colon
Studies with colonic tissue from human organ donors and with cultured colonocytes
Lumen
Niacin
Riboflavin Pyridoxine
Thiamine
Biotin/
Pantothanic acid
Folate
THTR2
??
RFT2
??
THTR1
SMVT
RFC
TPP
RFT1
THTR-1
MDR-3
Blood
Said et al 1995- present
Implications for the identification of efficient mechanisms for absorption
of water-soluble vitamins in the human colon are:
1) They indicate that the bacterially synthesized vitamins are
nutritionally available to the host and contribute toward overall vitamin
homeostasis, especially toward the cellular nutrition and health of the
local colonocytes.
2) Provides physiological basis for important nutritional and clinical
observations.
Intestinal absorption of water-soluble vitamins
I.
1)
Physiological aspects
Studies using a variety of intestinal preparations (intact tissue in
vitro and in vivo, purified isolated brush border and basolateral
membrane vesicles, cultured intestinal epithelial cell models) have
shown that the trans-epithelial and the trans-membrane transport
events of water-soluble vitamins are all specific and carriermediated in nature.
2. Energetics of intestinal transport processes of water-soluble vitamins:
i) The case for biotin
Na+
Na+
Biotin-Biotin
hSMV
T
Brush Border Membrane
Biotin-
Basolateral Membrane
2. Energetics of intestinal transport processes of water-soluble vitamins:
ii) The case with folate
H+
H+
Folate-Folate
PCFT
Brush Border Membrane
Folate-
Basolateral Membrane
II. Molecular aspects
1) Molecular identity of many of the transporters of water-soluble vitamins have been determined
by cloning.
Predicted topology of hTHTR-1
Asn63
Ser49
Ser186
1
2
3
4
5
Asn314
6
7
Ser292
Thr22
Thr158
NH2
Ser222
Thr223
Asn414
8
129
10
11
12
Ser357
Thr360
Thr477
COOH
Thr17
Cytosol
PKC phosphorylation sites
PKA phosphorylation site
N-glycosylation sites
2. The 5’ regulatory region (promoters) of a number of the genes that
encode transporters of water-soluble vitamins have also been cloned and
characterized both in vitro and in vivo.
SLC19A2 (hTHTR-1)-Promoter
SLC19A3 (hTHTR-2)-Promoter
Luciferase
Luciferase
Reidling and Said, AJP, 285:C633-41, 2003
Nabokina
and Said, AJP 287:G822-9, 2004
.
In vivo validation of promoter activity in transgenic mice.
SLC19A2 Promoter
SLC19A3 Promoter
Luciferase
Luciferase
In vivo validation of promoter activity of the C. elegans folate transporter cfolt1 (fused to GFP) at the integrative whole animal level
AJP 293:C670-681, 2007
-
3) Relative contribution of water-soluble vitamin transporters
toward carrier-mediated uptake processes
i) Gene-specific knock down
ii) Gene-specific knockout
i) Gene-specific knock down (siRNA)
Relative contributions of hTHTR-1 and hTHTR-2 toward carrier-mediated thiamin uptake by
human intestinal epithelial Caco-2 cells
0.06
0.04
0.03
0.02
0.01
Scrambled
siRNA hTHTR-1
+ hTHTR-2
siRNA hTHTR-2
siRNA hTHTR-1
0
Control
Carrier-mediated 3H-Thiamine Uptake
(pmol/mg protein/3 min)
0.05
AJP 286:G491-G498, 2003
ii) Gene-specific knockout: the mouse model
Intestinal thiamin absorption in THTR-2 KO mouse model: In vivo perfusion
P < 0.01
Gastroenterology 138:1802-1809, 2010
Intestinal thiamin absorption in THTR-1 KO mouse model: In vivo perfusion
Relative expression of THTR-2 in THTR-1-/- mouse intestine
500
Wt
THTR-1 -/-
THTR-2
400
_ -actin
300
200
100
0
Wt
THTR-1 -/-
II.
Cell Biology Aspects
1) Live cell confocal imaging showed expression of hTHTR-1 at both the apical and
basolateral membrane domains (A, B), while that of hTHTR-2 (C, D) only at the
apical membrane domain of polarized human epithelial cells.
JBC 278:3976-84, 2003; JBC 281:5233-45, 2006
2. Targeting of water-soluble vitamin transporters to the apical
membrane domain of polarized intestinal/renal epithelia involves
specific motifs (signals) that are embodied in the individual
polypeptide: The story with the human folate transporter, PCFT.
AJP 294:C233-240, 2008
3. A predicted β-turn motif between TMD 2 and 3 of PCFT was found
using a β-Turn Predictive Algorithm Program: Progressive mutagenesis
of amino acids within this region is predicted to disrupt formation of the
β-turn.
A
xz
xy
hPCFT-YFP
hPCFT[GRR112114AAA]-YFP
3H-Folic acid uptake(pmol/mg protein/3min)
4. Disrupting the β-turn between TMD 2 and 3 of the PCFT polypeptide leads
to: A) intracellular retention of the mutant protein in polarized epithelial cells,
and 3) inhibition in the induction of folate uptake.
0.8
B
0.6
0.4
0.2
0
Control
hPCFT-YFP
hPCFT[GRR112114AAA]-YFP
5. Different mutants of hTHTR-1 found in patients with TRMA display
different cellular expression phenotypes.
a
Clin Sci (Lond). 113: 93-102, 2007
6. Intracellular movement of hTHTR -1 & 2 (fused to GFP) in living
human epithelial cells involves trafficking vesicles (A), whose
movement depends on an intact microtubule network (B).
A. Control
B. Nocodazol
JBC 278:3976-84, 2003; JBC 281:5233-45, 2006
7. Specific accessory proteins interact with membrane transporters of watersoluble vitamins and modulate their function, stability, and membrane
expression: Studies using bacterial and yeast two-hybrid system to screen
human intestinal cDNA libraries.
hTHTR1
hSMVT
hRFC
Tspan1
PDZD11
AJP 301:G808-13, 2011
AJP 300:G561-7, 2010
Dynein
light chain
road block
AJP 297:G480-7, 2009
III. Regulatory aspects of the intestinal absorption
processes of water-soluble vitamins
A) Adaptive - regulation by dietary (extracellular) substrate levels.
B)
Developmental - regulation during early stages of life.
C)
Differentiation - dependent regulation.
D) Regulation by specific intracellular protein kinase-mediated
pathways.
Adaptive - regulation of the intestinal biotin
absorption process
1) Dietary-induced biotin deficiency in rats leads to a specific induction
in intestinal biotin uptake, while dietary over-supplementation of
biotin leads to suppression of the uptake.
Vmax (pmol/mg
protein/20 sec)
Apparent Km
(µM)
Control
2.2
14.5
Biotin - Deficiency
5.4
11.1
Biotin - Over
Supplementation (X100)
1.1
14.0
Condition
AJP 256:G306-311, 1989
2) Similarly, maintaining the human-derived intestinal epithelial Caco-2
and HuTu-80 cells under biotin-deficient conditions leads to a specific
induction in biotin uptake and in the level of expression of the hSMVT
protein and mRNA.
*p < 0.01
AJP 292:G275-281, 2007
3) The effect of biotin deficiency on biotin uptake by Caco-2 and HuTu80 cells was not mediated via changes in mRNA stability of hSMVT.
RNA decay rate assay (i.e., RNA stability assay)
4) The induction in hSMVT mRNA levels in Caco-2 and HuTu-80 cells in
biotin deficiency is mediated, at least in part, via transcriptional mechanism(s).
hSMVT (SLC5A6)- promoter Luciferase
*p < 0.01
5) The biotin-deficiency responsive region of the hSMVT P1 is located in a
specific (103 bp) region between -130 and -233
6) A KLF4 cis-regulatory element in the biotin deficiency-responsive region of
the hSMVT P1 is responsible for mediating the biotin deficiency effect on the
hSMVT promoter.
Integrative aspects of the adaptive - regulation of vitamin transport
by substrate level:
Whole animal studies utilizing living C. elegans
1) Folate over-supplementation inhibits folate uptake (A), as well as the level
of expression of the cfolt-1 mRNA (B) in adult C. elegans
1.0
0.5
0
*p < 0.01 for both
B
Relativefolt-1 mRNA expression
overb-actin (in folds)
[3H] -folic acid uptake
(fmol/5 animals/5 min)
A
2
1
0
AJP 293:C670-681, 2007
2) Folate over-supplementation suppresses the activity of the cfolt-1 promoter
(fused to GFP) in living C. elegans.
Over-supplemented
Level of GFP fluorescence in the C. elegans intestine
GFP fluorescence intensity (%)
Deficient
100
50
0
(p < 0.01)
Developmental - regulation of intestinal and renal
thiamin uptake process
1. Carrier-mediated uptake of [3H]-Thiamine by mouse
intestinal BBMV during development was found to decrease
with maturation (suckling > weanling > adult).
2. A decrease in levels of the mouse endogenous
mTHTR-1 and mTHTR-2 protein and mRNA (suckling
> weanling > adult) was observed in the intestine during
developmental maturtion using Western analysis and
qPCR
3. Luciferase activity in the intestine of transgenic mice
carrying the human SLC19A2 or SLC19A3 promoters showed
a decrease in activity with maturation
(suckling > weanling > adult).
4. Carrier-mediated uptake of [3H]-thiamine by mouse kidney
BBMV during development was found to decrease with
maturation (suckling > weanling > adult).
5. A decrease in levels of the mouse endogenous
mTHTR-1 and mTHTR-2 protein and mRNA (suckling
> weanling > adult) was observed in the kidney during
developmental maturation using Western analysis and
qPCR
6. Luciferase activity in the kidney of transgenic mice
carrying the human SLC19A2 or SLC19A3 promoters showed
a decrease in activity with maturation
(suckling > weanling > adult).
IV. Mechanism of Disease
A) Effect of chronic alcohol use on intestinal (and renal) absorption of
water-soluble vitamins.
A) Effect of Enteropathogenic Escherichia coli (EPEC) on intestinal
absorption of water-soluble vitamins.
A) Thiamin-Responsive Megaloblastic Anemia (TRMA):
-Why only certain tissues are affected?
-How mutations in hTHTR-1 in patients with TRMA impair thiamin
uptake.
Mechanism of Disease-----continues
Effect of chronic alcohol feeding/exposure
on cellular and molecular parameters of the
intestinal (and renal) thiamin absorption
process
- Thiamin deficiency and sub-optimal levels are highly prevalent in
chronic alcoholics (up to 75%) and leads to serious clinical
consequences (e.g., Wernicke-Korsakoff syndrome).
- We examined the physiological and molecular parameters of the
intestinal (and renal) thiamin absorption process that are affected by
chronic alcohol consumption.
1. Chronic alcohol feeding of rats leads to a significant inhibition in
thiamin uptake by jejunal BBMV.
*p < 0.01 for all
AJP 299:G23-31, 2010
2. Chronic alcohol feeding of rats also leads to a significant inhibition
in thiamin uptake by jejunal BLMV.
*p < 0.01
3. Chronic alcohol feeding of rats also inhibits thiamin uptake in the
colon, suggesting possible impairment in uptake of the bacterially
synthesized biotin.
*p < 0.01
4. Chronic alcohol feeding of rats inhibits the expression of THTR-1 (but not
THTR-2) protein at the intestinal BBM.
*p < 0.01
5. Chronic alcohol feeding of rats inhibits mRNA expression of
THTR-1 (but not THTR-2) in the jejunum.
*p < 0.01
7. Chronic alcohol exposure (72 hr) of cultured human-derived intestinal
epithelial HuTu-80 cells leads to significant inhibition in thiamin uptake.
*p < 0.01
8. Chronic alcohol exposure (72 hr) of HuTu-80 cells leads to a
significant inhibition in the level of expression of the hTHTR-1 and
hTHTR-2 proteins.
*p < 0.01 for both
9. Chronic alcohol exposure (72 hr) of HuTu-80 cells also leads to significant
inhibition in the expression of the hTHTR-1 and hTHTR-2 mRNA.
*p < 0.01 for both
10. Effect of chronic alcohol exposure (72 hr) of human intestinal epithelial
HuTu-80 cells on the activity of hTHTR-1 (SLC19A2) and hTHTR-2 (SLC19A3)
promoters.
hTHTR-1 (SLC19A2)-Promoter)
*p < 0.01 for both
Luciferase
hTHTR-2 (SLC19A3)-Promoter)
Luciferase
11. Chronic alcohol feeding of transgenic mice carrying the SLC19A2 (hTHTR1)- and SLC19A3 (hTHTR-2)- promoters leads to a significant inhibition
in activity of the human promoters in the jejunum.
SLC19A2 Promoter
Luciferase
SLC19A2 Promoter
120
Relative Luciferase activity
120
Relative luciferase activity
Luciferase
100
80
60
40
20
100
80
60
40
20
0
0
Control
(Pair-fed)
*p < 0.01 for both
Alcohol
Control
(Pair-fed)
Alcohol
Effect of chronic alcohol feeding on physiological and molecular
parameters of renal thiamin transport
1) Effect on [3H]thiamin uptake by rat renal BBMV
2) Effect of chronic alcohol feeding on [3H]thiamin uptake
by rat renal BLMV
3) Effect of chronic alcohol feeding on level of expression of THTR1 and THTR-2 in kidney cortex of rats fed alcohol chronically
4) Effect of chronic alcohol feeding of rats on level of expression of
heterogeneous nuclear RNA (hnRNA) of the Slc19a2 & Slc19a3 genes
5) Chronic alcohol feeding of transgenic mice carrying the SLC19A2 and
SLC19A3 promoters leads to a significant inhibition
in activity of the human promoters in the renal cortex.
SLC19A2 Promoter
SLC19A2 Promoter
Luciferase
120
_
60
*
0
Control
(Pair-fed)
* p < 0.01
Relative SLC19A3 luciferase activity
(% of control)
Relative SLC19A2 luciferase activity
(% of control)
120
Luciferase
60
*
0
Alcohol
Control
(Pair-fed)
Alcohol
Effect of Enteropathogenic Escherichia coli (EPEC) infection
and intestinal thiamin uptake
1) EPEC, a gram-negative food-borne pathogen, infects human intestine
leading to significant morbidity and mortality, especially in infants.
Infection with EPEC is common in developing countries; it also
occurs in developed countries as a result of food contamination and
improper hygiene.
2) Whereas diarrhea is a major consequence of EPEC infection,
malnutrition also occurs especially in severe and prolonged cases.
3) Pathogenicity of EPEC involves attachment of the bacteria to
enterocytes, effacement in the microvilli, and delivery of effector
molecules via a syringe-like type III secretion system (TTSS).
4) Nothing is known about the effect of EPEC infection on intestinal
absorption of thiamin. Addressing this issue of physiological and
nutritional importance since humans have limited capability to store
thiamin, and thus, prolonged and severe infection with EPEC may
negatively impact normal body homeostasis leading to further
aggravation of the health status of the infected hosts (many of whom
are already nutritionally compromised).
Results
1) EPEC treatment of Caco-2 cells leads to a significant inhibition in thiamine uptake.
Uptake was performed immediately after treatment (A) or 6 hr later (B).
A
*p < 0.01 for both
B
AJP 297: G825-833. 2009
2) The inhibition in thiamin uptake by Caco-2 cells caused by EPEC (100 MOI)
increases as a function of the pretreatment (contact) time.
3) The inhibition in thiamin uptake by Caco-2 cells requires live EPEC.
*p < 0.01
4) EPEC inhibits thiamin uptake at both the nanomolar range (mediated
by hTHTR-2) and the micromolar range (mediated by hTHTR-1).
5) EPEC reduces the level of expression of the hTHTR-1 and hTHTR-2
proteins at the apical membrane domain of confluent Caco-2 monolayers.
*p < 0.01 for both
Biotinylation assay
6) EPEC inhibits the level of mRNA expression of hTHTR-1 (A),
and hTHTR-2 (B).
A
*p < 0.01 for both
B
7) EPEC, but not the non pathogenic E. coli, suppresses the activity of the human
SLC19A2 and SLC19A3 promoters in Caco-2 cells.
*p < 0.01 for both
8) Functional type III secretion system (TTSS) of EPEC is required for the
bacteria to inhibit thiamin uptake by Caco-2 cells.
*p < 0.01
“Few Take Home Messages”
1) Absorption of dietary water-soluble vitamins in the small intestine
involves specific, and regulated carrier-mediated systems.
2) The water-soluble vitamins synthesized by the normal microflora of
the large intestine can be absorbed via efficient carrier-mediated
systems, and thus, contribute to the overall body homeostasis of these
micronutrients, and especially toward the cellular nutrition and health of
the local colonocytes.
3) A variety of conditions/factors interfere with the intestinal
absorption of water-soluble vitamins; this may lead to a compromise in
their normal body homeostasis.
Thank you