ARTICLE
Auteur(s) : Lusliany J Rondón, Yves Rayssiguier, Andrzej Mazur
INRA, Unité de Nutrition Humaine, Centre de Recherche en
Nutrition Humaine d’Auvergne, Theix, 63122 St Genès Champanelle,
France
Numerous animal and human studies performed in our and other
laboratories have pointed to the beneficial effects of complex
fermentable carbohydrates on mineral absorption, particularly in
improving Mg2+ absorption in distal parts of the
intestine and hence ameliorating Mg2+ status [1-10].
Various mechanisms at the origin of this increased Mg2+
absorption in the large intestine have been proposed but not yet
completely elucidated. In particular, in addition to the passive
transport, the identity and role of specific transporters is not
well known in the large intestine. Recently identified proteins -
the transient receptor potential melastatin 6 and 7 (TRPM6 and
TRPM7) channels have been shown to be essential for whole body and
cellular Mg2+ homeostasis and to be regulated by dietary
Mg2+ levels [11-15]. TRPM6 and TRPM7 potentially
contribute to the maintenance of Mg2+ homeostasis since
TRPM6 transports Mg2+ across the apical membrane of the
epithelial cells in kidney and large intestine [11, 16] and the
ubiquitously expressed TRPM7 regulates cellular Mg2+
uptake [12]. A strong link has been demonstrated between TRPM6
expression and Mg2+ status [15, 17].
Based on these data, we designed a study to determine the
modulation of TRPM6 and TRPM7 expression in the kidney and large
intestine by long-chain inulin ingestion in C57B16J mice.
Inulin-type fructans were selected for this study because these
fermentable carbohydrates have been shown to efficiently increase
Mg2+ absorption from large intestine [9, 18]
Materials and methods
Animals and diets
Twenty four male C57B16J mice four months old were purchased from
Janvier (Le Genest-Saint-Isle, France). During the first week of
the experiment, the mice were fed a control diet (for composition
see table 1). Then, the mice were
randomly divided into two groups and over the following two weeks,
each group received one of two diets: a control diet (the same as
initially) or a diet enriched with long-chain inulin by
substituting 10% of starch in the control diet with an equivalent
quantity of long chain inulin from chicory (Inulin
BeneoTM HP, generous gift from Beneo-Orafti, Tienen,
Belgium) (table 1). The Mg2+
and Ca2+ content of the diets were 0.1% (wt/wt) and 0.4%
(wt/wt) respectively. All diets were prepared in our laboratory.
Distilled water and food were provided ad libitum. During the
experiment, mice were housed one per cage (wire-bottomed to limit
coprophagy) and maintained in a temperature-controlled room (22°C),
with a 12-hour light/dark cycle. The last three days of the
experiment the mice were housed in metabolic cages and food and
water intake as well as urine and feces excretion were recorded
daily. The animals were maintained and handled according to the
recommendations of the Institutional Ethics Committee (INRA, Theix,
France), in accordance with decree no. 87-848.
Table 1 Composition of experimental diets.
|
Diets
|
Control (g/kg)
|
Long-chain Inulin (g/kg)
|
|
Ingredients:
|
|
|
|
Casein
|
200
|
200
|
|
Corn starch
|
650
|
585
|
|
Inulin
|
0
|
65
|
|
Fiber alphacel
|
50
|
50
|
|
Corn oil
|
50
|
50
|
|
Mineral mix*
|
35
|
35
|
|
Vitamins AIN 93A†
|
10
|
10
|
|
DL-methionine
|
3
|
3
|
|
Choline
|
2
|
2
|
|
MgO
|
1.67
|
1.67
|
*Mineral mix composition (g/kg): calcium phosphate
dibasic 500, sodium chloride 74, potassium citrate monohydrate 220,
potassium sulphate 52, manganese carbonate 3.5, ferric citrate 6,
zinc carbonate 0.53, cupric carbonate 0.1, sodium selenite 0.0033,
chromium potassium sulphate 0.55, sucrose 135.3.
†AIN vitamin mixture (mg/kg): thiamine hydrochloride
600, riboflavin 600, pyridoxine hydrochloride 700, nicotinic acid
3000, D-calcium panthothenate 1600, folic acid 200, D-biotin 20,
cyanocobalamin (vitamin B12) 1, retinyl palmitate
(vitamin A) premix 1 600, DL-α-tocopherolalcium acetate 20 000,
cholecalciferol (vitamin D3) 250, menaquinone (vitamin
K2) 50, sucrose, finely powdered 972.9 g.
Sampling procedures
At the end of the experiment, the animals were sacrificed and blood
(collected from the heart), bones (tibia), kidney, cecum and colon
were harvested. The cecum, complete with content, was removed and
weighed (total cecum weight). The caecal walls were cleaned with
PBS, blotted on filter paper and weighed (caecal wall weight). All
tissues (except bones) were cleaned from the blood and immediately
frozen in liquid nitrogen and then stored at - 80°C until
analyses. Bones were cleaned from muscles and stored at 4°C.
Plasma and Erythrocyte collection
Blood from the heart was collected in heparin-containing tubes.
Plasma was obtained by centrifugation (10 min, 3 500 rpm,
4°C). For erythrocyte Mg2+ determination, erythrocytes
were washed three times with saline solution and then hemolyzed in
water-containing tubes. Both were frozen at - 20°C for later
analysis.
Mineral Analysis
Plasma, erythrocyte and urine Mg2+ concentrations were
determined after dilution with 0.1% (w/v) LaCl3 as
previously described [19, 20]. For tibia and feces the samples were
weighed, dry-ashed (10 hrs at 500°C) and dissolved with
concentrated HNO3 (14M) and H2O2
(30%), on a heating plate until complete discoloration was
achieved. The mineral solution was adjusted to 10 ml with distilled
water and diluted with 0.1% LaCl3. In the overall
samples, Mg2+ content was determined by atomic
absorption spectrophotometry (using a Perkin-Elmer AA800, Quebec,
Canada) at 285 nm.
Creatinine analysis
For creatinine measurement urine was diluted 20 times, and the
creatinine concentration was determined using an automated chemical
analysis kit, following the manufacturer’s instructions (Kone
Progress Plus, Kone Instruments Oy, Espoo, Finland).
Quantitative Real-Time PCR analysis
Total RNA was extracted from complete segments of kidney, cecum and
colon using the RNeasy Mini Kit (QIAGEN, Courtaboeuf, France),
following the manufacturer’s protocol. Two μg of RNA was used for
reverse transcriptase reactions with the Moloney murine leukemia
virus Ready-To-Go You-Prime First-Strand Beads (Amersham, Orsay,
France), following the manufacturer’s protocol. The mRNA levels of
TRPM6 and TRPM7 were determined by SYBR Green quantitative
real-time PCR in kidney, cecum and colon, using a
Mastercycler® ep realplex system (Eppendorf AG, Hamburg,
Germany). The mRNA level of the hypoxanthine-guanine phosphoribosyl
transferase (HPRT) was used as a control (considered as a house
keeping gene). Primers for the target genes used were obtained as
previously described [15].
Immunohistochemistry (IHC)
Cryosections (7-μm thick) of
periodate-lysine-paraformaldehyde-fixed kidney were stained as
previously described [21-23]. Antiserum against TRPM6 [1:1,500
diluted with TNB buffer (TNT buffer containing blocking reagent)]
(courtesy from R. J. Bindels, Nijmegen Centre for Molecular Life
Sciences, The Netherlands) [22] (as primary antibody) and
biotin-labeled, affinity-purified, goat anti-guinea pig IgG
(1:2000; Sigma Chemical Co., St. Louis, MO) (as secondary antibody)
were used. Micrographs of the cortex regions were acquired with an
Olympus fluorescence microscope (Reichert-Jung Polyvar, Vienna,
Austria) equipped with a Sony XC-71P CCD RGB digital camera
(Kenmore, WA, US).
Calculations and Statistical analysis
Mg2+ absorption in this study was expressed as “net
absorption”, which was calculated by substracting the
Mg2+ intake (mg/d) from the Mg2+ excretion in
feces (mg/d).
The apparent absorption rate as “absorption rate” was calculated
by multiplying the Mg2+ net absorption (mg/d) to 100 and
dividing it by Mg2+ intake (mg/d), the results are
expressed as %.
Values are expressed as mean ± SE. Differences between the
groups were tested by the Student’s t-test. Differences were
considered significant at p < 0.05. The analyses were performed
with the SigmaStat 2.0 Statistical software (SPSS Inc, Chicago
Illinois, USA).
Results
Animal weight and cecum weight
There were no significant differences in final body masses between
the two groups studied (p = 0.14) (table
2). However, mice fed the long-chain inulin supplemented
diet showed a significant increase in whole cecum weight (+ 143.9 ±
16.6%, p < 0.001), cecum content weight (+ 95.08 ± 26.3%, p =
0.003) and cecum wall weight (+ 265.7 ± 22.4%, p < 0.001) when
compared to the control diet group (table
2).
Table 2 Body weight and cecum weight in male mice fed a
control or long-chain inulin supplemented diet for two
weeks†.
|
Control (n = 12)
|
Long-chain Inulin (n = 12)
|
|
Mean
|
SE
|
Mean
|
SE
|
|
Mouse weight (g)
|
27.09
|
0.37
|
26.37
|
0.20
|
|
Whole cecum weight (g)
|
0.24
|
0.02
|
0.58
|
0.04
|
|
Cecum content weight (g)
|
0.13
|
0.01
|
0.26**
|
0.03
|
|
Wall cecum weight (g)
|
0.1
|
0.01
|
0.32
|
0.02
|
†For details of diet and procedures, see “materials and
methods”.
Intestinal absorption, urine excretion and balance
of Mg2+
The parameters studied concerning Mg2+ balance
evaluation are presented in table 3. In
the present study mice were fed ad libitum and we did not observe
any difference in total food intake of inulin supplementation (not
shown), thus Mg2+ intake was similar in both groups
(table 3). Fecal Mg2+
excretion was shown to be significantly lower in mice fed the
inulin supplemented diet (- 27.0 ± 2.58%, p < 0.001) when
compared to the control diet mice. Nevertheless, the calculated net
Mg2+ absorption did not vary between the groups.
A significant increase of Mg2+ absorption rate is
evidenced in mice fed the inulin supplemented diet (+ 9.1 ± 1.1%, p
< 0.001) when compared to the control group (table 3).
Twenty four hours urine Mg2+ excretion was not
significantly different in mice fed the inulin supplemented diet
from that of controls. However, when correcting urine
Mg2+ excretion by creatinine, we evidenced an increased
urine Mg2+ excretion (+ 15.7% ± 6.2%) in mice fed the
inulin supplemented diet as compared to controls (p = 0.04) (table 3). A slight but not significant
increase of net Mg2+ balance was observed in mice fed
the inulin supplemented diet (table
3).
Table 3 Intake, faecal excretion, absorption, urinary
excretion and net balance of Mg2+ in male mice fed a
control or long-chain inulin supplemented diet for 2
weeks†.
|
Control (n = 12)
|
Long-chain Inulin (n = 12)
|
|
Mean
|
SE
|
Mean
|
SE
|
|
Mg2+ Intake (mg/d)
|
3.32
|
0.14
|
3.19
|
0.12
|
|
Mg2+ Faecal excretion (mg/d)
|
0.84
|
0.01
|
0.61
|
0.02
|
|
Mg2+ Net absorption (mg/d)
|
2.43
|
0.14
|
2.58
|
0.12
|
|
Absorption rate (% intake)
|
73.95
|
1.1
|
80.7
|
0.8
|
|
Mg2+ Urinary excretion (mg/d)
|
0.78
|
0.05
|
0.84
|
0.04
|
|
Creatinine excretion (mg/d)
|
0.52
|
0.03
|
0.48
|
0.03
|
|
Mg2+ Urinary excretion/creatinine (μg/mg creatinine)
|
1523.7
|
61.0
|
1762.4*
|
94.5
|
|
Mg2+ Net balance (mg/d)
|
1.66
|
0.14
|
1.74
|
0.08
|
†For details of diet and procedures, see “materials and
methods”.
Blood and bone Mg2+ content
Plasma and RBC Mg2+ concentrations did not show any
significant differences between the two groups studied (table 4). However, bone Mg2+ content
was significantly higher (+ 11.78 ± 1.65%, p < 0.007) in mice
fed the inulin supplemented diet when compared to the control diet
mice.
Table 4 Plasma, erythrocytes and bone Mg2+
content in male mice fed a control or long-chain inulin
supplemented diet for 2 weeks†.
|
Control (n = 12)
|
Long-chain Inulin (n = 12)
|
|
Mean
|
SE
|
Mean
|
SE
|
|
Plasma Mg2+ (mmol/L)
|
0.79
|
0.04
|
0.81
|
0.03
|
|
Erythrocytes Mg2+ (mmol/L)
|
2.08
|
0.05
|
2.11
|
0.02
|
|
Bone Mg2+ (mmol/Kg)
|
103.2
|
3.87
|
115.6**
|
1.71
|
†For details of diet and procedures, see “materials and
methods”.
Effect of dietary inulin on TRPM6 and TRPM7
expression in kidney and large intestine
Mice fed the inulin supplemented diet had a lower kidney TRPM6
expression than those fed a control diet (- 21.2 ± 7%, p = 0.04)
(figure 1A). IHC
analysis of the kidneys confirmed that the inulin supplemented mice
had lower levels of TRPM6 protein (figure 1B). Long-chain
inulin supplementation did not significantly affect TRPM7
expression in the kidney (figure 1C).
The inulin supplemented diet induced no significant changes
TRPM6 expression in cecum, however, a significantly higher TRPM7
expression (+ 26 ± 8%, p = 0.03) was observed in mice fed the
inulin supplemented diet when compared to the control group (figure 2A, B).
Concerning the colon, no significant difference in TRPM6 and
TRPM7 expression was observed in the ascendant colon when comparing
the two groups (figure
2C, D). Nonetheless, inulin supplementation induced TRPM6
(+ 61.8 ± 11%, p = 0.003) and TRPM7 (+ 29.4 ± 8.6%, p = 0.01)
expression in the descendent colon (figure 2E, F).
Discussion
Here we demonstrate that complex fermentable carbohydrate intake
(in this case long-chain inulin) improves Mg2+
absorption and consequently Mg2+ stores in the body, as
shown by a higher Mg2+ content in bones. The consumption
of this high-fiber diet and the subsequent Mg2+
metabolism modifications are also accompanied by modulations in the
expression of the two newly discovered Mg2+ channels,
TRPM6 and TRPM7, in the kidney and large intestine.
In this study, several indices point to an improved
Mg2+ absorption in animals fed an inulin-rich diet. This
is in agreement with previously published work showing concomitant
improvement of the Mg2+ absorption rate, decreased
Mg2+ fecal excretion [3, 5-8] and Mg2+
retention [5, 10, 24] by inulin ingestion. As has been observed by
others [6], a slight but not significant increase was observed in
Mg2+ net balances. In this study, the difficulty of
observing a significant effect of inulin on Mg2+ balance
is probably related to the short period of mineral balance and to
the variability of measured parameters. However, as we and others
observe [7, 25] the increased Mg2+ absorption is
translated into increased Mg2+ bone stores. In
concordance with previously published studies [2, 6, 24, 26, 27],
no changes were observed in plasma and erythrocyte Mg2+
levels. This undoubtedly results from a homeostatic adaptation
because animals in the present study were fed a Mg2+
adequate diet.
The increased Mg2+ absorption results from the effect
of the high-fiber diet on the large intestine. The inulin-rich diet
in the present study, and as has been described before led to a
cecal weight rise, due to the increase in cecal content and cecal
wall weight [24, 27, 28]. In fact, the inulin-type fructans are non
digestible oligosaccharides [29-31]. Because of their β-(2→1)
fructosyl-fructose linkages, inulin-type fructans resist enzymatic
hydrolysis in small intestine and are fermented in the large
intestine. The mechanisms involved in the increased Mg2+
absorption in the intestine are still a matter of discussion.
Acidification of the luminal contents and greater solubilization by
SCFA production [32], hypertrophy of the intestinal mucosa [6, 18],
and increased paracellular and transcellular transport may lead to
an increase in Mg2+ uptake by the intestinal cells
[32-34].
Interestingly, in this study, it is evidenced for the first time
that stimulated Mg2+ absorption, and consequently
Mg2+ status, by supplementation with complex fermentable
carbohydrates is accompanied by upregulation of TRPM6 and TRPM7
expression in the distal parts of the intestine. Similarly,
Groenestege et al. [15] observed that Mg2+
supplementation induced TRPM6 expression in the colon.
These observations point to the possible regulation of TRPM6
expression by complex fermentable carbohydrates and thus an induced
high Mg2+ status, however, it is not clear if this
effect is direct or indirect. It is known that the saturable
absorptive process functions only at very low dietary
Mg2+ intakes in the small intestine, but this regulation
is not well known in the large intestine [35]. Another mechanism
for this could be acidification of the lumen induced by SCFA
production. In fact it has been shown that these two channels are
pH sensitive [36] but the effect of on their expression is not
known.
In this study we also observed that TRPM7 expression was induced
in the cecum and colon of inulin-fed mice. In addition to
mechanisms discussed above, this may have a link with the strong
proliferative effect of dietary fiber [2, 37]. Considering that
TRPM7 is a Mg2+-permeant channel responsible for
transcellular Mg2+ transport and an important mediator
of cell growth [38, 39] it can be hypothesized that TRPM7
upregulation could be a response for increased cell proliferation
and growth.
In the present work we have also shown that neither TRPM6 nor
TRPM7 kidney expression was lower in inulin-fed mice, as compared
to controls. The downregulation of TRPM6 expression is an expected
homeostatic response to the increased Mg2+ absorption.
This is in agreement with results from studies on Mg2+
supplemented animals [15, 17]. It is also well known that complex
fermentable carbohydrates may also stimulate Ca2+
absorption [32]. The impact of this effect on different gene
expression, such as TRPM6 and TRPM7, is not defined in this
particular condition.
In conclusion, inulin ingestion leads to an improved
Mg2+ absorption and modulates TRPM6 and TRPM7 expression
in the distal parts of the large intestine. The downregulation of
TRPM6 in the kidney supports the beneficial effect of dietary
fibers on Mg2+ absorption and stores. The origins and
roles of the modulation of TRPM6 and TRPM7 expression in the large
intestine are not known. Changes in Mg2+ fluxes, lower
pH of the digestive content and increased cell proliferation could
be involved.
Acknowledgments
The excellent technical assistance of D. Bayle, S. Thien and J.C.
Tressol is gratefully acknowledged.
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