Introduction
Inflammatory Bowel Diseases (IBD), such as ulcerative colitis (UC) and Crohn's
disease (CD), are important public health problems [1]. These conditions adversely affect the quality of life of affected
individuals, particularly impacting the younger demographic, given that fewer than
20% of those afflicted with the ailment are aged 65 and older [2]. The etiology of inflammatory bowel diseases
remains unclear; however, it appears to be linked to genetically predisposed
individuals due to a compromised immune response against intestinal microorganisms,
to deregulate both innate and adaptive immunity [3].
The prevalence of IBD increased worldwide, mainly in industrialized countries in the
second half of the 20th century [4]. The highest prevalence is found in Europe and North America, in people
living in urban areas with a higher socioeconomic pattern [5]. Furthermore, the evolution of IBD
prevalence has been postulated into four epidemiological stages: Emergence,
Acceleration in Incidence, Compounding Prevalence, and Prevalence Equilibrium.
Following Kaplan and Windsor [6] developing
countries were in the Emergence stage, while newly industrialized countries were in
the Acceleration in Incidence stage, and Western regions were in the Compounding
Prevalence stage in 2020.
Nevertheless, the current therapy for treating IBD, among which the majority involves
the use of aminosalicylates, has its drawbacks. For example, there is a low
remission rate among patients using aminosalicylates, and those using steroid
anti-inflammatories experience their adverse effects. [7]. In addition, the cost associated with
biological therapy [8] is a limiting point.
Thus, there is a need to search for new treatments, which can be adjunctive or
complementary in the treatment of IBD.
The pharmacological potential of antioxidants has been reviewed and discussed [9]
[10],
including treating digestive diseases [11].
Vitamin C (L- ascorbic acid, [Fig. 1].) is a
very popular antioxidant compound, but many other important aspects of this
multifaceted compound have been studied [12].
Recent studies have shown that vitamin C may have beneficial effects on IBD and that
a deficiency of ascorbic acid leads to IBD development. However, the exact
mechanisms associated with the putative intestinal anti-inflammatory effects of
ascorbic acid are unknown.
Fig. 1 Ascorbic acid chemical structure.
In this context, studies ([Table 1]) were
gathered in this perspective as a narrative review to promote a critical discussion
on the potential of Vitamin C to treat IBD aiming to guide future research. To
retrieve articles related to this study, the descriptors previously consulted from
the DeCs (Health Sciences Descriptors) were used: “Ascorbic acid”, “Vitamin C”,
“inflammatory bowel diseases”, “colitis”, and “Crohn’s disease”, with the Boolean
operator AND in the following portals: PubMed, Virtual Health Library, Scielo, and
LILACS. The criteria for inclusion of the articles were: 1) publications in English,
Portuguese, or Spanish; and 2) original non-clinical or clinical studies. However,
reviews, letters to the editor, editorial, protocol for clinical study protocol for
systematic reviews, or data solely presented by poster presentation were
excluded.
Table 1 Studies about the role of Vitamin C in
IBD.
|
Title
|
Dose/Concentration
|
Administration route
|
Type of study/ Experimental model
|
Main results
|
References
|
|
Altered ascorbic acid status in the mucosa from inflammatory
bowel disease patients
|
Mucosal concentration of ascorbic acid
|
Not applicable
|
A clinical study using biopsies from (IBD) patients
|
The results of biopsies demonstrated reduced levels of ascorbic
acid and less antioxidant activity on non-inflamed mucosa. As
well, the inflamed biopsies showed ascorbic acid levels depleted
and harmed the antioxidant defense. However, the study indicates
that vitamin supplements are not effective to increase plasma
ascorbic acid levels
|
[14]
|
|
Ascorbic acid deficiency induces hepatic and intestinal
expression of inflammation-related genes irrespective of the
presence or absence of gut microbiota in ODS rats
|
Ascorbic acid-deficient diet ad libitum
|
Oral/Diet
|
An experimental model to investigate the relation between gut
microbiota and hepatic and intestinal inflammatory changes in
germ-free ODS rats
|
Ascorbic acid deficiency can promote inflammation in the liver
and intestine. This deficiency can increase hepatic mRNA levels
of APPs, SOCS3 and IL-1β, IL-6, and TNF.
|
[15]
|
|
Ascorbic acid deficiency increases hepatic expression of acute
phase proteins through the intestine-derived IL-6 and hepatic
STAT3 pathway in ODS rats
|
300 mg/kg
|
Oral/Diet
|
An experimental model to investigate the role of the intestine in
hepatic inflammation in ascorbic acid-deficient rats
|
It suggests that IL-6 was produced in the intestine due to
ascorbic acid deficiency. This IL-6 reaches the liver via the
portal vein, contributes to hepatic STAT3 activation and the
elevated expression of acute phase proteins.
|
[16]
|
|
Low Ascorbic Acid Intake Induces Inflammatory Changes in
Intestine and Liver of ODS Rats
|
30, 40 and 300 mg/kg
|
Oral/Diet
|
An experimental model to analyze the changes promoted by a diet
containing ascorbic acid in inflammatory markers in the
intestine and liver of ODS rats
|
Deficiency and Low intake of ascorbic acid can increase
inflammatory changes at intestine and liver of ODS rats.
|
[17]
|
|
Effect of vitamin C on azoxymethane (AOM)/dextran sulfate sodium
(DSS)-induced colitis-associated early colon cancer in mice
|
60 and 120 mg/kg
|
Oral/Gavage
|
An experimental model of early colon cancer associated with
colitis induced by Azoxymethane (AOM) and DSS in mice
|
The vitamin C decreased the disease activity and inhibited the
shortening of the colon and reduced histological damage. Also,
vitamin C supplementation suppressed mRNA levels of
pro-inflammatory cytokines and reduced the expression of the
proliferation markers.
|
[26]
|
|
Ameliorative Effect of High-Dose Vitamin C Administration on
Dextran Sulfate Sodium-Induced Colitis Mouse Model
|
4 g/kg
|
Intraperitoneal
|
An experimental study evaluating DSS- induced colitis in mice
|
Higher doses of Vitamin C improved inflammatory and oxidative
parameters, including IL-6, TNF, and hydrogen peroxide, and
increased free iron levels in the colon of mice exposed to
DSS.
|
[27]
|
|
Ascorbic Acid Derivative 2- O-β-d-Glucopyranosyl-l-Ascorbic Acid
from the Fruit of Lycium barbarum Modulates Microbiota in the
Small Intestine and Colon and Exerts an Immunomodulatory Effect
on Cyclophosphamide-Treated BALB/c Mice
|
300 mg/kg
|
Oral
|
An experimental study evaluating DSS- induced colitis in mice
|
2-O-β-d-Glucopyranosyl-l-ascorbic acid (AA-2βG) modulated
the intestinal microbiota and showed an immunomodulatory effect
in immunosuppressive mice exposed to DSS.
|
[28]
|
|
Vitamin C Enema Advances Induction of Remission in the Dextran
Sodium Sulfate-Induced Colitis Model in Rats
|
460 mg/kg
|
Enema
|
An experimental study evaluating DSS- induced colitis in mice
|
Vitamin C reduced the colitis signs and promoted mucosal healing.
In addition, ascorbic acid enema decreased COX-2 expression and
increased in the collagen type I expression, TGF-β and
TFF-3.
|
[29]
|
|
Vitamin C and B3 as new biomaterials to alter intestinal stem
cells
|
600 and 1200 μg/ml
|
Cells were incubated for 11 days with ascorbic acid.
|
In vitro study using four types of intestinal stem cells
(C3H Conv, C3H ASF, 129 ASF, and 129 ASF IL-10)
|
Vitamin C promoted the regulation of MUC-2 genes, which
demonstrates potential protection at the epithelial barrier due
to increased mucus secretion.
|
[30]
|
|
Combined effect of vitamin C and vitamin D3 on intestinal
epithelial barrier by regulating Notch signaling pathway
|
10, 100 and 200 mg/kg
|
Oral
|
An experimental study using DSS-induced colitis in guinea
pigs
|
Lower or higher doses of vitamin C combined with vitamin
D3 reduced the DSS-induced ulcerative colitis in
the guinea pig, increasing the expression of claudin-2 by
regulating Notch-1.
|
[31]
|
|
Preventive Effect of Vitamin C on Dextran Sulfate Sodium
(DSS)-Induced Colitis via the Regulation of IL-22 and IL-6
Production in Gulo(-/-) Mice
|
Ascorbic acid at 3.3 g/L
|
Oral drinking water
|
An experimental study using DSS-induced acute colitis in mice
|
Vitamin C improved colitis symptoms by regulating cytokines and
oxidative and inflammatory processes. However, the deficiency of
this vitamin is related to a decrease of IL-22, an increase of
IL-6, and the loss of mucin.
|
[32]
|
|
Ascorbic acid ameliorates oxidative stress and inflammation in
dextran sulfate sodium-induced ulcerative colitis in mice
|
100 mg/kg
|
Intraperitoneal
|
An experimental study using DSS- induced colitis in mice
|
The use of vitamin C improved the disease activity and reduce
inflammatory parameters such as myeloperoxidase activity and the
TNF, IL-1β, IL-6, and IL-17 levels. Also, the treatment
increased antioxidant defenses such as SOD, CAT, GPx, and
promoted the inhibition of NF- Κb activation, and iNOS and COX-2
expression
|
[25]
|
|
Vitamin C Deficiency in Inflammatory Bowel Disease: The Forgotten
Micronutrient
|
Vitamin C plasma level
|
Not applicable
|
A case study of 20 IBD patients.
|
IBD patients showed increased risk of vitamin C deficiency and
increased risk of having symptoms of this deficit.
|
[23]
|
|
Prevalence and factors associated with vitamin C deficiency in
inflammatory bowel disease
|
Vitamin C plasma level
|
Not applicable
|
A retrospective analysis of clinical, laboratory and endoscopic
data of IBD patients
|
Patients with inflammatory bowel disease showed elevated
inflammatory markers and patients with penetrating disease had
higher rates of vitamin C deficiency.
|
[24]
|
Vitamin C deficiency in IBD
Buffington and Doe [13] evaluated the
mucosal concentrations of reduced and total ascorbic acid and the redox status
in non-inflamed and inflamed mucosa using colonic biopsies from IBD patients.
The authors showed a decrease in reduced and total ascorbic acid content in
inflamed and non-inflamed intestinal mucosa from these patients. Furthermore,
the redox status of biopsies was significantly reduced in both diseases.
Moreover, the reduction of dehydroascorbic acid by reduced glutathione/
nicotinamide adenine dinucleotide phosphate (GSH/NADPH) dependent on
dehydroascorbic acid reductase was decreased in inflamed mucosa from UC
patients.
Unprecedented, Buffington and Doe [13]
demonstrated that even non-inflamed intestinal sites in patients suffering from
IBD are strongly oxidizing and that the oxidative stress from inflammatory cells
in inflamed sites contributes to the decrease of total and reduced ascorbate.
Therefore, the loss of the antioxidant buffering capacity would decrease the
capacity of the inflamed mucosa to prevent oxidative tissue damage and hinder
the recovery of the inflamed mucosa.
Kawade and colleagues [14] conducted an
experiment with Osteogenic Disorder Shionogi (ODS) rats, which are unable to
synthesize ascorbic acid, receiving vitamin C-deficient diets. Among the
results, ascorbic acid deficiency increased hepatic mRNA levels to acute phase
proteins (APPs) and some other inflammatory parameters. Furthermore, ascorbic
acid deficiency elevated intestinal IL-6 production in rats with normal
microbiota, inducing STAT3 (transducer and activator of transcription 3)
activation in the liver and increased APPS expression in the portal vein. These
findings pointed out that ascorbic acid deficiency can induce liver and
intestinal changes, and one of the possible mechanisms is that ascorbic acid
deficiency directly causes inflammatory changes in the intestine associated with
oxidative stress which leads to liver inflammation.
In another study, Kawade et al. [15]
investigated whether these hepatic and intestinal inflammatory changes by
ascorbic acid deficiency are induced in germ-free (GF) ODS rats. For this, male
specific pathogen-free (SPF) ODS rats and GF ODS rats were fed a diet containing
ascorbic acid at 600 mg/kg or an ascorbic acid-free diet. As expected, the
vitamin C deficiency elevated the hepatic expression of APPs and the intestinal
IL-6 and IL-1β mRNA levels in both SPF and GF rats. These findings agree with
the previously reported by Kawade and colleagues [14] but indicate that intestinal
inflammatory changes promoted by ascorbic acid deficiency do not involve the gut
microbiota.
Posteriorly, Kawade et al. [16] assessed
the inflammatory changes in ODS rats caused by low ascorbic acid intake and
compared them to ODS rats that were fed a diet supplemented with ascorbic acid
at a dose of 300 mg/kg. In this study, the authors performed a dose-response
curve with rats divided into groups treated with 0, 20, 40, and 300 mg/kg of
ascorbic acid for 22 days. Interestingly, the IL-1β and IL-6 mRNA levels were
higher in jejunal and ileal samples from rats that did not receive ascorbic acid
or that received 20 mg/kg than in the group treated with 300 mg/kg. Therefore,
these findings confirmed that inflammatory changes could occur in both ascorbic
acid deficient ODS rats and ODS rats with low ascorbic acid intake.
The mechanisms that explain the relationship between vitamin C deficiency and
susceptibility to intestinal inflammation remain unknown, even though much is
invested in the derangement of the redox tissue balance. On the other hand, it
is possible that intestinal inflammation also contributes to the reduction of
ascorbic acid absorption.
Intestinal inflammation and systemic bacterial infection have been associated
with an increase in the level of tumor necrosis factor (TNF) in the intestinal
mucosa and blood [17]
[18]. Notably, Subramanian et al. [19] showed that TNF inhibits intestinal
ascorbic acid uptake employing in vitro and in vivo systems, and this inhibitory
effect is mediated, at least in part, at the level of transcription of the gene
of the sodium-dependent vitamin C transporter-1 (SVCT-1) via the nuclear
transcription factor (NF-κB) pathway. Given that SVCT-1 is the major transporter
mediating intestinal vitamin C uptake, it is possible to infer that this is an
important mechanism to justify the decreased levels of ascorbic acid in the
intestinal mucosa of patients with IBD, thus reducing the tissue antioxidant
status.
In agreement with non-clinical results, micronutrient deficiencies have been
reported in patients with IBD. Indeed, Dunleavy et al. [20] reinforce that vitamin C deficiency
should be considered in IBD patients, particularly those with reduced fruit or
vegetable intake because signs and symptoms of scurvy occurred in 80% of the
cases followed up by the authors and the most common clinical features were
arthralgia (45%), dry brittle hair/hair loss (30%), pigmented rash (20%), and
gingivitis (15%).
Recently, Gordon et al. [21] studied
clinical, laboratory, and endoscopic data from 301 IBD patients in a
retrospective study. In their results, 21.6% of the patients had an ascorbic
acid deficiency, more specifically 24.4% of CD patients and 16.0% of UC
patients. Moreover, patients with elevated C-reactive protein (CRP) and fecal
calprotectin had significantly higher proportions of vitamin C deficiency
compared to those without. Different from Dunleavy et al. [20], no difference in the clinical symptoms
of scurvy was observed in those with vitamin C deficiency and those without.
However, the research of Gordon et al. [21] reinforced that vitamin C deficiency is common in IBD and that
patients with elevated inflammatory markers and severe disease had higher levels
of vitamin C deficiency.
Thus, clinical care for a patient with IBD needs to consider the levels of
vitamin C deficiency in this patient, as this has been identified as an
aggravating factor for the signs and symptoms of such diseases. In addition,
more clinical studies that test this correlation need to be performed, as well
as whether supplementation with ascorbic acid in usual doses could be beneficial
in this population.
Evidence about the beneficial effects of Vitamin C and its derivatives in
IBD
The effects of Vitamin C in colitis were first pointed out by Yan et al. [22] who found that intraperitoneal
administration of Vitamin C (100 mg/kg) for seven days in the Dextran Sodium Sulfate
(DSS)- induced colitis in mice improves the disease activity index, reducing the
histological damage. In the colon, the treatment significantly reduced inflammatory
parameters such as myeloperoxidase activity and the levels of TNF, IL-1β, IL-6, and
IL-17. In addition, ascorbic acid decreased the levels of malondialdehyde (MDA) and
increased the activity of superoxide dismutase (SOD), catalase (CAT), and
glutathione peroxidase (GPx), indicating the increase in antioxidant defenses
mitigating the damage caused by DSS. Furthermore, there was a regulation of
inflammation from the inhibition of NF-κB, nitric oxide synthase (iNOS), and
cyclooxygenase-2 (COX-2).
Next, the effect of oral treatment with Vitamin C (60 and 120 mg/kg) was evaluated by
Jeon et al. [23] in a model of early colon
cancer associated with colitis induced by Azoxymethane (AOM) and DSS in mice. Both
doses protected the colon from inflammation in early-stage colorectal cancer by
decreasing COX-2, microsomal prostaglandin E synthase-2 (mPGES-2), TNF, and IL-1β
and IL-6. Vitamin C administration decreased the total number of tumors and the
expression of PCNA mRNA, an important marker of tumor growth. Regarding the
composition of the gut microbiome, vitamin C improved inflammation related to the
levels of Lactococcus, a probiotic that acts on the intestinal barrier.
Kondo et al. [24] also evaluated the effect of
Vitamin C in the DSS-induced colitis model, however, unlike other studies, this one
used a high dose (4 g/kg) intraperitoneally for seven days. Despite the use of
higher doses, Vitamin C also improved colitis, by decreasing plasma levels of IL-6,
TNF, and hydrogen peroxide and increasing free iron levels. Together, these data
demonstrate an improvement in inflammatory parameters in inflamed colonic
mucosa.
The study of Kondo et al. [24] was the research
that tested the highest dose of ascorbic acid, 4 g/kg in mice, and the allometric
extrapolation of this dose for a human is 549.8 mg/kg, reaching approximately 38 g
by day for a human weighing 70 kg, remarkably too high a dose to apply in a clinical
study. Thus, non-clinical studies must investigate doses that allow translation to
be performed in clinical studies.
Huang et al. [25], used cyclophosphamide to
make BALB/c mice immunosuppressive and 2-O-β-d-Glucopyranosyl-l-ascorbic acid
(AA-2βG) was used to intervene in these immunosuppressive mice. The AA-2βG is a
natural and stable ascorbic acid derivative isolated from the fruits of Lycium
barbarum. In this study, the administration of AA-2βG promoted changes in
the immune system, accompanied by weight loss, reduction in colon length, and
changes in hepatic function markers. However, all these changes were reversed in
varying degrees by AA-2βG intervention. Notably, AA-2βG could change both mouse
colonic and small-intestinal microbiota, indicating that AA-2βG could modulate
microbiota in the small intestine and colon and exert an immunomodulatory effect.
Given these results, further studies to evaluate the effect of this ascorbic acid
derivative in a colitis model were needed.
Unlike other studies, Honjo et al. [26]
evaluated the effects of a Vitamin C solution (460 mg/kg/day) by enema in rats with
1% DSS-induced colitis over ten days. Animals treated with Vitamin C obtained a
reduction in the clinical symptoms by the decrease in COX-2 expression and an
increase in collagen type-I expression. In addition, it was also possible to observe
that the treatment by this route promoted mucosal healing through a decrease in the
number of neutrophils, and suppression of the release of activated macrophages.
Likewise, an increase in the expression of transforming growth factor β (TGF-β) and
trefoil factor 3 (TFF-3), important for collagen synthesis and tissue recovery,
respectively, was observed. These data indicate that Vitamin C is effective in
promoting epithelial regeneration in the colonic mucosa, as well as maintaining
remission even when given by enema.
Qi and colleagues [27] performed an in vitro
study to assess the potential of Vitamin C (600 μg/mL) in four types of intestinal
stem cells (C3H Conv, C3H ASF, 129 ASF, and 129 ASF IL-10) which are isolated from
mice bearing different microbiota. Interestingly, the authors used the organoid
technique and incubated Vitamin C in a minigut. The incubation with Vitamin C
(600 μg/mL and 1,200 μg/mL) upregulated the mRNA to MUC2 (an important glycoprotein
that makes up the intestinal barrier) in 129 ASF and C3H Conv. It suggests that
large amounts of glycoprotein may be produced after adding high concentrations of
vitamin C. Since inflammatory bowel disease depletes the MUC2 levels, this
antioxidant may help restore mucosal health due to an increase in the production of
glycoproteins and mucus, consequently.
The effect of vitamin C on the intestinal epithelial barrier was evaluated by Qiu et
al. [28] using a model of colitis induced by
2% DSS in guinea pigs. The animals were pre-treated with low (10 mg/kg), medium
(100 mg/kg), and high doses (200 mg/kg) of Vitamin C. However, these groups also
received vitamin D concomitantly. It was observed that the combined treatment of
Vitamin C and D3 was more efficient when compared to Vitamin D3 alone. The average
dose did not show any difference and maintained the tight junctions of the
intestinal epithelium. The combination of these two vitamins showed a protective
role in the intestinal mucosa barrier through tissue repair caused by the increase
in Notch-1 expression and decrease in intestinal permeability from the inhibition of
claudin-2 expression. However, this study did not evaluate the effects of each
vitamin in an isolated manner, and did not measure the disease activity index, which
is an important score to analyze the severity of colitis in animals.
Recently, the effect of Vitamin C on the development and progression of colitis was
evaluated in mice that cannot synthesize Vitamin C, called Gulo (-/-). In
experiments performed by Jo et al. [29], these
animals were treated with Vitamin C (3.3 g/L) discontinuously for three weeks.
Vitamin C deficiency in these mice was associated with an increase in the severity
of colitis. The authors described that Gulo (-/-) mice presented an increase in
inflammatory and oxidative parameters, including the loss of mucin in the colon, a
decrease in IL-22, and an increase in IL-6. These data showed that Vitamin C has the
potential to treat IBD, regulating the secretion of cytokines and in turn the
inflammatory processes. However, a limiting point in this research was the
administration route because the intake of ascorbic acid in the drinking water does
not reveal accuracy in the amount of this compound ingested by each animal.
The facts presented above demonstrate that Vitamin C's usefulness in IBD extends
beyond its role as a free radical scavenger. Ascorbate's anti-inflammatory
activity may therefore be mediated by several pathways. Gęgotek and Skrzydlewska
[30] reviewed ascorbate's methods of
action, including activation of intracellular antioxidant systems, effect on the
NFκB/TNF pathway, and apoptosis. In addition, ascorbate can interact with
small-molecule antioxidants such tocopherol, glutathione, and thioredoxin. This
connection can also boost biosynthesis and activate antioxidant enzymes like SOD,
CAT, and GPx [30]. Gęgotek and Skrzydlewska
[30] pointed out that ascorbate stimulates
the transcriptional activity of nuclear factor, erythroid 2-like 2 (Nrf2), redox
effector factor 1 (Ref-[1]), and activator
protein 1 (AP-1), enabling the production of genes encoding antioxidant proteins.
Given these possible activities and the results discussed here, it is easy to
conclude that Vitamin C has the potential to treat IBD, even if only as an
adjuvant.
While vitamin C is generally safe and well-tolerated at recommended dietary levels,
excessive use (5 to 10 g/day) might cause gastrointestinal problems such as brief
osmotic diarrhea, stomach pain, and bloating. In the absence of harmful effects,
vitamin C is considered safe even at high doses [31].
Concerns have also been raised about the potential pro-oxidant effects of high doses
of vitamin C. It is suggested that ascorbic acid's pro-oxidative activity is
linked to its interaction with transition metal ions, primarily iron and copper, and
occurs under conditions of high millimolar ascorbate concentration. Vitamin C
promotes the reduction of free transition metal ions, resulting in the production of
oxygen radicals. Furthermore, reduced iron ions combine with hydrogen peroxide to
create reactive hydroxyl radicals or peroxide ions, which occurs in the presence of
oxygen [32].
However, despite the large quantity of evidence confirming the pro-oxidative
capabilities of vitamin C in the presence of transition metals in vitro, convincing,
and unequivocal evidence of such activity in vivo is absent [32]. Thus, additional investigations are still
needed to deepen the discussion on the pro-oxidant effects of vitamin C in
neutralizing its antioxidant effects in the context of inflammatory bowel
diseases.
Perspectives and conclusion
The pathogenesis of IBD is closely related to oxidative stress due to an intense
inflammatory insult and the use of vitamin C in IBD, as well as the role of its
deficiency, is currently being investigated. Therefore, this perspective
reviewed the pharmacological potential of this vitamin to treat and prevent
these diseases. In this approach, Vitamin C may help the integrity of the
intestinal barrier under the inflammatory stimulus, and enhance intestinal
mucosal barrier function, while reducing oxidative stress.
However, a point that is worthy of attention in non-clinical studies presented
here is the dose used, which must be adequate for extrapolation in humans.
Studies suggest that a daily intake of vitamin C from 100 to 400 mg promotes
100% of the bioavailability and reaches a maximum serum content of 70–80 µmol/L
[33]
[34]. In addition, when the intake of vitamin C exceeds 500 mg/day, a
further increase in plasma concentration is inhibited and when doses greater
than 1,000 mg of ascorbic acid are administered in a single dose the
bioavailability can decrease by 30% [34].
This occurs because when 500–1,000 mg of vitamin C are administered orally, the
intestinal transporter quickly achieves its maximal saturation, while the
vitamin is progressively excreted by urine [34]
[35].
Another important point, which has not yet been studied, is the impact of the pH
of the ascorbic acid solution used in the experimental studies. Since the pH of
an ascorbic acid solution is very low it is expected that its administration can
reduce the pH at the injection site, intestine, and colon if an enema was used.
So, further studies need to address this bias and evaluate the use of buffered
ascorbic acid solutions.
In this sense, future experimental studies using mice should explore the effects
of vitamin C in doses ranging from 41.56–51.96 mg/kg, which are allometrically
determined doses based on discussed above. As some reviewed studies found
beneficial effects in doses close to these and given the evidence that the
deficit of this vitamin is a harmful factor during IBD, this perspective
encourages further studies in this field.
Furthermore, the determination of the specific mechanism, administration route,
and ideal treatment methods needs to be investigated. Clinical studies could be
carried out after filling these gaps.
