Perspectives About Ascorbic Acid to Treat Inflammatory Bowel Diseases

Abstract

It is known that reactive oxygen species cause abnormal immune responses in the gut during inflammatory bowel diseases (IBD). Therefore, oxidative stress has been theorized as an agent of IBD development and antioxidant compounds such as vitamin C (L-ascorbic acid) have been studied as a new tool to treat IBD. Therefore, the potential of vitamin C to treat IBD was reviewed here as a critical discussion about this field and guide future research. Indeed, some preclinical studies have shown the beneficial effects of vitamin C in models of ulcerative colitis in mice and clinical and experimental findings have shown that deficiency in this vitamin is associated with the development of IBD and its worsening. The main mechanisms that may be involved in the activity of ascorbic acid in IBD include its well-established role as an antioxidant, but also others diversified actions. However, some experimental studies employed high doses of vitamin C and most of them did not perform dose-response curves and neither determined the minimum effective dose nor the ED₅₀. Allometric extrapolations were also not made. Also, clinical studies on the subject are still in their infancy. Therefore, it is suggested that the research agenda in this matter covers experimental studies that assess the effective, safe, and translational doses, as well as the appropriate administration route and its action mechanism. After that, robust clinical trials to increase knowledge about the role of ascorbic acid deficiency in IBD patients and the effects of their supplementation in these patients can be encouraged.

Keywords

ascorbic acid - colitis - inflammation - oxidative stress - reactive oxygen species - vitamin

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 20^th 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.

Conflict of interest

The authors declare that there is no conflict of interest.

^‡ The authors had an equal contribution: Ian Richard Lucena Andriolo, Larissa Venzon

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Publication History

Received: 28 December 2023

Accepted: 05 February 2024

Article published online:
11 March 2024