Inflammatory bowel disease (IBD) is a chronic condition that affects the relapsing gastrointestinal tract, with periods of exacerbation and remission [1
]. Its main forms of presentation are ulcerative colitis (UC) and Crohn’s disease (CD). Its etiopathogenesis is believed to be due to a loss of tolerance to the intestinal microbiota associated with marked immune responses and environmental factors in genetically susceptible individuals [3
The conventional approach to IBD aims to induce and maintain clinical remission free of corticosteroids, thus minimizing the impact on quality of life [4
]. Currently, corticosteroids, sulfasalazine, mesalamine (5-ASA), and immunomodulators are treatment options for patients with IBD. However, it is worth mentioning that conventional treatments cause numerous side effects due to a marked immune response suppression, which negatively impacts the quality of life of these individuals [5
]. Studies indicate that a substantial proportion of patients do not fully respond to the conventional treatments for IBD, or that its efficacy wanes over time [7
]. Corticosteroid resistance/refractoriness rates range from 8.9% to 25% in individuals with IBD [8
Identifying safe and effective therapeutic agents for complementary therapies remains an unmet need for these patients. Curcuma longa
is a plant from the Zingiberaceae family that is native to India and Southeast Asia and is well known in Asian cultures. Known commonly as turmeric, it has long been used in Ayurvedic medicine to treat inflammatory diseases. It has attracted the attention of researchers because of its compounds, called curcuminoid pigments, which are polyphenols with important medicinal properties [12
Curcumin is the main pharmacologically active curcuminoid pigment in turmeric. It acts by modulating various cell-signaling pathways, producing anti-inflammatory, anti-tumor, anti-oxidant, and immunomodulatory effects [14
]. The main components of commercial turmeric are curcumin I (77%), curcumin II (~17%), and curcumin III (~3%), with only 2–5% of the powdered seasoning consisting of curcumin [15
]. The mechanism of its anti-inflammatory action deemed to be the most relevant is the inhibition of NF-κB, by blocking IκB kinase, which prevents cytokine-mediated phosphorylation and the degradation of IκB, an NF-κB inhibitor, thereby inhibiting the expression of pro-inflammatory cytokines (IL-1, IL-6, and TNF) [16
Curcumin also acts by inhibiting the activity of pro-inflammatory proteins such as activated protein-1, peroxisome proliferator-activated receptor gamma, signal translators, and transcription activators, as well as the expression of b-catenin, cyclooxygenase 2, 5-lipoxygenase, and inducible nitric oxide synthase isoform, which play a key role in inflammation [17
]. In addition, it acts by blocking the binding between TNF-α and its receptor, preventing the perpetuation of inflammation caused by this cytokine [18
This systematic review aims to analyze the studies published so far, to review the positive or negative effects of the use of curcumin, and to determine whether it is safe and effective as a complementary therapy in the management of IBD, offering fewer side effects than conventional therapies.
This systematic review included six RCT studies [28
] that compared the use of curcumin as a complementary therapy given in combination with 5-ASA in patients with UC. In four of the five studies included, there was a significant improvement in the clinical response with curcumin, allied with no serious AEs. Five studies [28
] reported that curcumin was able to reduce the symptoms of the disease, achieve clinical remission, and/or prevent relapse when used as a complementary therapy to mesalamine.
The study by Kedia et al. [32
], using lower doses of oral capsule curcumin than other studies [28
], which used 2000 mg/day, 3000 mg/day and 1500 mg/day, respectively, was the only study in which no significant difference was found between clinical remission and the endoscopic remission rates in the intervention and placebo group (UCDAI). It is understood that very low doses of curcumin may not achieve the desired effect unless administered locally in the form of an enema, as in the study by Singla et al. [29
], or in more bioavailable nanoformulations such as SinaCurcumin®
, used in the study by Masoodi et al. [31
The curcuminoid gelatin capsule is dissolved in the acidic environment of the stomach and the nanomicelles are released, which are stable for up to 6 h and are absorbed into the intestine [34
]. Importantly, curcumin absorption may be lower when it is administered orally than when it is administered in an enema when it comes to IBD, due to the direct delivery to the site-of-action. Therefore, RCTs should also explore the enema administration of curcumin in order to define the most effective route of administration, since only one RCT [29
] has evaluated this route so far.
Most of the studies did not describe the purity of the curcumin used. Singla et al. [29
] only described the percentage of curcumin in the extract used, while Lang et al. [30
] reported using Cur-Cure®
(a preparation containing 95% pure curcumin); the other four studies did not provide any such information. Any comparison of this study with others that do not describe the composition of the capsule is hampered by the fact that it is not known exactly what the intervention groups in the other studies were given. An important caveat is that capsule curcumin found on pharmaceutical and nutritional store shelves often contains numerous chemical additives, as does the turmeric powder sold commercially as a spice.
Only Hanai et al. reported some mild AEs, such as abdominal distension, nausea and an increased number of bowel movements in a Japanese population. These non-specific symptoms may be related to factors not controlled by the researchers, such as dietary factors (lactose, fodmaps, gluten) and the presence of associated functional diseases, such as IBS (irritable bowel syndrome). Therefore, it cannot be confirmed that these symptoms experienced by only 7 of 89 patients are related to curcumin use.
The Food and Drug Administration states that curcumin is “generally recognized as safe” and has no known toxic effects. According to the Food and Agriculture Organization of the United NationsFAO/WHO Joint Food Additives Expert Committee and the European Food Safety Authority, the acceptable daily intake of curcumin is 0–3 mg/kg/day [35
]. Lao et al. [37
] administered 500–12,000 mg of curcumin (95% standardized extract of curcumin) in healthy subjects to examine its maximum tolerance and safety dose, and found that an ingestion of up to 12 g/day of curcumin brought about no ill effects. Based on this recommendation, a healthy 70 kg individual could consume 4–10 g turmeric powder, or two tablespoons, per day, which is well above the usual consumption in western countries.
The bioavailability of orally ingested unformulated curcumin is low. High doses of curcumin (2–4 g) are usually required to improve bioavailability due to its hydrophobic nature, but recently, in addition to nanoformulations, studies have been conducted into a self-micro emulsifying drug delivery system (SMEDDS) for curcumin: hydrophilic drug droplets that can diffuse easily into the bloodstream, resulting in higher intraintestinal concentrations than when conventional curcumin is used [26
]. Although SMEDDS has been used successfully in a study, the current evidence on its usefulness is still scant. In a single-blind crossover study on healthy adults, the bioavailability of the curcumin micellar formulation was found to be 185 times higher than that of the same dose of unformulated curcumin [38
]. Despite promising results concerning curcumin micellization, the study was conducted on healthy subjects; there are no studies on individuals with IBD. This nanometer-sized drug delivery system could become an effective strategy for treating IBD [39
In a recent systematic review, Jamwal [40
] compared the pharmacokinetic effect of different curcumin formulations in healthy subjects. The formulations that exhibited a better bioavailability than unformulated curcumin were: NovaSol®
, and LongVida®
, which were found to achieve a 185, 136, and 100 times higher bioavailability, respectively. The studies cited report promising preliminary results from in vitro and in vivo experimental trials by developing specific curcumin delivery systems, protecting against rapid degradation, and targeting the inflamed colon. However, it is not yet known which would be the best option from those among the most bioavailable formulations for treating IBD.
Another strategy for improving bioavailability, the use of piperine (a component of black pepper, Piper nigrum
, and long pepper, Piper longum
) as an adjunct to curcumin, has been described for a long time. Shoba et al. [41
] demonstrated that 20 mg of piperine administered concomitantly with 2 g of curcumin increases the bioavailability of curcumin 20-fold in humans. One experimental study by Li et al. [42
], using CUR-PIP-SMEDDS (an emulsified curcumin and piperine formulation), reported that the administration of this formulation through an enema in rats had an effect similar to 5-ASA in maintaining remission in dextran sulfate sodium DSS-induced colitis. As a substance that inhibits the metabolism of several active compounds, piperine may cause toxicity when associated with some drugs [43
]. Moreover, the gastrointestinal transit time has been reported to be significantly reduced by the consumption of 20 mg of piperine by rats [44
], which in individuals with IBD may not be beneficial.
Despite the small number of studies, the average intervention time that appears to be sufficient to present the outcomes is four to eight weeks. However, this time may vary according to the pharmaceutical formulation used. Shorter intervention periods seem to be associated with more bioavailable curcumin formulations.
It is noteworthy that phytochemicals are not evenly distributed among plant parts: the curcumin content of mother rhizomes is higher than the curcumin content of primary and secondary rhizomes, both fresh and dried [45
]. The seasonality, altitude, temperature, solar incidence, water availability, and nutrient content in the soil may also alter the presence or concentration of phytochemicals [46
]. Post-harvest processing for the production of dry powder results in a reduced curcumin content in the mother’s rhizomes and fingers, as it is easily decomposed when exposed to light and is sensitive to high temperatures (>60 °C) [47
In addition, the pre-harvest management, specifically cultivation practices, also play a significant role in the quantity and quality of turmeric phytochemicals. In the study by Choudhury et al. [47
], the application of nitrogen, phosphorus, potassium (NPK)inorganic fertilizers resulted in a 31–43% increase in the curcumin content of the mother rhizome compared to the non-application of NPK fertilizers. Similarly, the application of organic fertilizers (pig and poultry manure) also increased the curcumin content of mother rhizomes by 18–36%. All the factors mentioned may have influenced the curcumin content used in the studies and, consequently, the results obtained.
Efforts are currently being made by different research groups to improve curcumin’s bioavailability, and further efforts will be needed to answer questions related to curcumin therapy in IBD. New well-designed, long-term RCTs with a large enough sample size to demonstrate clinically significant effects and to determine the efficacy of new pharmaceutical formulations are required.
Considering the six trials included, five of them demonstrated good results related to the clinical and/or endoscopic remission/response. The findings suggest that curcumin may be a safe, effective therapy for maintaining or inducing UC remission when administered with standard treatments; the same cannot be said for CD, due to the absence of RCTs with a low risk of bias when investigating patients with this condition. However, based on these findings it is not yet possible to establish the best protocol for the use of curcumin, considering that the determination of the therapeutic dose and the duration of treatment depend on the identification of the ideal pharmaceutical formulation, which has not yet been determined for this population.
We recognize that this study inevitably has some limitations and so its results should be interpreted with caution. Firstly, it was based on only six RCTs, all with a relatively small sample size. Additionally, although the studies included were well designed, randomized, placebo-controlled studies that rated highly on the Jadad scale [22
] and in the Cochrane Handbook bias analysis [21
], they used different doses and formulations of curcumin and different administration routes. This itself may add bias to the results of our study.