1. Review
Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease
Angélica M. González Sánchez – University of Puerto Rico at Cayey
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Abstract
Inflammatory bowel disease (IBD) is one of the most serious diseases of the
gastrointestinal tract. Although its causes are not well known, it has been linked to a deregulation
on the molecules that control stress response in the intestinal tissue. These uncontrolled
molecules cause severe inflammation in the intestine as an immune response to stress. Curcumin
is a natural herb-derived compound commonly used for cooking and as an organic remedy for
common illnesses. Recent researches have shown a relationship between curcumin and IBD. It
has been concluded that curcumin has a direct effect on regulating the molecules that are
decontrolled in IBD intestinal tissue. The reasons why curcumin does this are not thoroughly
understood by the scientific community, but they have been linked to its antioxidant properties,
as well as to its capacity to bind to several proteins and enzymes. More research needs to be done
in order to fully comprehend curcumin’s behavior, to establish its safe dosage, to increase its
bioavailability and to prove it as a viable therapeutic alternative for IBD.
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Keywords: Inflammatory Bowel Disease (IBD) / curcumin / stress-response pathways / NF-κB
/ cytokines / chemokines / white blood cells / p38 MAPK / MPO / antioxidant / bioavailability.
Introduction
Inflammatory bowel disease (IBD) is an causes a stress response and leads to IBD, it is
acute syndrome on which the gastrointestinal thought that it arises from uncontrolled
wall suffers severe inflammation. Its causes pathways of molecules related to the immune
remain unknown, although recent investigations system (Salh et al., 2003).
have linked it to genetic, environmental and Intestinal mucosa has several functions,
immunological factors, which are the most mostly on absorbing nutrients and on protecting
prominent ones (Pithadia and Jain, 2011). Even the organism from infections. When swollen,
though it is a rare condition statistically (Jian et this mucosal doesn’t work as it’s supposed to,
al., 2005), its implications on people’s quality of leading to mayor complications. Some of these
life make it a huge and relevant field for complications can be reflected as severe
investigations. symptoms such as abdominal pain, ulcers,
Despite origins of IBD are uncertain, its bleeding diarrhea, weight loss due to the
main source is the inflammation of the intestinal diarrhea, anemia, between others. Other
mucosa. Because inflammation is almost always conditions have also been associated to side
linked to an immune response, analysis of IBD effects of IBD, such as osteoporosis, arthritis,
has focused on stress-response causes. Since skin rashes, liver disease and colon cancer. IBD
there haven’t been found any pathogen that rarely causes death on its own, but some of its
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2. Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease
complications, such as extreme diarrhea and the herb Curcuma longa. It can take many
anemia can cause weakness of the organism, chemical structures, called curcuminoids
which can make it susceptible to other illnesses. (Anand et al., 2008), but its main constituents
IBD can be divided into two main types: always are several hydroxyl radicals (HO),
Ulcerative colitis and Crohn’s disease. Both of hydroxide ions (OH-), oxides (O2), methyl
these share the characteristic inflammation of (CH3) and methoxides (CH3O-) groups which
the intestinal mucosa but they differ on the join together forming rings which make the
specific areas of the intestinal tract that they compound a hydrophobic polyphenol. It has
affect. While Ulcerative colitis affects only the been traditionally used in foods as a component
colon, Crohn’s disease can affect any area from of the spice turmeric and as an herbal remedy
the gastrointestinal tract, especially the lowest for several illnesses because polyphenols are
part of the small intestine, called the ileum. known to be natural antioxidants (Rajasekaran,
Actual treatments for IBD focus on 2011). Since its first documented use as a
lessening and delaying the symptoms of the medical treatment in 1937 (Srivastava et al.,
condition, but not necessarily on effectively 2011), curcumin has revealed antioxidant, anti-
transposing the causes of the inflammation, inflammatory, antimicrobial and anti-
which will be described further on. Most of carcinogenic activities (Anand et al., 2008).
them consist on anti-inflammatory medicines Exactly how curcumin accomplishes these
and immune-suppressors, such as duties is not well known. However, it has been
aminosalicylates, monoclonal antibodies, linked to its ability to bind to several proteins
corticosteroids, antibiotics, between others. and regulatory enzymes and to inhibit oxidation
These treatments have been improving in the chain reactions which can cause damage or
last decades by the development of targeted death to the cell by activating multiple
biologic therapies, the optimization of older intracellular signaling pathways (Srivastava et
therapies, and a better understanding of the al., 2011). That way, curcumin regulates the
mucosal immune system involved in the presence of several molecules, which in turn
pathogenesis of IBD (Pithadia and Jain, 2011). control a great number of cellular processes
However, these therapies are still very especially stress response. The regulation of
unspecific, meaning that they would treat some these molecules, which are mostly transcription
of the symptoms but others might remain factors, enzymes and proteins, is directly related
untreated. They also cause lots of side effects, as to immunity and inflammation. That’s why
for example steroid dependence, anaphylaxis curcumin has been linked to the treatment of
and pancreatitis. These treatments are vastly immune and inflammatory diseases, such as
expensive too. That’s why new, more accessible IBD.
and natural therapies for IBD are needed This paper is intended to present the
currently. relationship between curcumin and IBD and
A new therapeutic approach for IBD that why it is considered a potential treatment for
has been studied since decades ago is the use of this condition. It will do so by presenting studies
curcumin. This compound, also called that have proved its benefits and its limitations
diferuloylmethane, is obtained from the roots of as a therapeutic alternative.
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3. Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease
Macroscopic effects of curcumin on IBD inflammation and eventual elimination of
As shown by several studies of rat disease-causing agents. They are mostly present
models with induced IBD, curcumin effectively in T helper cells, which are a type of white
counteracts many of the effects of IBD in many blood cell. When well regulated, cytokines and
ways. On the rat colitis models, it showed chemokines contribute to the health of the
tangible effects out of the intestine were an organism and help to maintain a balance on
increase in the rate of survival and weight gain inflammation. As for example, for cytokines
were noticeable (Jian et al., 2005) (Salh et al., there are both inflammatory and anti-
2003). Curcumin also caused a decrease in the inflammatory ones. The inflammatory ones,
inflammation of the intestinal tissues. The such as interleukin-1 beta (IL-1β), activate at
studies concluded that all of these macroscopic any threatening signal, but when the attack is
effects are directly related to microscopic counteracted, the anti-inflammatory ones, such
processes of the cell (see Figure 2). as interleukin-10 (IL-10), activate and make the
tissue go back to normal. Chemokines are
Deregulated molecules in IBD responsible for sending signals to alert on the
There are several proteins and presence of foreign agents, therefore inducing
transcription factors that are responsible of the production of leucocytes (white blood cells),
regulating immunity in the intestines and, especially macrophages to engulf them. After
therefore, they are in charge of protecting it the pathogen is eliminated, the signaling stops.
from external damaging agents or pathogens. On IBD, NF-κB binding activity is
When appropriately regulated, these proteins increased, which leads to a rise in the immune
and transcription factors help on the well- and inflammatory response by the
functioning of the intestinal tract and normal overproduction of cytokines and chemokines.
protection given by the intestinal mucosa. Therefore, in inflammatory bowel disease
However, when deregulated they can cause an chemokines are up-regulated and provide a
uncontrollable inflammation in the tissue with continuous signal for the production of white
no apparent cause. This happens because the blood cells, which results on inflammation (Jian
overproduction or underproduction of these et al., 2005). Equally, pro-inflammatory
agents alters normal cell pathways, as those cytokines are highly expressed in IBD, while
related to immunity, which are stress-response anti-inflammatory cytokines are at low rates
pathways. This occurs on IBD (see Figure 1). (Salh et al., 2003).
One of the transcription factors whose There are other deregulated proteins in
presence is not normal in the intestinal tissue IBD that alter pathways related to intrusion, also
and mucosa of IBD patients is the nuclear factor called stress-responsive signaling pathways.
kappa-light-chain-enhancer of activated B cells One of them is the mitogen-activated protein
(NF-κB). This factor binds to the DNA to kinase 38 (p38 MAPK) which, under stress,
produce proteins such as cytokines and helps to produce lymphocytes (a type of white
chemokines. These proteins are responsible of blood cell), cyclooxygenases and lipoxygenases.
detecting foreign cells and pathogens, creating These lasts ones are enzymes responsible of
an immune response which can result in modulating inflammation by the production of a
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4. Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease
hormone called prostaglandin. This p38 MAPK Microscopic effects of curcumin on IBD
also secretes chemokines, as does NF-κB. In the
case of IBD, p38 MAPK is over-activated,
which leads to an overproduction of
lymphocytes, chemokines, cyclooxygenases and
lipoxygenases (Srivastava et al., 2011),
consequently causing extreme inflammation.
Because of the huge presence of white
blood cells in the intestinal tissues of IBD
patients, there’s also an over-expression of
myeloperoxidase (MPO) in IBD (Salh et al.,
2003). MPO is a peroxidase enzyme present in
neutrophil granulocytes, a type of white blood
cells. This enzyme produces hypoclorous acid
radical and the amino acid tyrosyl radical upon
oxidation. In other words, the oxidation of MPO Figure 2: Summary
causes the formation of highly reactive of the macroscopic
molecules with negative charge which are used and microscopic
by the neutrophils to kill bacteria and other effects of curcumin
pathogens when they are well-regulated. When on IBD.
they are not well-regulated, they can run free in
the body and cause many reactions that might
lead to aging, degenerative diseases, and cancer. Most of the recent researches on
curcumin have concluded that it displays
Figure 1: Summary of
immunomodulatory activity upon the
the deregulated
deregulation of molecules on IBD (Srivastava et
molecules responsible for
al., 2011). It has shown to regulate the NF-κB
inflammation on IBD.
pathway and to suppress its binding activity.
Therefore, it has functioned to reduce IL-1β
expression and to increase IL-10 expression
(Rajasekaran, 2011). As a consequence it
inhibits the proliferation of macrophages and
other types of white blood cells. Curcumin is
also useful on diminishing the activation of p38
MAPK, therefore controlling the production of
lymphocytes, cyclooxygenases and
lipoxygenases. The ways by which curcumin
achieves all these activities are still not well
known, but there are being studies conducted
about it (Srivastava et al., 2011). It has been
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5. Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease
preliminarily linked to curcumin’s ability on suitable environment for curcumin’s
binding to several proteins and enzymes. transference. By adding itself to curcumin it can
Finally, curcumin has presented an effect therefore promote its absorbance because of its
on the offsetting of myeloperoxidase activity lipophilic-hydrophobic inside and hydrophilic
because of its antioxidant properties (Salh et al., outside (Yadav et al., 2009). Other
2003). As an antioxidant, curcumin functions to investigations have proposed to block
inhibit the oxidation of MPO by oxidizing itself, curcumin’s metabolic pathways, to improve its
therefore preventing free radicals from running effective transportation through the body with
freely in the body and reducing the oxidation the use of new nanoparticle systems and to
chain reactions. encapsulate the compound (Rajasekaran, 2011).
More development still has to be done to reach
Curcumin’s usage and limitations curcumin’s enhancement.
Actual reviews on curcumin’s effective Figure 3:
concentration dose reveal some ambiguity. Curcumin’s
While ones say that it has shown to be safe at limitations
very high doses (Anand et al., 2008), other as a
studies imply that it’s effective and safe dosages therapeutic
can vary upon the type of cell treated. For some alternative
cells it might be toxic at high concentrations, for IBD.
and for others not (Srivastava et al., 2011).
Further investigations need to be done to define
at which concentration curcumin’s functionality
increases and is secure enough for human
consumption. That might be one of the reasons
why curcumin isn’t commonly used for
therapeutic purposes. Conclusion
Another limitation of curcumin has been Although not so many researches have
proved to be its low oral bioavailability due to been accomplished on relating curcumin to IBD,
its poor solubility and rapid metabolism most of them have shown similar conclusions
(Rajasekaran, 2011). Bioavailability is the on its proactivity on this disease. Not all of them
amount of substance that is really absorbed and have concluded curcumin’s effects in all the
used by an organism when the substance, mostly same molecules and pathways, but all of them
a drug, is introduced into the body. Recent have related its outcomes on its regulatory
research has shown that curcumin’s low properties. Moreover, it can be concluded that
bioavailability is compensable by making curcumin is a good modulator of the appropriate
certain modifications to the compound. One of quantities of molecules needed for stress
those modifications can be making an inclusion response. Since IBD has been linked to a
complex between curcumin and a soluble deregulation on the stress response pathways,
compound, such as cyclodextrin (CD). This curcumin’s therapeutic effects on IBD have
complex is very soluble and can create a been observable. However, we can determine
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6. Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease
that there are still many aspects about curcumin Pithadia A, Jain S. 2011. Treatment of inflammatory
that aren’t well comprehended (see Figure 3). bowel disease (IBD). Pharmacological Reports.
We conclude that additional research is 63(1):629-642.
necessary. Eventually, as more research on this Rajasekaran S. 2011. Therapeutic potential of
curcumin in gastrointestinal diseases. World
topic is promoted, curcumin’s use would be
Journal of Gastrointestinal Pathophysiology. 2(1):
better understood and it will probably be able to
1-14.
function as an alternative treatment for IBD.
Salh B, Assi K, Templeman V, Parhar K, Owen D,
Gómez A, Jacobson K. 2003. Curcumin attenuates
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