Review paper angelica

Review

Curcumin’s Therapeutic Effects on Inflammatory Bowel Disease

Angélica M. González Sánchez – University of Puerto Rico at Cayey

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November 2011

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.

____________________________________________________________________________

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

acute syndrome on which the gastrointestinal

wall suffers severe inflammation. Its causes

remain unknown, although recent investigations

have linked it to genetic, environmental and

immunological factors, which are the most

prominent ones (Pithadia and Jain, 2011). Even

though it is a rare condition statistically (Jian et

al., 2005), its implications on people’s quality of

life make it a huge and relevant field for

investigations.

Despite origins of IBD are uncertain, its

main source is the inflammation of the intestinal

mucosa. Because inflammation is almost always

linked to an immune response, analysis of IBD

has focused on stress-response causes. Since

there haven’t been found any pathogen that

causes a stress response and leads to IBD, it is

thought that it arises from uncontrolled

pathways of molecules related to the immune

system (Salh et al., 2003).

Intestinal mucosa has several functions,

mostly on absorbing nutrients and on protecting

the organism from infections. When swollen,

this mucosal doesn’t work as it’s supposed to,

leading to mayor complications. Some of these

complications can be reflected as severe

symptoms such as abdominal pain, ulcers,

bleeding diarrhea, weight loss due to the

diarrhea, anemia, between others. Other

conditions have also been associated to side

effects of IBD, such as osteoporosis, arthritis,

skin rashes, liver disease and colon cancer. IBD

rarely causes death on its own, but some of its


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complications, such as extreme diarrhea and

anemia can cause weakness of the organism,

which can make it susceptible to other illnesses.

IBD can be divided into two main types:

Ulcerative colitis and Crohn’s disease. Both of

these share the characteristic inflammation of

the intestinal mucosa but they differ on the

specific areas of the intestinal tract that they

affect. While Ulcerative colitis affects only the

colon, Crohn’s disease can affect any area from

the gastrointestinal tract, especially the lowest

part of the small intestine, called the ileum.

Actual treatments for IBD focus on

lessening and delaying the symptoms of the

condition, but not necessarily on effectively

transposing the causes of the inflammation,

which will be described further on. Most of

them consist on anti-inflammatory medicines

and immune-suppressors, such as

aminosalicylates, monoclonal antibodies,

corticosteroids, antibiotics, between others.

These treatments have been improving in the

last decades by the development of targeted

biologic therapies, the optimization of older

therapies, and a better understanding of the

mucosal immune system involved in the

pathogenesis of IBD (Pithadia and Jain, 2011).

However, these therapies are still very

unspecific, meaning that they would treat some

of the symptoms but others might remain

untreated. They also cause lots of side effects, as

for example steroid dependence, anaphylaxis

and pancreatitis. These treatments are vastly

expensive too. That’s why new, more accessible

and natural therapies for IBD are needed

currently.

A new therapeutic approach for IBD that

has been studied since decades ago is the use of

curcumin. This compound, also called

diferuloylmethane, is obtained from the roots of

the herb Curcuma longa. It can take many

chemical structures, called curcuminoids

(Anand et al., 2008), but its main constituents

always are several hydroxyl radicals (HO),

hydroxide ions (OH-), oxides (O

2), methyl

(CH3) and methoxides (CH3O-) groups which

join together forming rings which make the

compound a hydrophobic polyphenol. It has

been traditionally used in foods as a component

of the spice turmeric and as an herbal remedy

for several illnesses because polyphenols are

known to be natural antioxidants (Rajasekaran,

2011). Since its first documented use as a

medical treatment in 1937 (Srivastava et al.,

2011), curcumin has revealed antioxidant, anti-

inflammatory, antimicrobial and anti-

carcinogenic activities (Anand et al., 2008).

Exactly how curcumin accomplishes these

duties is not well known. However, it has been

linked to its ability to bind to several proteins

and regulatory enzymes and to inhibit oxidation

chain reactions which can cause damage or

death to the cell by activating multiple

intracellular signaling pathways (Srivastava et

al., 2011). That way, curcumin regulates the

presence of several molecules, which in turn

control a great number of cellular processes

especially stress response. The regulation of

these molecules, which are mostly transcription

factors, enzymes and proteins, is directly related

to immunity and inflammation. That’s why

curcumin has been linked to the treatment of

immune and inflammatory diseases, such as

IBD.

This paper is intended to present the

relationship between curcumin and IBD and

why it is considered a potential treatment for

this condition. It will do so by presenting studies

that have proved its benefits and its limitations

as a therapeutic alternative.


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Macroscopic effects of curcumin on IBD

As shown by several studies of rat

models with induced IBD, curcumin effectively

counteracts many of the effects of IBD in many

ways. On the rat colitis models, it showed

tangible effects out of the intestine were an

increase in the rate of survival and weight gain

were noticeable (Jian et al., 2005) (Salh et al.,

2003). Curcumin also caused a decrease in the

inflammation of the intestinal tissues. The

studies concluded that all of these macroscopic

effects are directly related to microscopic

processes of the cell (see Figure 2).

Deregulated molecules in IBD

There are several proteins and

transcription factors that are responsible of

regulating immunity in the intestines and,

therefore, they are in charge of protecting it

from external damaging agents or pathogens.

When appropriately regulated, these proteins

and transcription factors help on the well-

functioning of the intestinal tract and normal

protection given by the intestinal mucosa.

However, when deregulated they can cause an

uncontrollable inflammation in the tissue with

no apparent cause. This happens because the

overproduction or underproduction of these

agents alters normal cell pathways, as those

related to immunity, which are stress-response

pathways. This occurs on IBD (see Figure 1).

One of the transcription factors whose

presence is not normal in the intestinal tissue

and mucosa of IBD patients is the nuclear factor

kappa-light-chain-enhancer of activated B cells

(NF-κB). This factor binds to the DNA to

produce proteins such as cytokines and

chemokines. These proteins are responsible of

detecting foreign cells and pathogens, creating

an immune response which can result in

inflammation and eventual elimination of

disease-causing agents. They are mostly present

in T helper cells, which are a type of white

blood cell. When well regulated, cytokines and

chemokines contribute to the health of the

organism and help to maintain a balance on

inflammation. As for example, for cytokines

there are both inflammatory and anti-

inflammatory ones. The inflammatory ones,

such as interleukin-1 beta (IL-1β), activate at

any threatening signal, but when the attack is

counteracted, the anti-inflammatory ones, such

as interleukin-10 (IL-10), activate and make the

tissue go back to normal. Chemokines are

responsible for sending signals to alert on the

presence of foreign agents, therefore inducing

the production of leucocytes (white blood cells),

especially macrophages to engulf them. After

the pathogen is eliminated, the signaling stops.

On IBD, NF-κB binding activity is

increased, which leads to a rise in the immune

and inflammatory response by the

overproduction of cytokines and chemokines.

Therefore, in inflammatory bowel disease

chemokines are up-regulated and provide a

continuous signal for the production of white

blood cells, which results on inflammation (Jian

et al., 2005). Equally, pro-inflammatory

cytokines are highly expressed in IBD, while

anti-inflammatory cytokines are at low rates

(Salh et al., 2003).

There are other deregulated proteins in

IBD that alter pathways related to intrusion, also

called stress-responsive signaling pathways.

One of them is the mitogen-activated protein

kinase 38 (p38 MAPK) which, under stress,

helps to produce lymphocytes (a type of white

blood cell), cyclooxygenases and lipoxygenases.

These lasts ones are enzymes responsible of

modulating inflammation by the production of a


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hormone called prostaglandin. This p38 MAPK

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

causes the formation of highly reactive

molecules with negative charge which are used

by the neutrophils to kill bacteria and other

pathogens when they are well-regulated. When

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.

Microscopic effects of curcumin on IBD

Most of the recent researches on

curcumin have concluded that it displays

immunomodulatory activity upon the

deregulation of molecules on IBD (Srivastava et

al., 2011). It has shown to regulate the NF-κB

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

Figure 1: Summary of

the deregulated

molecules responsible for

inflammation on IBD.

Figure 2: Summary

of the macroscopic

and microscopic

effects of curcumin

on IBD.


November 2011 5

preliminarily linked to curcumin’s ability on

binding to several proteins and enzymes.

Finally, curcumin has presented an effect

on the offsetting of myeloperoxidase activity

because of its antioxidant properties (Salh et al.,

2003). As an antioxidant, curcumin functions to

inhibit the oxidation of MPO by oxidizing itself,

therefore preventing free radicals from running

freely in the body and reducing the oxidation

chain reactions.

Curcumin’s usage and limitations

Actual reviews on curcumin’s effective

concentration dose reveal some ambiguity.

While ones say that it has shown to be safe at

very high doses (Anand et al., 2008), other

studies imply that it’s effective and safe dosages

can vary upon the type of cell treated. For some

cells it might be toxic at high concentrations,

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.

Another limitation of curcumin has been

proved to be its low oral bioavailability due to

its poor solubility and rapid metabolism

(Rajasekaran, 2011). Bioavailability is the

amount of substance that is really absorbed and

used by an organism when the substance, mostly

a drug, is introduced into the body. Recent

research has shown that curcumin’s low

bioavailability is compensable by making

certain modifications to the compound. One of

those modifications can be making an inclusion

complex between curcumin and a soluble

compound, such as cyclodextrin (CD). This

complex is very soluble and can create a

suitable environment for curcumin’s

transference. By adding itself to curcumin it can

therefore promote its absorbance because of its

lipophilic-hydrophobic inside and hydrophilic

outside (Yadav et al., 2009). Other

investigations have proposed to block

curcumin’s metabolic pathways, to improve its

effective transportation through the body with

the use of new nanoparticle systems and to

encapsulate the compound (Rajasekaran, 2011).

More development still has to be done to reach

curcumin’s enhancement.

Conclusion

Although not so many researches have

been accomplished on relating curcumin to IBD,

most of them have shown similar conclusions

on its proactivity on this disease. Not all of them

have concluded curcumin’s effects in all the

same molecules and pathways, but all of them

have related its outcomes on its regulatory

properties. Moreover, it can be concluded that

curcumin is a good modulator of the appropriate

quantities of molecules needed for stress

response. Since IBD has been linked to a

deregulation on the stress response pathways,

curcumin’s therapeutic effects on IBD have

been observable. However, we can determine

Figure 3:

Curcumin’s

limitations

as a

therapeutic

alternative

for IBD.


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that there are still many aspects about curcumin

that aren’t well comprehended (see Figure 3).

We conclude that additional research is

necessary. Eventually, as more research on this

topic is promoted, curcumin’s use would be

better understood and it will probably be able to

function as an alternative treatment for IBD.

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Review paper angelica